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Chronic hypoxia-induced pulmonary hypertension (CHPH) is a severe disease that is characterized by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) leading to pulmonary vascular remodeling. The resulting increase in pulmonary vascular resistance (PVR) causes right ventricular hypertrophy and ultimately right heart failure. In addition, increased PVR can also be a consequence of hypoxic pulmonary vasoconstriction (HPV) under generalized hypoxia. Increased proliferation and migration of PASMCs are often associated with high intracellular Ca2+ concentration. Recent publications suggest that Ca2+-permeable nonselective classical transient receptor potential (TRPC) proteins—especially TRPC1 and 6—are crucially involved in acute and sustained hypoxic responses and the pathogenesis of CHPH. The aim of our study was to investigate whether the simultaneous deletion of TRPC proteins 1, 3 and 6 protects against CHPH-development and affects HPV in mice. We used a mouse model of chronic hypoxia as well as isolated, ventilated and perfused mouse lungs and PASMC cell cultures. Although right ventricular systolic pressure as well as echocardiographically assessed PVR and right ventricular wall thickness (RVWT) were lower in TRPC1, 3, 6-deficient mice, these changes were not related to a decreased degree of pulmonary vascular muscularization and a reduced proliferation of PASMCs. However, both acute and sustained HPV were almost absent in the TRPC1, 3, 6-deficient mice and their vasoconstrictor response upon KCl application was reduced. This was further validated by myographical experiments. Our data revealed that 1) TRPC1, 3, 6-deficient mice are partially protected against development of CHPH, 2) these changes may be caused by diminished HPV and not an altered pulmonary vascular remodeling.

Abstract Background For patients with esophageal adenocarcinoma or cancer of the gastroesophageal junction, radical esophagectomy with 2-field lymphadenectomy is the cornerstone of the multimodality treatment with curative intent. Both conventional minimally invasive esophagectomy (MIE) and robot assisted minimally invasive esophagectomy (RAMIE) were shown to be superior compared to open transthoracic esophagectomy considering postoperative complications. However, no randomized comparison exists between MIE and RAMIE in the Western World for patients with esophageal adenocarcinoma. Methods This is an investigator-initiated and investigator-driven multicenter randomized controlled parallel-group superiority trial. All adult patients (age ≥ 18 and ≤ 90 years) with histologically proven, surgically resectable (cT1-4a, N0–3, M0) esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 218) with resectable esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction are randomized to either RAMIE (n = 109) or MIE (n = 109). The primary outcome of this study is the total number of resected abdominal and mediastinal lymph nodes specified per lymph node station. Conclusion This is the first randomized controlled trial designed to compare RAMIE to MIE as surgical treatment for resectable esophageal adenocarcinoma or adenocarcinoma of the gastroesophageal junction in the Western World. The hypothesis of the proposed study is that RAMIE will result in a higher abdominal and mediastinal lymph node yield specified per station compared to conventional MIE. Short-term results and the primary endpoint (total number of resected abdominal and mediastinal lymph nodes per lymph node station) will be analyzed and published after discharge of the last randomized patient within this trial. Trial registration ClinicalTrials.gov Identifier: NCT04306458 . Registered 13th March 2020, https://clinicaltrials.gov/ct2/show/NCT04306458; Date of first enrolment 18.01.2021; Target sample size 218; Recruitment status: Recruiting; Protocol version 2; Issue date 10.03.2020; Rev. 02.02.2021; Authors ET, PCvdS, PPG.

