Molecular aspects of pancreatic cancer: focus on reprogrammed metabolism in a nutrient-deficient environment and potential therapeutic targets.

Pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the reprogrammed metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. Research results suggest that genetic and metabolic disorders may precede the onset of neoplastic changes, which should allow for earlier appropriate treatment. Glycolysis and glutaminolysis are the most investigated pathways associated with the highest aggressiveness of pancreatic tumors. Blocking of selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation may inhibit cancer development, increase cancer cells death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). Depriving cancer cells of important nutrients (glucose, glutamine) revealed tumor "checkpoints" for the mechanisms that drive cell proliferation and metastasis formation in order to determine its accuracy for individualization of the therapeutic approach. The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention has been paid to the adaptive metabolism of pancreatic cancer, which promotes its development in an oxygen-deficient and nutrient-poor environment.

Pancreatic cancer and adaptive metabolism in a nutrient-deficient environment.

Despite tremendous progress in the treatment of many cancer types, leading to a significant increase in survival, pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality rates (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the adaptive metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. It was found that blocking selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells, improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation, may inhibit cancer development, increase cancer cell death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention is paid to the adaptive metabolism of pancreatic cancer, including fatty acids, autophagy, macropinocytosis, and deregulated cell-surface glycoproteins, which promotes cancer cell development in an oxygen-deficient and nutrient-poor environment.

The relationship between the degree of malnutrition and changes in selected parameters of the immune response in critically ill patients.

Patients treated in intensive care units (ICUs) are at high risk of malnutrition and the resulting homeostasis, metabolic, histological and immunological disorders, especially leading to organ failure and increased susceptibility to infection. In 163 patients with malnutrition [mild in 33 (19.6%), moderate in 69 (42.9%), severe in 61 (37.4%)] treated in the ICU, changes in the concentration of selected proteins [interleukin (IL)-1Ra, tumor necrosis factor α (TNF-α), soluble tumour necrosis factor receptor-1 (sTNFR1), IL-6, IL-10, sTLR4, MyD88, A20, HSP70, HMGB1] were examined. In the whole group of malnourished patients, median values of sTNFR1, TNF-α, IL-6, TLR4, IL-1Ra were significantly increased, while the levels of MyD88 and A20 proteins were significantly reduced (in comparison to the well-nourished healthy group). Only the sTNFR1 protein showed a significant difference between mild, moderate and severe malnutrition, and increased concentrations as the severity of malnutrition increased (the correlation study found that as the degree of malnutrition increased, the sTNFR1 concentrations increased; p = 0.0000, R = 0.5442). It was observed that death was significantly more frequent in the group of patients who on the first day of hospitalization in the ICU scored 5 or more points on the NRS 2002 scale (p = 0.0004). In the patients who died significantly higher concentrations of sTNFR1, IL-6, IL-10, HSP70 were observed in comparison to the patients who survived. The present results are encouraging and indicate the desirability of undertaking multicentre clinical trials including monitoring of sTNFR1 in assessing the severity of malnutrition and immune disorders in the first hours after admission to the ICU, because it can be assumed that without early diagnosis of innate immunity disorders any attempts at their modulation may be ineffective.

Infection-induced innate antimicrobial response disorders: from signaling pathways and their modulation to selected biomarkers.

Severe infections are a major public health problem responsible for about 40-65% of hospitalizations in intensive care units (ICU). The high mortality (30-50%) of persons diagnosed with severe infection is caused by largely unknown mechanisms of sepsis-induced immune system response. Severe infections with dynamic progress are accompanied with SIRS (systemic inflammatory reaction syndrome) and CARS (compensatory anti-inflammatory response syndrome), and require a biological treatment appropriate to the phase of immune response. The mechanisms responsible for severe infection related to immune system response particularly attract extensive interest of non-specific defense mechanisms, including signaling pathways of Toll-like receptors (mainly TLR4 and TLR2) that recognize distinct pathogen-associated molecular patterns (PAMP) and play a critical role in innate immune response. There are attempts of treatment, followed by blocking ligand binding with TLR or modulation of intracellular signaling pathways, to inhibit signal transduction. Moreover, researches regarding new and more efficient diagnostics biomarkers were mostly focused on indicators related to innate response to infection as well as connections of pro-inflammatory response with anti-inflammatory response.According to these studies, in case of ICU septic patients with high-risk of mortality, the solution for the problem will require mainly early immune and genetic diagnostics (e.g. cytokines, microRNA, cluster of differentiation-64 [CD64], triggering receptor expressed on myeloid cells-1 [TREM-1], and high mobility group box 1 protein [HMGB1]).

