Burning pain was induced in healthy human subjects by intracutaneous injections of capsaicin (20 microl, 0.1%) in the innervation territory of the cutaneous branch of the peroneal nerve and the pain responses were compared with the activation patterns of afferent C-fibres recorded by microneurography. Responsiveness of single units to mechanical or heat stimuli or to sympathetic reflex provocation tests was determined by transient slowing of conduction velocity following activation (marking technique). Capsaicin activated each of 12 mechano-responsive and 17 of 20 mechano-insensitive C-units. However, the duration of the responses to capsaicin was significantly longer in mechano-insensitive C-units (median 170 s; quartiles 80-390) compared with mechano-responsive C-units (8 s; 4-10). The activation times of mechano-insensitive C-units closely matched the duration of capsaicin-induced pain responses, whereas activation of mechano-responsive C-units was too short to account for the duration of the burning pain. The latter generally were desensitized to mechanical stimulation at the injection site, whereas 8 of 17 of the originally mechano-insensitive C-units became responsive to mechanical probing at the injection site after capsaicin. Responses typically started several seconds after the onset of the mechanical stimulus in parallel with pain sensations. We did not observe sensitization to brushing or to punctate stimuli in uninjured parts of the innervation territory. Differential capsaicin sensitivity adds to the cumulating evidence for the existence of two categories of functionally different nociceptors in human skin, with a special role for mechano-insensitive fibres in sensitization and hyperalgesia. Possible structural differences between these two categories are discussed, including the role of tetrodotoxin-resistant sodium channels.

The air-blood barrier with its complex architecture and dynamic environment is difficult to mimic in vitro. Lung-on-a-chips enable mimicking the breathing movements using a thin, stretchable PDMS membrane. However, they fail to reproduce the characteristic alveoli network as well as the biochemical and physical properties of the alveolar basal membrane. Here, we present a lung-on-a-chip, based on a biological, stretchable and biodegradable membrane made of collagen and elastin, that emulates an array of tiny alveoli with in vivo-like dimensions. This membrane outperforms PDMS in many ways: it does not absorb rhodamine-B, is biodegradable, is created by a simple method, and can easily be tuned to modify its thickness, composition and stiffness. The air-blood barrier is reconstituted using primary lung alveolar epithelial cells from patients and primary lung endothelial cells. Typical alveolar epithelial cell markers are expressed, while the barrier properties are preserved for up to 3 weeks.

Objectives Thoracic trauma (TT) is the third most common cause of death after abdominal injury and head trauma in polytrauma patients. Its management is still a very challenging task. The purpose of this study was to analyse the risk factors affecting the outcome in a high-volume trauma centre and the efficacy of a specialised trauma team in level 1 trauma centres. Patients and methods Between January 2003 and December 2012, data of all patients admitted to the accident and emergency (A&E) department were prospectively collected at the German Trauma Registry (GTR) and thereafter retrospectively analysed. Patients with chest trauma, an Injury Severity Score (ISS) ≥ 18 and an Abbreviated Injury Scale (AIS) > 2 in more than one body region were included. Patients were divided into two groups: group I included patients presenting with thoracic trauma between January 2003 and December 2007. The results of this group were compared with the results of another group (group II) in a later 5-year period (Jan. 2008–Dec. 2012). Univariate and multivariate analyses were performed, and differences with p < 0.05 were considered statistically significant. Results There were 630 patients (56%) with thoracic trauma. A total of 540 patients (48%) had associated extrathoracic injuries. Group I consisted of 285 patients (197 male, mean age 46 years). Group II consisted of 345 patients (251 male, mean age 49 years). Overall 90-day mortality was 17% ( n = 48) in group I vs. 9% ( n = 31) in group II ( p = 0.024). Complication rates were higher in group I ( p = 0.019). Higher Injury Severity Scores (ISSs) and higher Abbreviated Injury Acale (AIS) scores in the thoracic region yielded a higher rate of mortality ( p < 0.0001). Young patients (< 40 years) were frequently exposed to severe thoracic injury but showed lower mortality rates ( p = 0.014). Patients with severe lung contusions ( n = 94) (15%) had higher morbidity and mortality ( p < 0.001). Twenty-three (8%) patients underwent emergency thoracotomy in group I vs. 14 patients (4%) in group II ( p = 0.041). Organ replacement procedures were needed in 18% of patients in group I vs. 31% of patients in group II ( p = 0.038). Conclusions The presence of severe lung contusion, a higher ISS and AIS thoracic score and advanced age are independent risk factors that are directly related to a higher mortality rate. Management of blunt chest trauma with corrective chest tube insertion, optimal pain control and chest physiotherapy results in good outcomes in the majority of patients. Optimal management with better survival rates is achie...