Introduction The only curative treatment for most gastric cancer is radical gastrectomy with D2 lymphadenectomy (LAD). Minimally invasive total gastrectomy (MIG) aims to reduce postoperative morbidity, but its use has not yet been widely established in Western countries. Minimally invasivE versus open total GAstrectomy is the first Western multicentre randomised controlled trial (RCT) to compare postoperative morbidity following MIG vs open total gastrectomy (OG).Methods and analysis This superiority multicentre RCT compares MIG (intervention) to OG (control) for oncological total gastrectomy with D2 or D2+LAD. Recruitment is expected to last for 2 years. Inclusion criteria comprise age between 18 and 84 years and planned total gastrectomy after initial diagnosis of gastric carcinoma. Exclusion criteria include Eastern Co-operative Oncology Group (ECOG) performance status >2, tumours requiring extended gastrectomy or less than total gastrectomy, previous abdominal surgery or extensive adhesions seriously complicating MIG, other active oncological disease, advanced stages (T4 or M1), emergency setting and pregnancy.The sample size was calculated at 80 participants per group. The primary endpoint is 30-day postoperative morbidity as measured by the Comprehensive Complications Index. Secondary endpoints include postoperative morbidity and mortality, adherence to a fast-track protocol and patient-reported quality of life (QoL) scores (QoR-15, EUROQOL EuroQol-5 Dimensions-5 Levels (EQ-5D), EORTC QLQ-C30, EORTC QLQ-STO22, activities of daily living and Body Image Scale). Oncological endpoints include rate of R0 resection, lymph node yield, disease-free survival and overall survival at 60-month follow-up.Ethics and dissemination Ethical approval has been received by the independent Ethics Committee of the Medical Faculty, University of Heidelberg (S-816/2021) and will be received from each responsible ethics committee for each individual participating centre prior to recruitment. Results will be published open access.Trial registration number DRKS00025765.

Objective:. This Delphi exercise aimed to gather consensus surrounding risk factors, diagnosis, and management of chyle leaks after esophagectomy and to develop recommendations for clinical practice. Background:. Chyle leaks following esophagectomy for malignancy are uncommon. Although they are associated with increased morbidity and mortality, diagnosis and management of these patients remain controversial and a challenge globally. Methods:. This was a modified Delphi exercise was delivered to clinicians across the oesophagogastric anastomosis collaborative. A 5-staged iterative process was used to gather consensus on clinical practice, including a scoping systematic review (stage 1), 2 rounds of anonymous electronic voting (stages 2 and 3), data-based analysis (stage 4), and guideline and consensus development (stage 5). Stratified analyses were performed by surgeon specialty and surgeon volume. Results:. In stage 1, the steering committee proposed areas of uncertainty across 5 domains: risk factors, intraoperative techniques, and postoperative management (ie, diagnosis, severity, and treatment). In stages 2 and 3, 275 and 250 respondents respectively participated in online voting. Consensus was achieved on intraoperative thoracic duct ligation, postoperative diagnosis by milky chest drain output and biochemical testing with triglycerides and chylomicrons, assessing severity with volume of chest drain over 24 hours and a step-up approach in the management of chyle leaks. Stratified analyses demonstrated consistent results. In stage 4, data from the Oesophagogastric Anastomosis Audit demonstrated that chyle leaks occurred in 5.4% (122/2247). Increasing chyle leak grades were associated with higher rates of pulmonary complications, return to theater, prolonged length of stay, and 90-day mortality. In stage 5, 41 surgeons developed a set of recommendations in the intraoperative techniques, diagnosis, and management of chyle leaks. Conclusions:. Several areas of consensus were reached surrounding diagnosis and management of chyle leaks following esophagectomy for malignancy. Guidance in clinical practice through adaptation of recommendations from this consensus may help in the prevention of, timely diagnosis, and management of chyle leaks.

As many teachers feel overwhelmed by teaching inclusively, teacher education programs have to find ways to prepare them for this future challenge. Due to particular conditions, physical education (PE) teachers might be a particular target group in this context. With regard to the state of research, there is a need to identify inputs or learning situations that might improve the best physical education teachers’ competencies and underlying cognitive and affective-motivational aspects, such as attitudes, self-efficacy, or stress perception, to empower physical education teachers for teaching physical education inclusively. Practical experiences seem to be a key aspect in this context. Therefore, we conducted a quantitative evaluated quasi-experimental intervention study with physical education pre-service teachers to test different forms of promoting inclusion competencies and their underlying cognitive and affective-motivational constructs. Intervention group 1 (IG 1) followed an information-based seminar, whereas intervention group 2 (IG 2) was also taught theoretical units in combination with practical lessons in the gym that were prepared and conducted by the pre-service teachers themselves. The control group (CG) did not receive any specific information or practical experiences on inclusively teaching physical education. We first hypothesized that both intervention groups (IG 1 and IG 2), in contrast to the control group, would significantly improve their attitudes toward inclusion and the self-efficacy to teach inclusively, and would decrease their perceived stress related to teaching physical education inclusively (hypothesis 1). Second, we hypothesized that participants of intervention group 2 would have a significantly stronger increase in positive attitudes toward inclusion, a stronger increase in self-efficacy, and a greater decrease in the level of perceived stress related to teaching physical education inclusively than participants of intervention group 1 (hypothesis 2). Based on ANCOVA analysis, we found significant results for some subscales of the attitudes, but no significant results for stress perception and self-efficacy. In total, the teaching strategy in intervention group 2 seemed to work best in enhancing physical education pre-service teachers’ inclusion competencies.