Association between disease-related malnutrition and innate immunity gene expression in critically ill patients at intensive care unit admission.

The aim of the study was to analyse the relationship between nutritional disorders and the expression of innate antibacterial response genes in patients admitted to the intensive care unit (ICU). In 46 patients with severe malnutrition and life-threatening surgical complications, nutritional status tests were performed on the basis of the NRS 2002 (Nutritional Risk Screening) scale, cytokine, albumin, C-reactive protein concentrations, anthropometric tests, and body composition analysis. Concurrently, the expression of Toll-like receptor 2, NOD1, TRAF6, and HMGB1 genes was determined in peripheral blood leukocytes at the mRNA level using real-time polymerase chain reaction. It was found that both the nutritional status and the gene expression changed depending on the group of patients studied (including the group of survivors vs. non-survivors). Significant correlations were found between the results of routine tests used in the diagnostics of malnutrition (including NRS 2002, resistance, reactance, phase angle, excess of extracellular water) and the expression of the studied genes. Moreover, the expression of TRAF6 and HMGB1 genes correlated with the Acute Physiology and Chronic Health Evaluation II scale and the age of the patients. The results of the research suggest that the expression of innate antibacterial response genes may be a new diagnostic tool complementing the assessment of nutritional disorders in surgical patients admitted to the ICU. These tests may be helpful in providing more accurate diagnostics of the genetic effects of malnutrition and in the monitoring of patients for whom nutritional treatment is planned to support the functions of the immune system, thereby increasing the effectiveness of this type of treatment in the ICU.

The soluble tumor necrosis factor receptor 1 as a potential early diagnostic and prognostic markers in intensive care unit patients with severe infections.

INTRODUCTION: Substantial causes of high mortality (30-50%) of people with severe infections treated in intensive care units (ICUs) are still inadequately known in terms of mechanisms and insufficient diagnostic tools for immune responses in sepsis. MATERIAL AND METHODS: The aim of this study was to establish a practical value of determining the concentration of chosen proteins (by ELISA) in peripheral blood as potential in early diagnostics of severe infections, paying special attention to their prognostic values. RESULTS: In 163 patients treated in ICUs, changes were assessed in the concentration of chosen proteins relating to the TLR4 receptor signalling pathway, including its effectors of pro- and anti-inflammatory cytokines (IL-1Ra, TNF-α, sTNFR1, IL-6, IL-10, sTLR4, MyD88, TNFAIP3/A20, HSP70, and HMGB1). In the analysis of changes in the process of immune response in severely ill patients with and without infections, a significantly higher concentration of sTNFR1 was observed in patients with infections than those who deceased. In the ROC curves tests, it was noted that an assessment of the concentration of sTNFR1 proteins (AUC = 0.686 and cut-off point = 24.841 pg/ml) was a particularly efficient tool, with prognostic significance in patients with infections. CONCLUSIONS: In other patients treated in an ICU, the efficiency of determining IL-6 (AUC = 0.736) was confirmed and at the same time, the effectiveness of this cytokine in predicting death in cases with infections was excluded. The results of the present study are encouraging, suggesting the benefits of undertaking multi-center clinical trials, which consider monitoring sTNFR1 in different groups of patients with infections treated in intensive care units.

Soluble tumour necrosis factor receptor I is a promising early indicator of complicated clinical outcome in patients following severe trauma.

Post-traumatic mortality rates are still very high and show an increasing tendency. Early identification of patients at high risk of severe complications has a significant impact on treatment outcomes. The aim of the study was to better understand the early pathological inflammatory response to injury and infection, and to determine the usefulness of the assessment of TNF-α and sTNFR1 concentrations in the peripheral blood as early indicators of severe post-traumatic complications. The study was carried out in a group of 51 patients after trauma, treated in the ED, including 32 patients who met the inclusion criteria for immunological analysis. Patients were divided into two groups using the ISS scale (A ISS ≥ 20, B ISS < 20). The highest TNF-α and sTNFR1 concentrations in both groups were recorded at admission and were significantly higher in group A compared to group B (A vs. B TNF-α 2.46 pg/ml vs. 1.78 pg/ml; sTNFR1 1667.5 pg/ml vs. 875.2 p < 0.005). The concentration of sTNFR1 in patients with severe complications was significantly higher compared to patients without complications and preceded clinical symptoms of complications (C+ vs. C- 1561.5 pg/ml vs. 930.6 pg/ml, p < 0,005). The high diagnostic sensitivity calculated from the ROC curves was found for the concentrations of both cytokines: TNF-α (AUC = 0.91, p = 0.004) and sTNFR1 (AUC = 0.86, p = 0.011). Elevated levels of sTNFR1, determined in the peripheral blood shortly after injury, are significantly associated with the occurrence of later complications, which in some patients lead to death. In contrast, high levels of TNF-α shortly after injury are associated with mortality.