Background: Intrinsic or acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is common, thus strategies for the management of EGFR-TKIs resistance are urgently required. Ferroptosis is a recently discovered form of cell death that has been implicated in tumorigenesis and resistance treatment. Accumulating evidence suggests that ferroptosis can be therapeutically exploited for the treatment of solid tumors; however, whether ferroptosis can be targeted to treat EGFR mutant lung cancer and/or overcome the resistance to EGFR-TKIs is still unknown. Methods:The effect of ferroptosis inducers on a panel of EGFR mutant lung cancer cell lines, including those with EGFR-TKI intrinsic and acquired (generated by long-term exposure to the third-generation EGFR-TKI osimertinib), was determined using cytotoxicity assays. Further, drug candidates to enhance the effect of ferroptosis inducers were screened through implementing WGCNA (weighted gene co-expression network analysis) and CMAP (connectivity map) analysis. Flow cytometry-based apoptosis and lipid hydroperoxides measurement were used to evaluate the cell fates after treatment.Results: Compared with EGFR-TKI-sensitive cells, those with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers. In addition, Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers, leading to a dramatic increase of hydroperoxides in EGFR mutant lung cancer cells with intrinsic or acquired resistance to EGFR-TKI. Mechanistically, Vorinostat promotes ferroptosis via xCT downregulation.Conclusions: Ferroptosis-inducing therapy shows promise in EGFR-activating mutant lung cancer cells that display intrinsic or acquired resistance to EGFR-TKI. Histone deacetylase inhibitor (HDACi)Vorinostat can further promote ferroptosis by inhibiting xCT expression.

Background Intratumoural heterogeneity has been previously shown to be related to clonal evolution and genetic instability and associated with tumour progression. Phenotypically, it is reflected in the diversity of appearance and morphology within cell populations. Computer-extracted features relating to tumour cellular diversity on routine tissue images might correlate with outcome. This study investigated the prognostic ability of computer-extracted features of tumour cellular diversity (CellDiv) from haematoxylin and eosin (H&E)-stained histology images of nonsmall cell lung carcinomas (NSCLCs). MethodsIn this multicentre, retrospective study, we included 1057 patients with early-stage NSCLC with corresponding diagnostic histology slides and overall survival information from four different centres. CellDiv features quantifying local cellular morphological diversity from H&E-stained histology images were extracted from the tumour epithelium region. A Cox proportional hazards model based on CellDiv was used to construct risk scores for lung adenocarcinoma (LUAD; 270 patients) and lung squamous cell carcinoma (LUSC; 216 patients) separately using data from two of the cohorts, and was validated in the two remaining independent cohorts (comprising 236 patients with LUAD and 335 patients with LUSC). We used multivariable Cox regression analysis to examine the predictive ability of CellDiv features for 5-year overall survival, controlling for the effects of clinical and pathological parameters. We did a gene set enrichment and Gene Ontology analysis on 405 patients to identify associations with differentially expressed biological pathways implicated in lung cancer pathogenesis.Findings For prognosis of patients with early-stage LUSC, the CellDiv LUSC model included 11 discriminative CellDiv features, whereas for patients with early-stage LUAD, the model included 23 features. In the independent validation cohorts, patients predicted to be at a higher risk by the univariable CellDiv model had significantly worse 5-year overall survival (hazard ratio 1•48 [95% CI 1•06-2•08]; p=0•022 for The Cancer Genome Atlas [TCGA] LUSC group, 2•24 [1•04-4•80]; p=0•039 for the University of Bern LUSC group, and 1•62 [1•15-2•30]; p=0•0058 for the TCGA LUAD group). The identified CellDiv features were also found to be strongly associated with apoptotic signalling and cell differentiation pathways. Interpretation CellDiv features were strongly prognostic of 5-year overall survival in patients with early-stage NSCLC and also associated with apoptotic signalling and cell differentiation pathways. The CellDiv-based risk stratification model could potentially help to determine which patients with early-stage NSCLC might receive added benefit from adjuvant therapy.