Abstract We propose quivers for Coulomb branch constructions of universal implosions for orthogonal and symplectic groups, extending the work on special unitary groups in [1]. The quivers are unitary-orthosymplectic as opposed to the purely unitary quivers in the A-type case. Where possible we check our proposals using Hilbert series techniques.

Novoyatleva et al investigate the role of receptor tyrosine kinase Axl in Pulmonary arterial hypertension (PAH), finding that the small molecule inhibitor R428 reduces human pulmonary arterial smooth muscle cells proliferation and migration, but causes toxicity in human pulmonary arterial endothelial cells. They further show that Axl enhances endothelial BMPR2 signaling, altogether providing insights into mechanisms of PAH.

Abstract The Pulmonary Vascular Research Institute GoDeep meta‐registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta‐registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714). Retrospective and prospective PH patient data (diagnosis based on catheterization; individuals with exclusion of PH are included as a comparator group) are mapped to a common clinical parameter set of more than 350 items, anonymized and electronically exported to a central server. Use and access is decided by the GoDeep steering board, where each center has one vote. As of April 2022, GoDeep comprised 15,742 individuals with 1.9 million data points from eight PH centers. Geographic distribution comprises 3990 enrollees (25%) from America and 11,752 (75%) from Europe. Eighty‐nine perecent were diagnosed with PH and 11% were classified as not PH and provided a comparator group. The retrospective observation period is an average of 3.5 years (standard error of the mean 0.04), with 1159 PH patients followed for over 10 years. Pulmonary arterial hypertension represents the largest PH group (42.6%), followed by Group 2 (21.7%), Group 3 (17.3%), Group 4 (15.2%), and Group 5 (3.3%). The age distribution spans several decades, with patients 60 years or older comprising 60%. The majority of patients met an intermediate risk profile upon diagnosis. Data entry from a further six centers is ongoing, and negotiations with >10 centers worldwide have commenced. Using electronic interface‐based automated retrospective and prospective data transfer, GoDeep aims to provide in‐depth epidemiological and etiological understanding of PH and its various groups/subgroups on a global scale, offering insights for improved management.

The present treatments for lung cancer include surgical resection, radiation, chemotherapy, targeted therapy, and immunotherapy. Despite advances in therapies, the prognosis of lung cancer has not been substantially improved in recent years. Chimeric antigen receptor (CAR)-T cell immunotherapy has attracted growing interest in the treatment of various malignancies. Despite CAR-T cell therapy emerging as a novel potential therapeutic option with promising results in refractory and relapsed leukemia, many challenges limit its therapeutic efficacy in solid tumors including lung cancer. In this landscape, studies have identified several obstacles to the effective use of CAR-T cell therapy including antigen heterogeneity, the immunosuppressive tumor microenvironment, and tumor penetration by CAR-T cells. Here, we review CAR-T cell design; present the results of CAR-T cell therapies in preclinical and clinical studies in lung cancer; describe existing challenges and toxicities; and discuss strategies to improve therapeutic efficacy of CAR-T cells.

Abstract Magnetic quivers and Hasse diagrams for Higgs branches of rank r 4d N $$ \mathcal{N} $$ = 2 SCFTs arising from ℤ ℓ S $$ \mathcal{S} $$ -fold constructions are discussed. The magnetic quivers are derived using three different methods: 1) Using clues like dimension, global symmetry, and the folding parameter ℓ to guess the magnetic quiver. 2) From 6d N $$ \mathcal{N} $$ = (1, 0) SCFTs as UV completions of 5d marginal theories, and specific FI deformations on their magnetic quiver, which is further folded by ℤ ℓ . 3) From T-duality of Type IIA brane systems of 6d N $$ \mathcal{N} $$ = (1, 0) SCFTs and explicit mass deformation of the resulting brane web followed by ℤ ℓ folding. A choice of the ungauging scheme, either on a long node or on a short node, yields two different moduli spaces related by an orbifold action, thus suggesting a larger set of SCFTs in four dimensions than previously expected.

