Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer.

BackgroundPancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena.MethodsWe examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined.ResultsCombination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2.ConclusionThe ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer

Increased Rates of Prolonged Length of Stay, Readmissions, and Discharge to Care Facilities among Postoperative Patients with Disseminated Malignancy: Implications for Clinical Practice.

BackgroundThe impact of surgery on end of life care for patients with disseminated malignancy (DMa) is incompletely characterized. The purpose of this study was to evaluate postoperative outcomes impacting quality of care among DMa patients, specifically prolonged length of hospital stay, readmission, and disposition.MethodsThe American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for years 2011-2012. DMa patients were matched to non-DMa patients with comparable clinical characteristics and operation types. Primary hepatic operations were excluded, leaving a final cohort of 17,972 DMa patients. The primary outcomes were analyzed using multivariate Cox regression models.ResultsDMa patients represented 2.1% of all ACS-NSQIP procedures during the study period. The most frequent operations were bowel resections (25.3%). Compared to non-DMa matched controls, DMa patients had higher rates of postoperative overall morbidity (24.4% vs. 18.7%, p<0.001), serious morbidity (14.9% vs. 12.0%, p<0.001), mortality (7.6% vs. 2.5%, p<0.001), prolonged length of stay (32.2% vs. 19.8%, p<0.001), readmission (15.7% vs. 9.6%, p<0.001), and discharges to facilities (16.2% vs. 12.9%, p<0.001). Subgroup analyses of patients by procedure type showed similar results. Importantly, DMa patients who did not experience any postoperative complication experienced significantly higher rates of prolonged length of stay (23.0% vs. 11.8%, p<0.001), readmissions (10.0% vs. 5.2%, p<0.001), discharges to a facility (13.2% vs. 9.5%, p<0.001), and 30-day mortality (4.7% vs. 0.8%, p<0.001) compared to matched non-DMa patients.ConclusionSurgical interventions among DMa patients are associated with poorer postoperative outcomes including greater postoperative complications, prolonged length of hospital stay, readmissions, disposition to facilities, and death compared to non-DMa patients. These data reinforce the importance of clarifying goals of care for DMa patients, especially when acute changes in health status potentially requiring surgery occur

Overcoming inadvertent barriers to entry in large infrastructure projects

The history behind the award of Brisbane City Council's Legacy Way project is discussed and the possible impact of cognitive bias in the Expression of Interest (EOI) process together with the steps that were taken during the EOI development and evaluati

The discovery of the endocrine heart

To travel down the memory lane with reference to the discovery of the atrial natriuretic factor (ANF) and hence of the endocrine function of the heart is a slippery slope. It is so because it takes me down to my very young years during which, somehow, I had decided to be a research scientist. And now I realize that this had nothing to do with my education, family influences or role models. It was just that: one wants to be a scientist since very early in life and nobody, including you, knows exactly why. Call it a vocation. With that emotional package in hand I parted after completing my secondary education from my natal city of Parana, Entre Rios to Rosario, Santa Fe to study to become a clinical biochemist. Why biochemistry and not medicine? Because I somehow knew that biochemistry would provide a biomedical scientist with more basic tools that medicine would. How did I know that? I don't know. And here comes the part where the Providence really starts to show its hand.Número especial: Timeline of physiological discoveries. Milestones that paved the way to today's knowledgeSociedad Argentina de Fisiologí

Transcriptional analysis of the mammalian heart with special reference to its endocrine function

<p>Abstract</p> <p>Background</p> <p>Pharmacological and gene ablation studies have demonstrated the crucial role of the endocrine function of the heart as mediated by the polypeptide hormones ANF and BNP in the maintenance of cardiovascular homeostasis. The importance of these studies lies on the fact that hypertension and chronic congestive heart failure are clinical entities that may be regarded as states of relative deficiency of ANF and BNP. These hormones are produced by the atrial muscle cells (cardiocytes), which display a dual secretory/muscle phenotype. In contrast, ventricular cardiocytes display mainly a muscle phenotype. Comparatively little information is available regarding the genetic background for this important phenotypic difference with particular reference to the endocrine function of the heart. We postulated that comparison of gene expression profiles between atrial and ventricular muscles would help identify gene transcripts that underlie the phenotypic differences associated with the endocrine function of the heart.</p> <p>Results</p> <p>Comparison of gene expression profiles in the rat heart revealed a total of 1415 differentially expressed genes between the atria and ventricles based on a 1.8 fold cut-off. The identification of numerous chamber specific transcripts, such as ANF for the atria and Irx4 for the ventricles among several others, support the soundness of the GeneChip data and demonstrates that the differences in gene expression profiles observed between the atrial and ventricular tissues were not spurious in nature. Pathway analysis revealed unique expression profiles in the atria for G protein signaling that included Gα_o1, Gγ₂and Gγ₃, AGS1, RGS2, and RGS6 and the related K⁺channels GIRK1 and GIRK4. Transcripts involved in vesicle trafficking, hormone secretion as well as mechanosensors (e.g. the potassium channel TREK-1) were identified in relationship to the synthesis, storage and secretion of hormones.</p> <p>Conclusion</p> <p>The data developed in this investigation describes for the first time data on gene expression particularly centred on the secretory function of the heart. This provides for a rational approach in the investigation of determinants of the endocrine of the heart in health and disease.</p

