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.

Primary small bowel adenocarcinoma: current view on clinical features, risk and prognostic factors, treatment and outcome.

Small bowel adenocarcinoma (SBA) is a rare but increasing cause of gastrointestinal malignancy, being both a diagnostic and therapeutic challenge. The goal of treatment is margin negative resection of a lesion and local lymphadenectomy, followed by modern adjuvant chemotherapy combinations in selected cases. Improved outcomes in patients with SBA are encouraging, but elucidation of mechanisms of carcinogenesis and risk factors as well as improved treatment for this malignancy is very needed.

Disorders of nutritional status in sepsis - facts and myths.

The problem of diagnosing nutritional status disorders in septic patients remains unresolved. This is associated with the necessity of the introduction of newer and newer methods of assessing nutritional status, often requiring precise and expensive equipment as well as employment of professionals in this field in hospital wards, primarily including intensive care units (ICU). Methods that have been applied thus far for assessing nutritional status, also used in severely ill septic patients, have little impact on improving treatment results. This is due to the high dynamics of changes in nutritional status in these patients, healing process variability in individual patients, and the "mismatch" of methods for assessing nutritional status in relation to the patient's clinical status. The diagnostic value of the traditional methods of assessing nutritional status, i.e. anthropometric analysis and selected laboratory tests, as markers of nutritional status disorders in septic patients, is still debatable. There is still no precise method that could become the "gold standard" allowing for early identification of malnutrition in these group of patients. Phase angle, bioelectrical impedance vector analysis (BIVA), and the "illness marker", obtained directly from the resistance, reactance, and impedance, can be used as prognostic or nutritional indices in severely ill septic patients, but the intensity of research on this subject needs to be increased. Detailed assessment of nutritional status should include tests of selected inflammation markers (including TLC, HMGB1, IL-6, IL-10, IL-1ra, sTNFRI).

Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances.

Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.

Diagnostic value of selected markers and apoptotic pathways for pancreatic cancer.

Pancreatic cancer occupies the fourth place as a cause of death from cancer, and the mortality rate is similar to the number of newly detected cases. Due to the late diagnosis, only 5-6% of patients with pancreatic cancer survive for five years. Given that early diagnosis is critical for improving patients' survival rates, there is an urgent need for the discovery and validation of new biomarkers with sufficient sensitivity and specificity to help diagnose pancreatic cancer early. Detection of serum tumor markers (CA19-9, CEA, CA125 and CA242) is conducive to the early diagnosis of pancreatic cancer. The combination of miR-16, miR-196a and CA19-9 plasma level was more effective, especially in early tumor screening. Furthermore, recent studies reported that mainly miR-21, miR-155 and miR-196 were dysregulated in IPMN (intraductal papillary mucinous neoplasms) and PanIN (pancreatic intraepithelial neoplasia) lesions, suggesting their usefulness as early biomarkers of these diseases. The reduced rate of apoptosis plays a crucial role in carcinogenesis, and it is one of the most important characteristics acquired by pancreatic cancer cells, which protects them from attack by the immune system and reduces the effectiveness of pharmacological treatment. This review summarizes the data concerning the clinical utility of selected biomarkers in pancreatic cancer patients. The review mainly focuses on the genetic aspects of signaling pathway disorders associated with apoptosis in the pathogenesis and diagnosis of pancreatic cancer.

Dysregulation of signaling pathways associated with innate antibacterial immunity in patients with pancreatic cancer.

Disorders of innate antibacterial response are of fundamental importance in the development of gastrointestinal cancers, including pancreatic cancer. Multi-regulatory properties of the Toll-like receptors (TLRs) (e.g., regulation of proliferation, the activity of NF-κB, gene transcription of apoptosis proteins, regulation of angiogenesis, HIF-1α protein expression) are used in experimental studies to better understand the pathogenesis of pancreatic cancer, for early diagnosis, and for more effective therapeutic intervention. There are known numerous examples of TLR agonists (e.g., TLR2/5 ligands, TLR6, TLR9) of antitumor effect. The direction of these studies is promising, but a small number of them does not allow for an accurate assessment of the impact of TLR expression disorders, proteins of these signaling pathways, or attempts to block or stimulate them, on the results of treatment of pancreatic cancer patients. It is known, however, that the expression disorders of proteins of innate antibacterial response signaling pathways occur not only in tumor tissue but also in peripheral blood leukocytes of pancreatic cancer patients (e.g., increased expression of TLR4, NOD1, TRAF6), which is one of the most important factors facilitating further tumor development. This review mainly focuses on the genetic aspects of signaling pathway disorders associated with innate antibacterial response in the pathogenesis and diagnosis of pancreatic cancer.

Innate immunity gene expression changes in critically ill patients with sepsis and disease-related malnutrition.