Abstract For any gauge theory, there may be a subgroup of the gauge group which acts trivially on the matter content. While many physical observables are not sensitive to this fact, the choice of the precise gauge group becomes crucial when the magnetic lattice of the theory is considered. This question is addressed in the context of Coulomb branches for 3d N $$ \mathcal{N} $$ = 4 quiver gauge theories, which are moduli spaces of dressed monopole operators. We compute the Coulomb branch Hilbert series of many unitary-orthosymplectic quivers for different choices of gauge groups, including diagonal quotients of the product gauge group of individual factors, where the quotient is by a trivially acting subgroup. Choosing different such diagonal groups results in distinct Coulomb branches, related as orbifolds. Examples include nilpotent orbit closures of the exceptional E-type algebras and magnetic quivers that arise from brane physics. This includes Higgs branches of theories with 8 supercharges in dimensions 4, 5, and 6. A crucial ingredient in the calculation of exact refined Hilbert series is the alternative construction of unframed magnetic quivers from resolved Slodowy slices, whose Hilbert series can be derived from Hall-Littlewood polynomials.

Abstract We study Hasse diagrams of moduli spaces of 3d N $$ \mathcal{N} $$ = 4 quiver gauge theories. The goal of this work is twofold: 1) We introduce the notion of inverting a Hasse diagram and conjecture that the Coulomb branch and Higgs branch Hasse diagrams of certain theories are related through this operation. 2) We introduce a Hasse diagram to map out the entire moduli space of the theory, including the Coulomb, Higgs and mixed branches. For theories whose Higgs and Coulomb branch Hasse diagrams are related by inversion it is straight forward to generate the Hasse diagram of the entire moduli space. We apply inversion of the Higgs branch Hasse diagram in order to obtain the Coulomb branch Hasse diagram for bad theories and obtain results consistent with the literature. For theories whose Higgs and Coulomb branch Hasse diagrams are not related by inversion it is nevertheless possible to produce the Hasse diagram of the full moduli space using different methods. We give examples for Hasse diagrams of the entire moduli space of theories with enhanced Coulomb branches.

Abstract Magnetic quivers and Hasse diagrams for Higgs branches of rank 1 4d N = 2 SCFTs are provided. These rank 1 theories fit naturally into families of higher rank theories, originating from higher dimensions, which are addressed.

Abstract Magnetic quivers have led to significant progress in the understanding of gauge theories with 8 supercharges at UV fixed points. For a given low-energy gauge theory realised via a Type II brane construction, there exist magnetic quivers for the Higgs branches at finite and infinite gauge coupling. Comparing these moduli spaces allows one to study the non-perturbative effects when transitioning to the fixed point. For 5d N $$ \mathcal{N} $$ = 1 SQCD, 5-brane webs have been an important tool for deriving magnetic quivers. In this work, the emphasis is placed on 5-brane webs with orientifold 5-planes which give rise to 5d theories with orthogonal or symplectic gauge groups. For this set-up, the magnetic quiver prescription is derived and contrasted against a unitary magnetic quiver description extracted from an O7 − construction. Further validation is achieved by a derivation of the associated Hasse diagrams. An important class of families considered are the orthogonal exceptional En families (−∞ < n ≤ 8), realised as infinite coupling Higgs branches of Sp(k) gauge theories with fundamental matter. In particular, the moduli spaces are realised by a novel type of magnetic quivers, called unitary-orthosymplectic quivers.