MicroRNAs in pancreatic cancer diagnosis and therapy.

Pancreatic cancer remains a disease with very poor prognosis (only 5-6% of patients are still alive after five years). Attempts to improve the results of treatment of pancreatic cancer focus on a better understanding of the pathogenesis, and non-invasive diagnostic methods (genetic testing from peripheral blood), which would create the possibility of early diagnosis and early surgical treatment before the onset of metastasis. New hopes for the improvement of early diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC) are associated with genetic testing of microRNA expression changes. A large body of evidence has revealed that microRNAs are aberrantly expressed in the serum and in cancer tissues and elicit oncogenic or tumour-suppressive functions. Selected microRNAs can distinguish pancreatic ductal adenocarcinoma from non-cancerous lesions of the pancreas. This review focuses on the involvement of microRNAs in the early diagnosis of pancreatic cancer. Research results related to the development of a novel therapeutic strategy based on the modulation of microRNA expressions for a better outcome in patients with pancreatic cancer are also presented.

The diagnostic value of early cytokine response in patients after major trauma - preliminary report.

This study was aimed to give a better understanding of the mechanisms of early immune response to trauma by assessing the concentration of cytokines in peripheral blood. The study group comprised 32 patients admitted to the Emergency Department due to injury. Depending on the magnitude of the Injury Severity Score (ISS) trauma patients were divided into two groups. In group A (ISS ≥ 20), 13 patients had complications, and five died, while in group B (ISS < 20) only three patients had complications (e.g. respiratory failure and infections). Depending on the extent of the injury, significant differences were observed in the concentrations of cytokines in the treatment groups. The highest levels of IL-6 and IL-1Ra in both groups were recorded in the third hour of hospitalisation and were considerably higher in group A compared to the concentration of these cytokines in group B (p = 0.001). In patients with complications, IL-6 and IL-1Ra concentrations were significantly higher compared to those without complications. Spearman's rho-correlation showed a statistically significant positive correlation between baseline concentrations of IL-6 (r = 0.64, p < 0.001) and IL-1Ra (r = 0.37, p = 0.042) and the values of the ISS. A high diagnostic sensitivity calculated from ROC curves was found for IL-6 concentrations. In summary, our findings suggest that elevated levels of the cytokines tested, determined in the peripheral blood shortly after injury, may be significantly associated with the occurrence of severe complications, which in some patients can lead to death. Monitoring the levels of these cytokines in patients with a high risk of serious complications should be used routinely.

Immune disorders in anorexia.

Anorexia nervosa is a disease involving eating disorders. It mainly affects young people, especially teenage women. The disease is often latent and occurs in many sub-clinical and partial forms. Approximately from 0.3% to 1% of the population suffers from anorexia. It has been shown that patients with anorexia develop neurotransmitter-related disorders, leading to uncontrolled changes in the immune and endocrine systems. Interactions between cytokines, neuropeptides, and neurotransmitters play an important role in disease development. Significant malnutrition induces disorders and alterations in T-cell populations. The cellular response in patients with anorexia nervosa has been shown to be normal, although opinions on this issue are controversial. Laboratory studies on neutrophils in anorexia patients showed decreased adhesion and reduced bactericidal and cell activities. Despite such unfavourable results, patients with anorexia are resistant to infections, which are very rare in this group. Glutamine improves the performance of the human immune system. The administration of glutamine to anorexia patients, as a supplement to parenteral nutrition, has resulted in significant improvements in immune system parameters. The results of previous studies on the causes and risk factors in the development of anorexia nervosa are still ambiguous. One can hope that the differences and similarities between patients with anorexia nervosa and those with other forms of protein-calorie malnutrition may be helpful in determining the relationship between nutritional status and body defences and susceptibility to infection, and can help to broaden the knowledge about the aetiopathogenesis of anorexia nervosa.