The aim of this study was an attempt to determine whether the expression of genes involved in innate antibacterial response (TL R2, NOD 1, TRAF6, HMGB 1 and Hsp70) in peripheral blood leukocytes in critically ill patients, may undergo significant changes depending on the severity of the infection and the degree of malnutrition. The study was performed in a group of 128 patients with infections treated in the intensive care and surgical ward. In 103/80.5% of patients, infections had a severe course (sepsis, severe sepsis, septic shock, mechanical ventilation of the lungs). Clinical monitoring included diagnosis of severe infection (according to the criteria of the ACC P/SCC M), assessment of severity of the patient condition and risk of death (APACHE II and SAPS II), nutritional assessment (NRS 2002 and SGA scales) and the observation of the early results of treatment. Gene expression at the mRNA level was analyzed by real-time PCR. The results of the present study indicate that in critically ill patients treated in the IC U there are significant disturbances in the expression of genes associated with innate antimicrobial immunity, which may have a significant impact on the clinical outcome. The expression of these genes varies depending on the severity of the patient condition, severity of infection and nutritional status. Expression disorders of genes belonging to innate antimicrobial immunity should be diagnosed as early as possible, monitored during the treatment and taken into account during early therapeutic treatment (including early nutrition to support the functions of immune cells).

Host response, obesity, and oral health.

Proper food choices are part of preventing or reducing the risk of dental caries and periodontal disease. A significant association has been proven between oral diseases and the incidence of systemic diseases. Obesity, just like smoking, is one of the major risk factors for oral disease and is a serious social problem that has reached epidemic proportions in many developed countries. The results of studies on periodontitis confirm the relationship between the values of body mass index (BMI) and the prevalence of periodontal diseases. Adipose tissue is an active endocrine organ and it performs many important functions in the body, such as thermal isolation and protection, storage, and secretion. Many cytokines are secreted proportionally to the amount of fat present and are actively involved in the metabolism of the whole system, including the functioning of the immune system. Therefore, obesity may alter the response of the host to the antigens derived from bacterial plaque, and thus cause disturbances in the inflammatory response in the course of periodontal disease.

Current views on the mechanisms of immune responses to trauma and infection.

According to the World Health Organization, post-traumatic mortality rates are still very high and show an increasing tendency. Disorders of innate immune response that may increase the risk of serious complications play a key role in the immunological system response to trauma and infection. The mechanism of these disorders is multifactorial and is still poorly understood. The changing concepts of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) early inflammatory response, presented in this work, have been extended to genetic studies. Overexpression of genes and increased production of immune response mediators are among the main causes of multiple organ dysfunction syndrome (MODS). Changes in gene expression detected early after injury precede the occurrence of subsequent complications with a typical clinical picture. Rapid depletion of energy resources leads to immunosuppression and persistent inflammation and immune suppression catabolism syndrome (PICS). Early diagnosis of immune disorders and appropriate nutritional therapy can significantly reduce the incidence of complications, length of hospital stay, and mortality. The study presents the development of knowledge and current views explaining the mechanisms of the immune response to trauma and infection.

Host response, malnutrition and oral diseases. Part 1.

Effective defense response of the body requires the proper nutritional and metabolic preparation and adequate energy expenditure. Every pathological process with coexisting malnutrition is subject to an increased risk of failure and complications in medical treatment, which is a serious threat to human health and life. Malnutrition, particularly protein-calorie malnutrition, is characterized by a decrease in resistance, particularly involving cellular immune deficiency, which in turn causes a significant decrease in resistance to infections. Inflammation is the price that the organism has to pay for the effective antimicrobial defense. Therefore, uncontrolled changes may occur in the immune system in nutrition disorders, especially in a significant protein-calorie malnutrition, which in turn prevents the correct response to microbial infection, including bacterial infection, which occurs in the course of periodontitis or untreated caries disease. Research determining the relationship between the clinical state of oral health, selected immune parameters and indicators of nutritional status of the organism, is an alternative to other attempts undertaken to reduce these risks.

Host response, malnutrition and oral diseases. Part 2.

Acute phase proteins enhance antioxidant defenses; they are involved in the activation of complement components, opsonization and increase in platelet aggregation as well as inhibition of the respiratory burst in the course of inflammation. Malnutrition plays an important role in the course of response of acute phase proteins. The role of nutrients as antioxidants or as key components of antioxidant enzymes is commonly known. In the course of various inflammatory states, including oral diseases, disorders are observed in caloric requirements of the organism and the requirements for specific amino acids. Numerous experimental studies in animals have also confirmed the relationship between protein- calorie malnutrition and hypofunction of the salivary glands. Studies in children with malnutrition syndrome showed a significantly lower volume of saliva compared to properly nourished children. Depleted nutritional reserves due to long-term chronic malnutrition cause a significant reduction in resistance, progressive damage to the oral mucosa, and reduce resistance to colonization and invasion of pathogenic microorganisms.