There are several microRNAs that have been consistently reported to be differentially expressed in esophageal squamous cell carcinoma vs. normal squamous tissue, with prognostic associations for ...miR-21 (invasion, positive nodes, decreased survival), miR-143 (disease recurrence, invasion depth), and miR-375 (inversely correlated with advanced stage, distant metastasis, poor overall survival, and disease-free survival). There is also evidence that miR-375 regulates gene expression associated with resistance to chemotherapy. Hence, microRNA expression assays have the potential to provide clinically relevant information about prognosis and potential response to chemotherapy in patients with esophageal squamous cell carcinoma. Results are inconsistent, however, for microRNAs across different studies for esophageal adenocarcinoma (EAC) vs. its precursor lesion Barrett's esophagus. These inconsistencies may partly result from pathological and/or molecular heterogeneity in both Barrett's esophagus and EAC, but may also result from differences in study designs or different choices of comparator tissues. Despite these inconsistencies, however, several mRNA/protein targets have been identified, the cancer related biology of some of these targets is well understood, and there are clinico-pathological associations for some of these mRNA targets. MicroRNAs also have potential for use in therapy for esophageal cancers. The development of new delivery methods, such as minicells and autologous microvesicles, and molecular modifications such as the addition of aromatic benzene pyridine analogs, have facilitated the exploration of the effects of therapeutic microRNAs in vivo. These approaches are producing encouraging results, with one technology in a phase I/IIa clinical trial.
The microtubule plus-end tracking proteins (+TIPs) END BINDINGIb (EB1b) and SPIRALI (SPR1) are required for normal cell expansion and organ growth. EB proteins are viewed as central regulators of + ...TIPs and cell polarity in animals; SPR1 homologs are specific to plants. To explore if EB1b and SPR1 fundamentally function together, we combined genetic, biochemical, and cell imaging approaches in Arabidopsis thaliana. We found that eb1b-2 spr1-6 double mutant roots exhibit substantially more severe polar expansion defects than either single mutant, undergoing right-looping growth and severe axial twisting instead of waving on tilted hard-agar surfaces. Protein interaction assays revealed that EB1b and SPR1 bind each other and tubulin heterodimers, which is suggestive of a microtubule loading mechanism. EB1b and SPR1 show antagonistic association with microtubules in vitro. Surprisingly, our combined analyses revealed that SPR1 can load onto microtubules and function independently of EB1 proteins, setting SPR1 apart from most studied +TIPs in animals and fungi. Moreover, we found that the severity of defects in microtubule dynamics in spr1 eb1b mutant hypocotyl cells correlated well with the severity of growth defects. These data indicate that SPR1 and EB1b have complex interactions as they load onto microtubule plus ends and direct polar cell expansion and organ growth in response to directional cues.
TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and ...SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.
Abstract Objectives It has been reported that a higher galvanic skin response is seen when playing video games against another human player than when playing alone, which suggests increased effort. ...The objectives of this study were to compare energy expenditure when playing two popular active video game consoles, and to compare energy expenditure when playing in single and multiplayer modes. Design Crossover trial with randomised playing order. Participants Fourteen healthy adults with a mean age of 21 standard deviation (SD) 3 years. Methods and interventions Energy expenditure was measured using an indirect calorimeter at rest, during 10 minutes of play on Xbox Kinect™ Reflex Ridge in both single and multiplayer modes, and during 10 minutes of play on Wii™ Sports Boxing in both single and multiplayer modes. Main outcome measures Metabolic equivalents (METs), heart rate, oxygen consumption and kilocalories expended. Results The energy expenditure during all gaming conditions was of a light intensity. Playing on the Xbox Kinect elicited greater energy expenditure than playing on the Wii mean difference = 0.9 METs, 95% confidence interval (CI) 0.2 to 1.5. Playing games in multiplayer mode led to greater energy expenditure (mean difference = 0.5 METs, 95% CI 0.1 to 0.9) and heart rate (mean difference = 7.9 beats/minute, 95% CI 2.0 to 13.8) than playing in single player mode. Conclusions No gaming condition required moderate-intensity activity in this group of young healthy adults. Potential explanations for the difference in energy expenditure seen between consoles and modes are discussed.
Background
Cardiopulmonary exercise testing (CPX) can objectively measure fitness and oxygen uptake at anaerobic threshold. The relationship between fitness and postoperative outcomes after upper ...gastro-intestinal surgery is unclear. The aim of the present review is to assess the prognostic ability of CPX in predicting postoperative outcome associated with oesophagogastric surgery.
Methods
Relevant studies were identified through a systematic search of EMBASE, Medline, CINAHL, Cochrane Library, and Web of Science to July 2019. The eligibility criteria for studies included prognostic studies of upper gastro-intestinal surgery among adult populations using a preoperative CPX and measurement of postoperative outcome (mortality or morbidity or length of stay). Risk of bias was assessed using the QUIPS Quality in Prognostic Studies validated tool.
Results
Thirteen papers with a total of 1735 participants were included in data extraction. A total of 7 studies examined the association between CPX variables and postoperative mortality. Patients undergoing gastro-intestinal surgery with lower anaerobic threshold values were found to have an increased risk of postoperative mortality. Similarly, a lower rate of oxygen consumption was found to be associated with higher mortality. There was conflicting evidence regarding the association between CPX variables and postoperative morbidity. The evidence did not demonstrate any association between preoperative CPX variables and hospital length of stay.
Conclusion
Studies report an association between CPX variables and postoperative mortality; however, there is conflicting evidence regarding the association between CPX variables and postoperative morbidity.