Abstract It is widely considered that the classical Higgs branch of 4d N $$ \mathcal{N} $$ = 2 SQCD is a well understood object. However there is no satisfactory understanding of its structure. There are two complications: (1) the Higgs branch chiral ring contains nilpotent elements, as can easily be checked in the case of SU(N) with 1 flavour. (2) the Higgs branch as a geometric space can in general be decomposed into two cones with nontrivial intersection, the baryonic and mesonic branches. To study the second point in detail we use the recently developed tool of magnetic quivers for five-brane webs, using the fact that the classical Higgs branch for theories with 8 supercharges does not change through dimensional reduction. We compare this approach with the computation of the hyper-Kähler quotient using Hilbert series techniques, finding perfect agreement if nilpotent operators are eliminated by the computation of a so called radical. We study the nature of the nilpotent operators and give conjectures for the Hilbert series of the full Higgs branch, giving new insights into the vacuum structure of 4d N $$ \mathcal{N} $$ = 2 SQCD. In addition we demonstrate the power of the magnetic quiver technique, as it allows us to identify the decomposition into cones, and provides us with the global symmetries of the theory, as a simple alternative to the techniques that were used to date.

Abstract We explore the geometrical structure of Higgs branches of quantum field theories with 8 supercharges in 3, 4, 5 and 6 dimensions. They are symplectic singularities, and as such admit a decomposition (or foliation ) into so-called symplectic leaves, which are related to each other by transverse slices. We identify this foliation with the pattern of partial Higgs mechanism of the theory and, using brane systems and recently introduced notions of magnetic quivers and quiver subtraction, we formalise the rules to obtain the Hasse diagram which encodes the structure of the foliation. While the unbroken gauge symmetry and the number of flat directions are obtainable by classical field theory analysis for Lagrangian theories, our approach allows us to characterise the geometry of the Higgs branch by a Hasse diagram with symplectic leaves and transverse slices, thus refining the analysis and extending it to non-Lagrangian theories. Most of the Hasse diagrams we obtain extend beyond the cases of nilpotent orbit closures known in the mathematics literature. The geometric analysis developed in this paper is applied to Higgs branches of several Lagrangian gauge theories, Argyres-Douglas theories, five dimensional SQCD theories at the conformal fixed point, and six dimensional SCFTs.

BackgroundThe relevance of cor pulmonale in COPD and pulmonary hypertension due to COPD (PH-COPD) is incompletely understood. We aimed to investigate the relationship of right ventricular-pulmonary arterial (RV-PA) uncoupling with disease severity in COPD, and the relationship of RV-PA uncoupling and use of targeted PH therapies with mortality in PH-COPD.MethodsWe retrospectively analyzed 231 patients with COPD without PH and 274 patients with PH-COPD. COPD was classified according to GOLD stages and the modified Medical Research Council dyspnoea scale. PH was categorized as mild-to-moderate or severe. RV-PA uncoupling was assessed as the echocardiographic tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio.ResultsOf the cohort with COPD without PH, 21, 58, 54 and 92 were classified as GOLD I, II, III and IV, respectively. Patients in advanced GOLD stages and those with severe dyspnoea showed significantly decreased TAPSE/PASP.Of the PH-COPD cohort, 144 had mild-to-moderate PH and 130 had severe PH. During follow-up, 126 patients died. In univariate Cox regression, TAPSE/PASP and 6-min walk distance (6MWD; 10 m increments) predicted survival [hazard ratios (95% CI): 0.12 (0.03–0.57) and 0.95 (0.93–0.97), respectively]; notably, PH severity and simplified European Society of Cardiology/European Respiratory Society risk stratification did not. Among patients in the lowest or intermediate tertiles of TAPSE/PASP and 6MWD, those with targeted PH therapy had higher survival than those without (53 vs. 17% at 3 years).ConclusionCor pulmonale (decreased TAPSE/PASP and 6MWD) is associated with disease severity in COPD and predicts outcome in PH-COPD.

