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Phenytoin is a known human teratogen with unknown etiology. Several mechanisms have been proposed including disturbances in folate metabolism, induction of embryonic hypoxia following phenytoin-induced bradycardia, free radical formation following re-oxygenation and phenytoin-induced maternal hyperglycemia. Using high frequency ultrasound, we demonstrated that phenytoin induced a dramatic decrease in the heart rate of embryos. This coincided with a moderate transient decrease in maternal heart rate and blood glucose levels. Embryonic heart rate had not fully recovered 24 h later in some embryos despite normal maternal physiological parameters. In a separate study, extent of hypoxia was measured using the marker pimonidazole. Phenytoin-exposed embryos did not demonstrate increased hypoxia compared to control embryos at 2, 4, 8 or 24 h dosing. Together our results show that phenytoin induces malformations as a result of a combination of insults: embryonic bradycardia, maternal bradycardia and maternal hyperglycemia. However, this does not appear to result in measurable embryonic hypoxia in our animal model.

Introduction Mutant RAS guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRASG12C variant has recently become targetable by a new drug class specifically locking KRASG12C in its inactive guanosine diphosphate (GDP)-bound state. Clinical activity was demonstrated in patients with advanced lung cancers harbouring KRASG12C mutations but was limited by the development of resistance. Methods A biopsy from progressing lung cancer of a patient treated with the KRASG12C inhibitor sotorasib was obtained, and the underlying resistance factors were analysed. Mechanistic studies were performed in vitro and in vivo to uncover strategies to overcome resistance to KRASG12C inhibition. Results We demonstrated acquisition of HER2 copy number gain and KRASG12C mutation retention in the post-progression biopsy. To explore HER2 gain as the relevant resistance mechanism, we generated KRASG12C lung cancer models overexpressing HER2. MAPK pathway signalling remained active despite KRASG12C inhibitor treatment. Combined pharmacological inhibition of KRASG12C and SHP2 synergistically overcame HER2-mediated resistance in vitro and in vivo. Conclusions These findings establish HER2 copy number gain as a clinically relevant mechanism of resistance to pharmacological KRASG12C inhibition that can be overcome by co-targeting SHP2.

Objectives: Circulating levels of activin A (ActA) and follistatin (FST) have been investigated in various disorders including malignancies. However, to date, their diagnostic and prognostic relevance is largely unknown in small cell lung cancer (SCLC). Our aim was to evaluate circulating ActA and FST levels as potential biomarkers in this devastating disease. Methods: Seventy-nine Caucasian SCLC patients and 67 age- and sex-matched healthy volunteers were included in this study. Circulating ActA and FST concentrations were measured by ELISA and correlated with clinicopathological parameters and long-term outcomes. Results: Plasma ActA and FST concentrations were significantly elevated in SCLC patients when compared to healthy volunteers (p < 0.0001). Furthermore, extensive-stage SCLC patients had significantly higher circulating ActA levels than those with limited-stage disease (p = 0.0179). Circulating FST concentration was not associated with disease stage (p = 0.6859). Notably, patients with high (≥548.8 pg/ml) plasma ActA concentration exhibited significantly worse median overall survival (OS) compared to those with low (

The sports medicine literature is filled with associations between injury and causal factors. However, those results have been inconsistent. We’re left wondering which of our athletes might need more attention and where our efforts might be best spent. Resistance to injury is the result of interaction between many variables. These variables are interdependent with dynamic relationships which can be sometimes correlated, at times anti-correlated and from time to time show no relationship with injury risk. Relationships we may have seen yesterday do not necessarily hold true for today and we should not use those to infer what will happen. This perspective piece builds on prior works and describes how the complex interaction between injury determinants presents in other systems, why determinants are not stable and instead vary over time due to internal and external forcing and why our prediction ability remains limited even when determinants are identified. Patterns built from frequent time series data in conjunction with nonlinear dynamical methods can offer us a new approach to thinking about injury prediction.

Background Primary sarcomas of the chest wall are rare aggressive tumors. Surgery is part of the multimodal treatment. We describe our institutional patient cohort and evaluate prognostic factors. Methods All patients who had curative intent surgery for primary chest wall sarcoma from 2004 to 2019 were retrospectively reviewed. Impact on survival—calculated from the date of surgery until last follow-up— was assessed for the following variables: age, gender, type of resection, size, grading, stage, completeness of resection, and neoadjuvant and adjuvant therapy. Results Twenty-three patients (15 males, 65%) with a median age of 54 y (4 to 82) were included. Most common histology was chondrosarcoma (n = 5, 22%). Seven patients (30%) received neoadjuvant and 13 patients (57%) received adjuvant treatment. R0 resection was achieved in 83%. Extended chest wall resection was performed in 14 patients (61%), including lung (n = 13, 57%), diaphragm (n = 2, 9%) and pericardium (n = 1, 4%). Morbidity and 90-day mortality were 23% and 0%, respectively. Three- and 5-year overall survival was 53% and 35%, respectively. R0 resection was predictor of overall survival (P = 0.029). Tumor grade and extended resections were predictors for recurrence (P = 0.034 and P = 0.018, respectively). Conclusions Surgical resection of primary chest wall sarcoma is a safe procedure even when extended resection is required.