Cell division, growth, and cytoplasmic organization require a dynamic actin cytoskeleton. The filamentous actin (F-actin) network is regulated by actin binding proteins that modulate actin dynamics. ...These actin binding proteins often have cooperative interactions 1, 2. In particular, actin interacting protein 1 (AIP1) is capable of capping F-actin and enhancing the activity of the small actin modulating protein, actin depolymerising factor (ADF) in vitro 1, 3. Here, we analyze the effect of the inducible expression of AIP1 RNAi in Arabidopsis plants to assess AIP1s role in vivo. In intercalary growing cells, the normal actin organization is disrupted, and thick bundles of actin appear in the cytoplasm. Moreover, in root hairs, there is the unusual appearance of actin cables ramifying the root hair tip. We suggest that the reduction in AIP1 results in a decrease in F-actin turnover and the promotion of actin bundling. This distortion of the actin cytoskeleton causes severe plant developmental abnormalities. After induction of the Arabidopis RNAi lines, the cells in the leaves, roots, and shoots fail to expand normally, and in the severest phenotypes, the plants die. Our data suggest that AIP1 is essential for the normal functioning of the actin cytoskeleton in plant development.
Purpose. Multidisciplinary rehabilitation programmes providing exercise, nutrition support, education, and peer support can effectively meet the rehabilitation needs of upper gastrointestinal (UGI) ...cancer survivors. This study aimed to explore the experiences of participants who engaged in a telehealth, multidisciplinary rehabilitation programme for UGI cancer survivors. Methods. This single-arm feasibility study recruited participants who completed curative treatment for UGI cancer. Participants (n = 10, male = 9) aged 58–76 years were 5–17 months postsurgery. A 12-week telehealth rehabilitation programme was delivered via video call, consisting of group resistance training, remotely monitored aerobic training, 1 : 1 dietary counselling, 1 : 1 physiotherapy support, and group education sessions. Independent researchers conducted semistructured interviews at postintervention assessments. Transcripts were analysed using reflexive thematic analysis (RTA). Results. RTA of participant transcripts generated three overarching themes: (1) ReStOre@Home impacted psychosocial and physical needs by addressing a broad and meaningful gap in services, (2) paving a pathway towards prosperity, and (3) contrasting experiences with using technology. Participants’ preferences and recommendations for future telehealth programmes were discussed. Conclusions. A telehealth multidisciplinary rehabilitation programme supported participants in physical and psychosocial recovery. Qualitative analysis identified an important ongoing need for some in-person care and provided detailed insights into participant experiences during telehealth-delivered rehabilitation.
Background
Transthoracic esophagectomy for cancer triggers a massive inflammatory reaction. The data whether a minimally invasive esophagectomy (MIE) leads to less pronounced inflammatory response ...compared to open right-sided transthoracic esophagectomy (OE) are scarce. The aim of this study was to evaluate the extent of the inflammatory reaction, represented by levels of the pro-inflammatory interleukins IL-6 and IL-8, the anti-inflammatory IL-1 RA and the chemokines CINC-1 and MCP-1 in the right pleural fluid and the blood from patients undergoing standard OE or MIE.
Methods
Pleural drainage fluid and blood was collected at five different time points during the first 72 h following surgery, and the concentrations of IL-6, IL-8, IL-1 RA, CINC-1 and MCP-1 were analyzed using enzyme-linked immune-sorbent assays in 24 patients undergoing MIE or OE.
Results
The groups were matched for cancer stage and comorbidities. Pro- and anti-inflammatory mediator levels in the pleural fluid were markedly increased at the end of surgery and on postoperative days 1–3. The pleural inflammatory response of all cyto- and chemokines was lower in the MIE group, reaching significance at some time points. Cyto- and chemokine response levels measured in the blood were overall lower compared to those in the pleural fluid. The chemokines CINC-1 and MCP-1 reacted less pronounced or not at all. Preoperative pulmonary comorbidity, postoperative pulmonary morbidity and length of surgery were associated with an increased reaction in selected mediators.
Conclusions
The minimally invasive technique attenuates the inflammatory response, especially locally in the thoracic compartment. Length of procedure, preoperative pulmonary comorbidity and postoperative pulmonary complications are mirrored in an increase in individual inflammatory markers in the pleural fluid. The value of the chemokines CINC-1 and MCP-1 as markers of inflammation in the setting of esophagectomy is unclear.
De novo tissue generation stimulated by three angiogenic growth factors administered in a factorial design was studied in an in vivo murine tissue engineering chamber. A silicone chamber was ...implanted around the epigastric pedicle and filled with Matrigel with 100 ng/ml of recombinant mouse vascular endothelial growth factor-120 (VEGF120 ), recombinant human basic fibroblastic growth factor (FGF-2), or recombinant rat platelet-derived growth factor-BB (PDGF-BB) added as single, double, or triple combinations. Angiogenesis, supporting tissue ingrowth, and adipogenesis were assessed at 2 and 6 weeks by immunohistochemistry and morphometry. At 2 weeks angiogenesis was synergistically enhanced by VEGF120 + FGF-2 ( P = 0.019). FGF-2 ( P = 0.008) and PDGF-BB ( P = 0.01) significantly increased connective tissue/inflammatory cell infiltrate (macrophages, pericytes, and preadipocytes) in double and triple combinations compared with control. At 6 weeks sequential addition of growth factors increased the percent volume of adipose tissue ( P < 0.0005, each main effect), with a synergistic increase in adipose tissue in combination treatments ( P < 0.0005). Groups containing 300 ng/ml of single growth factors produced significantly less adipose tissue than the triple growth factor combination ( P < 0.0005, VEGF120 and PDGF-BB; P < 0.001, FGF-2). In conclusion, angiogenic growth factor combinations increased early angiogenesis and cell infiltration resulting in synergistically increased adipose tissue growth at 6 weeks. Two way and higher level synergies are likely to be important in therapeutic applications of angiogenic growth factors.
PDF
