Hvidbell1797

GRAPHICAL ABSTRACT http//cancerres.aacrjournals.org/content/canres/81/10/2714/F1.large.jpg.Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that Tet2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8+ T-cell activation. Tauroursodeoxycholic mouse Furthermore, the ETS family of transcription factors contributed to augmented CD8+ T-cell function following Tet2 depletion. Overall, our study establishes that Tet2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that Tet2 inactivation could promote antitumor immunity to suppress tumor growth. SIGNIFICANCE This study suggests that ablation of TET2+ from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.The sum of target lesions is routinely used to evaluate patient objective responses to treatment in the RECIST criteria, but it fails to address response heterogeneity across metastases. This study argues that spatiotemporal heterogeneity across metastases and organ-specific response is informative for drug efficacy and patient survival. We analyzed the longitudinal data of 11,404 metastatic lesions in 2,802 colorectal cancer patients from five phase III clinical trials. Initially, a metric Gower distance was applied to quantify response heterogeneity across metastases. Next, the spatiotemporal response heterogeneity across anatomic sites, therapies, and KRAS mutation status was assessed and examined for its association with drug efficacy and long-term patient survival. The response of metastatic lesions broadly differed across anatomic sites and therapies. About 60% of patients had at least one lesion respond contrarily from total tumor size. High interlesion heterogeneity was associated with shorter progression-free survival and overall survival. Targeted therapies (bevacizumab or panitumumab) combined with standard chemotherapy reduced interlesion heterogeneity and elicited more favorable effects from liver lesions (P 30% shrinkage) were associated with extended patient overall survival (P less then 0.001), in contrast to lesions in the lungs and lymph nodes. Altogether, the spatiotemporal response heterogeneity across metastases informed drug efficacy and patient survival, which could improve the current methods for treatment evaluation and patient prognosis. SIGNIFICANCE These findings support the modification of RECIST criteria to include individual lesion response to improve assessments of drug efficacy.

Advanced airway management is necessary in the prehospital environment and difficult airways occur more commonly in this setting. Failed intubation is closely associated with the most devastating complications of airway management. In an attempt to improve the safety and success of tracheal intubation, we implemented videolaryngoscopy (VL) as our first-line device for tracheal intubation within a UK prehospital emergency medicine (PHEM) setting.

An East of England physician-paramedic PHEM team adopted VL as first line for undertaking all prehospital advanced airway management. The study period was 2016-2020. Statistical process control charts were used to assess whether use of VL altered first-pass intubation success, frequency of intubation-related hypoxia and laryngeal inlet views. A survey was used to collect the team's views of VL introduction.

919 patients underwent advanced airway management during the study period. The introduction of VL did not improve first-pass intubation success, view of laryngeal inlet or intubation-associated hypoxia. VL improved situational awareness and opportunities for training but performed poorly in some environments.

Despite the lack of objective improvement in care, subjective improvements meant that overall PHEM clinicians wanted to retain VL within their practice.

Despite the lack of objective improvement in care, subjective improvements meant that overall PHEM clinicians wanted to retain VL within their practice.According to the organizational-activational hypothesis, the organizational effects of testosterone during (prenatal) brain development moderate the activational effects of adult testosterone on behavior. Accumulating evidence supports the notion that adolescence is another period during which sex hormones organize the nervous system. Here we investigate how pubertal sex hormones moderate the activational effects of adult sex hormones on social cognition in humans. To do so, we recruited a sample of young men (n = 507; age, ∼19 years) from a longitudinal birth cohort and investigated whether testosterone exposure during adolescence (from 9 to 17 years of age) moderates the relation between current testosterone and brain response to faces in young adulthood, as assessed with functional magnetic resonance imaging (fMRI). Our results showed that the cumulative exposure to testosterone during adolescence moderated the relation between adult testosterone and both the mean fMRI response and functional connectivity nce moderated the relation between adult testosterone and both the mean BOLD signal change and functional connectivity. Specifically, we observed a positive relationship between adult testosterone and the brain response to faces in participants with low exposure to testosterone during puberty, but not in participants with medium and high pubertal testosterone. Results of further analysis suggest that sensitivity to cues carried by the eyes might underlie the relationship between testosterone and brain response to faces, especially in the context of a potential threat.

Efficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD.

To explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling.

C57BL/6, BALB/c and



mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls.

Wild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in the



mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD.

Exposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.

Exposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.

Microbial exposure is critical to neonatal and infant development, growth and immunity. However, whether a microbiome is present in the fetal gut prior to birth remains debated. In this study, lambs delivered by aseptic hysterectomy at full term were used as an animal model to investigate the presence of a microbiome in the prenatal gut using a multiomics approach.

Lambs were euthanised immediately after aseptic caesarean section and their cecal content and umbilical cord blood samples were aseptically acquired. link2 Cecal content samples were assessed using metagenomic and metatranscriptomic sequencing to characterise any existing microbiome. Both sample types were analysed using metabolomics in order to detect microbial metabolites.

We detected a low-diversity and low-biomass microbiome in the prenatal fetal gut, which was mainly composed of bacteria belonging to the phyla Proteobacteria, Actinobacteria and Firmicutes. link3

was the most abundant species in the prenatal fetal gut. We also detected multiple microbial metabolites including short chain fatty acids, deoxynojirimycin, mitomycin and tobramycin, further indicating the presence of metabolically active microbiota. Additionally, bacteriophage phiX174 and Orf virus, as well as antibiotic resistance genes, were detected in the fetal gut, suggesting that bacteriophage, viruses and bacteria carrying antibiotic resistance genes can be transmitted from the mother to the fetus during the gestation period.

This study provides strong evidence that the prenatal gut harbours a microbiome and that microbial colonisation of the fetal gut commences in utero.

This study provides strong evidence that the prenatal gut harbours a microbiome and that microbial colonisation of the fetal gut commences in utero.Within the developing head, tissues undergo cell-fate transitions to shape the forming structures. This starts with the neural crest, which undergoes epithelial-to-mesenchymal transition (EMT) to form, amongst other tissues, many of the skeletal tissues of the head. In the eye and ear, these neural crest cells then transform back into an epithelium, via mesenchymal-to-epithelial transition (MET), highlighting the flexibility of this population. Elsewhere in the head, the epithelium loses its integrity and transforms into mesenchyme. Here, we review these craniofacial transitions, looking at why they happen, the factors that trigger them, and the cell and molecular changes they involve. We also discuss the consequences of aberrant EMT and MET in the head.Ciliopathies represent a growing class of diseases caused by defects in microtubule-based organelles called primary cilia. Approximately 30% of ciliopathies are characterized by craniofacial phenotypes such as craniosynostosis, cleft lip/palate and micrognathia. Patients with ciliopathic micrognathia experience a particular set of difficulties, including impaired feeding and breathing, and have extremely limited treatment options. To understand the cellular and molecular basis for ciliopathic micrognathia, we used the talpid2 (ta2 ), a bona fide avian model for the human ciliopathy oral-facial-digital syndrome subtype 14. Histological analyses revealed that the onset of ciliopathic micrognathia in ta2 embryos occurred at the earliest stages of mandibular development. Neural crest-derived skeletal progenitor cells were particularly sensitive to a ciliopathic insult, undergoing unchecked passage through the cell cycle and subsequent increased proliferation. Furthermore, whereas neural crest-derived skeletal differentiation was initiated, osteoblast maturation failed to progress to completion.