Ideally, patient-centered trial information material encourages the discussion with the treating physician, and helps patients making trade-offs regarding treatment decisions In a situation of possible equivalent treatment options in terms of overall survival (OS), it can make it easier to weigh up advantages and disadvantages. Preferences for choice of treatment in esophageal cancer (EC) are complex, and no standardized assessment tools are available. We will explore patient’s factors for treatment choice and develop a comprehensive patient information leaflet for the inclusion into randomized controlled trials (RCT) on EC. We conduct a cross-sectional, observational study based on a mixed-methods design with patients suffering from non-metastatic EC with post-neoadjuvant complete response after neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiation (nCRT), to develop patient-centered trial information material. This pilot study is performed in a concept development phase and a subsequent pilot phase. We start with patient interviews (n = 10–15) in the concept development phase to evaluate patients’ needs, and develop a Preference and Decision Aid Questionnaire (PDAQ). We pre-test the PDAQ with another n = 10 patients with EC after nCT or nCRT, former patients from a self-help organization, and n = 10 medical experts for their comments on the questionnaire. In the pilot phase, a multicenter trial using the PDAQ and additional measures is carried out (n = 120). Based on evidence of a possible equivalence in terms of OS of the treatment options “surgery as needed” and “surgery on principle” in patients with post-neoadjuvant complete response of EC, this pilot study on patient participation is conducted to assess patient’s needs and preferences, and optimize patients’ inclusion in a planned RCT. The aim is to develop patient-centered trial information material for the RCT to increase patients’ consent and compliance with the randomized treatment. The trial is registered at the German Clinical Trials Register (DRKS00022050, October 15, 2020).

The lung tumor microenvironment plays a critical role in the tumorigenesis and metastasis of lung cancer, resulting from the crosstalk between cancer cells and microenvironmental cells. Therefore, comprehensive identification and characterization of cell populations in the complex lung structure is crucial for development of novel targeted anti-cancer therapies. Here, a hierarchical clustering approach with multispectral flow cytometry was established to delineate the cellular landscape of murine lungs under steady-state and cancer conditions. Fluorochromes were used multiple times to be able to measure 24 cell surface markers with only 13 detectors, yielding a broad picture for whole-lung phenotyping. Primary and metastatic murine lung tumor models were included to detect major cell populations in the lung, and to identify alterations to the distribution patterns in these models. In the primary tumor models, major altered populations included CD324+ epithelial cells, alveolar macrophages, dendritic cells, and blood and lymph endothelial cells. The number of fibroblasts, vascular smooth muscle cells, monocytes (Ly6C+ and Ly6C–) and neutrophils were elevated in metastatic models of lung cancer. Thus, the proposed clustering approach is a promising method to resolve cell populations from complex organs in detail even with basic flow cytometers.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. Aim: we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. Methods: four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. Results: iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. Conclusion: taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard.

Acute respiratory distress syndrome (ARDS) is a serious complication of severe systemic or local pulmonary inflammation, such as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ARDS is characterised by diffuse alveolar damage that leads to protein-rich pulmonary oedema, local alveolar hypoventilation and atelectasis. Inadequate perfusion of these areas is the main cause of hypoxaemia in ARDS. High perfusion in relation to ventilation (V/Q

Several acute and chronic lung diseases are associated with alveolar hypoventilation leading to accumulation of CO2 (hypercapnia). The β-subunit of the Na,K-ATPase plays a pivotal role in maintaining epithelial integrity by functioning as a cell adhesion molecule and regulating cell surface stability of the catalytic α-subunit of the transporter, thereby, maintaining optimal alveolar fluid balance. Here, we identified the E3 ubiquitin ligase for the Na,K-ATPase β-subunit, which promoted polyubiquitination, subsequent endocytosis and proteasomal degradation of the protein upon exposure of alveolar epithelial cells to elevated CO2 levels, thus impairing alveolar integrity. Ubiquitination of the Na,K-ATPase β-subunit required lysine 5 and 7 and mutating these residues (but not other lysines) prevented trafficking of Na,K-ATPase from the plasma membrane and stabilized the protein upon hypercapnia. Furthermore, ubiquitination of the Na,K-ATPase β-subunit was dependent on prior phosphorylation at serine 11 by protein kinase C (PKC)-ζ. Using a protein microarray, we identified the tumor necrosis factor receptor-associated factor 2 (TRAF2) as the E3 ligase driving ubiquitination of the Na,K-ATPase β-subunit upon hypercapnia. Of note, prevention of Na,K-ATPase β-subunit ubiquitination was necessary and sufficient to restore the formation of cell-cell junctions under hypercapnic conditions. These results suggest that a hypercapnic environment in the lung may lead to persistent epithelial dysfunction in affected patients. As such, the identification of the E3 ligase for the Na,K-ATPase may provide a novel therapeutic target, to be employed in patients with acute or chronic hypercapnic respiratory failure, aiming to restore alveolar epithelial integrity.