Objectives Preoperative planning of lung resection extent is decisive for preoperative functional work-up and selection for multimodal treatment. It is mainly based on preoperative chest CT. We aimed at evaluating chest CT adequacy to predict the extent of lung resection and hypothesized a relation with CT interpreters’ level of experience. Materials and Methods A pseudonymized CT library was built from patients who had curative intent lung resection for centrally located NSCLC. CT library was interpreted by 20 thoracic surgery residents or attendings. Interpreters were blinded to intraoperative findings and scored one point when lung resection was adequately planned. Points were summed up in a score from 0 to 20. Interpreters’ experience was evaluated through nine variables: age, position (resident vs. attending), years of experience in evaluating chest CTs, number of anatomic resections and sleeve resections attended as first assistant or performed as surgeon in presence of a teaching assistant or as main surgeon/teaching assistant. Variables characterizing interpreters’ experience were divided into equal sized groups. Independent sample T-test and one-way ANOVA/Tukey post hoc tests were used to compare scores between groups. Results CT library included 20 patients. Lung resections were lobectomy (n = 7, 35 %), sleeve lobectomy (n = 10, 50 %), sleeve bilobectomy (n = 2, 10 %), pneumonectomy (n = 1, 5%). Twenty interpreters scored a median of 10 (4–14). Attending surgeons had significantly higher mean scores (11.2 ± 1.3) compared to residents (7.7 ± 2.3, p = 0.001). All scores were significantly different between groups related to interpreters’ levels of experience, except for interpreters’age. Conclusion Preoperative CT evaluation for predicting intraoperative lung resection for centrally located NSCLC strongly depends on interpreters’ experience.

The paper proposes a trajectory design method for overtaking maneuvers, in which several performances are incorporated. Thus, it leads to a multi-objective optimization task. It is based on a simple mathematical representation of feasible trajectories by using a potential field approach. The solution of the complex computations in the optimization is approximated by neural networks. The proposed solution is based on the idea that there are a large number of collision free feasible trajectories. The goal of the method is to find the trajectory, which is suitable for the specified objectives. The result of the paper is an integrated decision for both longitudinal and lateral directions, such as longitudinal acceleration command and the values of the defined path. The effectiveness of the method is presented through CarMaker simulation environment.

Background The definition of benign multiple sclerosis (BMS) is still debated. It is mainly based on physical status, however, there is an attempt to involve cognitive functioning or paraclinical factors in order to avoid unnecessary long-term treatment with disease-modifying therapies and to identify these subjects in the early stages of the disease. Therefore the aim of our two-year follow-up study was to investigate the pattern of cognitive functioning and depression in patients with BMS compared to treated relapsing-remitting MS (RRMS) patients and healthy controls. Methods A group of 22 BMS patients was tested against matched RRMS patients and healthy controls. All individuals underwent neuropsychological evaluation exploring mood and the cognitive domains most frequently impaired in MS. MS patients were retested at two-year follow-up. Results In terms of cognitive functions there were no differences between BMS and RRMS patients either at baseline or at two-year follow-up. Compared to healthy controls BMS patients showed poorer performance in long-term visuo-spatial memory and information processing speed, whereas, complex attention, working memory, long-term verbal memory – despite slower verbal learning – and executive function were found to be intact. RRMS patients showed significant difference in complex attention, long-term visual memory and information processing speed. Cognitive impairment differed in the patient groups in terms of severity. Both patient groups were depressed compared to controls, but significant differences were found only between BMS and healthy individuals. Conclusion The results of our study confirm that cognitive functions and mood can be affected in MS independent of disease course and disease modifying treatment. The “benign” label should be treated as only a reference to physical status and non-motor symptoms should be routinely monitored. Without receiving therapy it is an existing entity with longstanding minimal disability.

OBJECTIVES: To evaluate the effects of different surface conditioning methods on the immediate repair bond strength and integrity of the repaired composite interface.METHODS: One hundred and five resin composite blocks made of a nanohybrid resin composite were randomly assigned to one of the following surface conditioning groups (n = 15/group): Group 1: Gluma Self Etch™ adhesive system, Group 2: Tokuyama Bond Force II™ adhesive system, Group 3: non-roughened and non-conditioned surfaces, Group 4: sandblasting and Gluma Self Etch™, Group 5: sandblasting and Tokuyama Bond Force II™, Group 6: sandblasting only. A positive control group was also used. Resin composite identical to the substrate was applied and the repaired specimens were subjected to shear bond strength (SBS) testing. Representative samples from all groups were subjected to scanning electron microscopy and surface profilometry to determine their mode of failure. The data were analysed statistically using Analysis of Variance (ANOVA) and two independent sample t-test (α = 0.05).RESULTS: The mean SBS of all test groups ranged between 1.92 and 5.40 MPa and varied with the degree of composite surface roughness and the type of adhesive system employed. Significantly highest SBS values (5.40 ± 0.36 MPa) were obtained in Group 5 (p = 0.017) which were comparable to the coherent strength of the resin composite in the positive control group (p > 0.05).CONCLUSIONS: Under the tested conditions, significantly greater SBS of repaired resin composite was achieved when the substrate surface was conditioned by sandblasting followed by the application of the Tokuyama Bond Force II™ adhesive system.CLINICAL SIGNIFICANCE: Effecting a repair of a nanohybrid composite restoration with sandblasting and the application of TBF II would seem to enhance the interfacial bond strength and integrity of the repaired resin composite interface. Clinical trials are necessary to determine the usefulness of this technique.