The Role of Palliative Surgery for Malignant Bowel Obstruction and Perforation in Advanced Microsatellite Instability-High Colorectal Carcinoma in the Era of Immunotherapy: Case Report.

The role of palliative surgery in the management of acute complications in patients with disseminated malignancy remains controversial given the complexity of assessing acute surgical risk and long-term oncologic outcome. With the emergence of checkpoint blockade immunotherapy, there appears to be an increasing role for historically palliative procedures as a bridge to systemic immunotherapy. This is especially evident in advanced microsatellite instability-high (MSI-H) colorectal cancer where malignant obstruction and fistula formation are more common and where immunotherapy with checkpoint blockade (anti-PD-1/PD-L1, anti-CTLA-4) has a high response rate with potential for favorable oncologic outcomes. We present a series of three patients with MSI-H metastatic colorectal cancer complicated by malignant bowel obstruction and fistula formation, who having progressed on standard chemotherapy, underwent palliative intervention as a bridge to immune checkpoint blockade with durable and clinically meaningful anti-cancer responses. These cases highlight the need to re-evaluate the role of historically palliative operations in the setting of disease progression for immunotherapy-responsive tumors

Investigation of the mechanical behavior of electrodes after calendering and its influence on singulation and cell performance

Battery cell production is a complex process chain with interlinked manufacturing processes. Calendering in particular has an enormous influence on the subsequent manufacturing steps and final cell performance. However, the effects on the mechanical properties of the electrode, in particular, have been insufficiently investigated. For this reason, the impact of different densification rates during calendering on the electrochemical cell performance of NMC811 (LiNi$_{0.8}$Mn$_{0.1}$Co$_{0.1}$O$_{2}$) half-cells are investigated to identify the relevant calendering parameters. Based on this investigation, an experimental design has been derived. Electrode elongations after calendering in and orthogonal to the running direction of the NMC811 cathode are investigated in comparison with a hard carbon anode after calendering. Elongations orthogonal to the machine direction are observed to have no major dependencies on the compaction rate during calendering. In the machine direction, however, significant elongation occurs as a dependency of the compaction rate for both the hard carbon anode and the NMC811. In addition, the geometric shape of the NMC811 electrodes after separation into individual sheets is investigated with regard to different compaction rates during calendering. It is shown that the corrugations that occur during calendering are propagated into the single electrode, depending on the compaction rate

A mixed-methods pilot study of the acceptability and effectiveness of a brief meditation and mindfulness intervention for people with diabetes and coronary heart disease.

PublishedClinical TrialJournal ArticleResearch Support, Non-U.S. Gov'tMindfulness-based interventions can successfully target negative perseverative cognitions such as worry and thought suppression, but their acceptability and effectiveness in people with long-term conditions is uncertain. We therefore pilot tested a six-week meditation and mindfulness intervention in people (n = 40) with diabetes mellitus and coronary heart disease. We used a sequential mixed-methods approach that measured change in worry and thought suppression and qualitatively explored acceptability, feasibility, and user experience with a focus group (n = 11) and in-depth interviews (n = 16). The intervention was highly acceptable, with 90% completing ≥5 sessions. Meditation and mindfulness skills led to improved sleep, greater relaxation, and more-accepting approaches to illness and illness experience. At the end of the six-week meditation course, worry, and thought suppression were significantly reduced. Positive impacts of mindfulness-based interventions on psychological health may relate to acquisition and development of meta-cognitive skills but this needs experimental confirmation.NIHR Collaboration for Leadership in Applied Health Research and Care forGreater Manchester