A poor preoperative functional capacity increases the perioperative risk. Therefore, a web-based exercise approach has been initiated for a careful supervision and individual support of patients during their perioperative cancer therapy. Here, we present the data of a 57-year-old patient, scheduled for esophagectomy. Beside a five-week neoadjuvant chemoradiotherapy (CRT), the patient performed 10 weeks of a web-based prehabilitation exercise training (preconditioning) and continued the exercise program for 14 weeks after surgery. The patient performed 42 of 44 recommended training sessions in the preconditioning period in his home environment. This corresponds to a mean of 131 (±38) min of total training per week. The patient performed 52 of 48 recommended training sessions in the postconditioning period. This corresponds to a mean of 165 (±87) min of total training per week. The patient could maintain his functional capacity during CRT and enhanced his submaximal performance level to the end of the intervention. The patient’s adherence to the program was noteworthy. The most important features of this approach are the personalized design and the flexible scheduling precisely in tune with the patient’s needs, concerns, and therapy related downtimes. Thus, the patient nearly fulfilled the exercise guidelines at a sufficient exercise intensity even during the neoadjuvant therapy. The preconditional exercise prevented a presumed CRT-induced and tumor-associated loss of functional capacity. The postoperative exercise led to a structured and adequate return into regular physical activities after surgery. Finally, this approach complements a comprehensive clinical care, in a health-promoting, cost-effective, and patient-safely manner.

Abstract Background An important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown. Neoadjuvant treatment and surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy has not been reached. The aim of this study is to determine the distribution of lymph node metastases in patients with resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed. This can be the foundation for a uniform worldwide staging system and establishment of the optimal surgical strategy for esophageal cancer patients. Methods The TIGER study is an international observational cohort study with 50 participating centers. Patients with a resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will be included. All lymph node stations will be excised and separately individually analyzed by pathological examination. The aim is to include 5000 patients. The primary endpoint is the distribution of lymph node metastases in esophageal and esophago-gastric junction carcinoma specimens following transthoracic esophagectomy with at least 2-field lymphadenectomy in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and (disease free) survival. Discussion The TIGER study will provide a roadmap of the location of lymph node metastases in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored treatment can be developed based on these results, such as the optimal radiation field and extent of lymphadenectomy based on the primary tumor characteristics. Trial registration NCT03222895, date of registration: July 19th, 2017.

Abstract Background Several new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC), but the support for their use for resectable, borderline resectable and locally advanced PDAC is unclear. Methods A survey was distributed to the members of the European-African Hepato-Pancreato Biliary Association (E-AHPBA) and the pancreas group of the European Organization for Research and Treatment of Cancer (EORTC) regarding 1) definitions of local resectability, 2) indications for neoadjuvant therapy and 3) case-vignettes regarding the resectability and treatment of PDAC. Results In total, 114 participants from 37 countries were registered. About 35% of respondents, each, were of the opinion that borderline resectability is defined by any venous tumor contact and venous involvement 180°, respectively. The majority (75.4%) of participants believed that borderline resectable PDAC has a high risk for R1 resection and that neoadjuvant therapy might increase the R0-resection rate (79.8%) and improve oncological patient selection (84.2%). Chemotherapy was regarded useful to convert locally advanced to resectable PDAC by 55.7% of respondents. In the cases with resectable, borderline resectable, and locally advanced PDAC, 10 (8.8%), 78 (68.4%), 55 (48.2%) of participants would start with chemotherapy, respectively. Conclusions Although definitions for borderline resectability differ among European surgeons, there seems to be a rather strong support for preoperative chemotherapy in PDAC aiming at minimizing R1 resections while increasing resection rates.

Pulmonary hypertension is characterized by a metabolic switch similar to the Warburg effect in cancer. Here Dabral et al. describe a RASSF1a-HIF-1α feedforward loop driving the Warburg effect both in a mouse model of hypoxia-induced pulmonary hypertension and a subset of human cancer cells.