Multifunctional artificial saliva preparation – challenges and needs

Saliva plays a crucial role in maintaining homeostasis not only within the oral cavity but also in further sections of the gastrointestinal tract. Pleiotropic properties of saliva include participation in the digestion of carbohydrates, cleansing and moisturizing the oral cavity, and maintaining the composition of the oral microbiome. The result of impaired function of the salivary gland is reduced salivation – hyposalivation, leading to dry mouth – xerostomia. It is established that numerous physiological factors (age, sex, weight change) and pathological factors (polytherapy, head and neck cancer, coexisting diseases such as diabetes, depression, cardiovascular diseases) lead to the reduction in saliva secretion, and in effect, causing a dry mouth. Treatment of salivary secretion disorders involves pharmacological therapy (including hormone therapy) or replacement therapy which based on the use of saliva substitutes. In the case of disturbances in the secretion of natural saliva, the application of the artificial saliva preparations should support the chewing processes, moisturize the oral cavity, and fulfill the biological functions of saliva. However, to date, on the pharmaceutical market, there are no saliva substitutes that meet the biological criteria and maintaining favorable physicochemical properties and rheological parameters. Taking into account the problems of the patients which are burden by impaired salivary secretion, the aim of our research was to attempt to develop an artificial saliva preparation that reflecting as much as possible the properties of natural saliva, both in terms of mechanical and biological properties. As part of the research, the chemical composition was developed and a detailed study of the physicochemical and rheological parameters of artificial saliva preparations containing mucins as well as their microbiological and biocompatibility assessment, at in vitro level were carried out.

Strategies to improve the safety profile of CAR-T therapy

The chimeric antigen receptor (CAR) technology has become one of the greatest breakthroughs in immunotherapy in recent years. CARs facilitate the attack of immune effector cells such as T cells or NK cells being directed at virtually any molecule presented on the surface of a cancer cell. The exceptional efficacy of CAR receptors has been demonstrated for the CD19 molecule found on B cell-derived tumors. However, the efficacy of CAR-T therapy targeting other antigens is less satisfactory while being quite frequently associated with a number of adverse effects. The adverse effects are mainly due to the effector cells being activated in a simplified manner; the most serious effect consists in the antigen being detected on healthy cells (“the on-target, off-tumor” effect). A number of ongoing studies aim at enhancing the safety profile of therapies making use of CAR--modified effector cells. In part, this can be achieved by optimizing the structure of the CAR receptor itself or by using transient transfection to modify the effector cells. A more complex solution consists in obtaining remote control over CAR-T lymphocytes within the patient’s body. This approach makes use of different types of systems that limit the functionality of CAR-T cells in the patient, such as suicide genes, regulation at the transcriptional and protein levels, different types of adapters being used to activate the CAR-T cells. The most advanced system consists in the use of logic gates which make it possible for CAR-T cells to recognize and „understand” incoming signals from the environment, allowing for a certain degree of autonomy in the activation of the cells’ cytotoxic potential. This study presents key strategies to improve the safety profiles of CAR-T therapies.

The influence of iron availability on the structural changes of skeletal muscle cells and cardiac muscle cells

In the presented study, the influence iron availability on the cell morphology and structure was examined in skeletal myocytes cultured under normoxic and hypoxic conditions. The study showed that iron deficiency in vitro (especially in combination with hypoxia) has a detrimental effect on skeletal myocytes. Cellular disfunction was manifested by atrophic changes in cell morphology, structural remodeling of cells and increased expression of muscle atrophy markers. Interestingly, increased iron availability appeared to have some protective properties in the context of aforementioned changes. Moreover, based on clinical data and recent transgenic models, structural and functional abnormalities in iron-deficient cardiac muscle were described and the potential pathomechanisms behind them have been discussed.

The use of population modeling to optimize dosing of drugs used in anaesthesiology and intensive care

Effective pharmacotherapy requires an adequate drug dose that maximizes the effectiveness of therapy while minimizing adverse effects. Difficulties in dose selection arise from interindividual differences in drug pharmacokinetics and pharmacodynamics. Population modeling describes pharmacokinetic and pharmacodynamic processes in a population, taking into account the relationships in each patient, differences between patients, and the influence of covariates on drug pharmacokinetics and pharmacodynamics. The aim of this study was to develop population models for drugs used in anesthesiology and intensive care in special patient populations. The pharmacokinetics of sufentanil was described in infants and children after epidural and intravenous administration. The estimated absorption rate constant from the epidural space suggests slow systemic absorption of sufentanil and the possibility of flip-flop kinetics, which results in a slower decline in plasma concentrations at the end of drug administration compared with intravenous administration. The dependence of metabolic clearance on body weight and age was also demonstrated. A population model for the pharmacokinetics of tigecycline was developed for patients with sepsis or septic shock. No relationship between pharmacokinetic parameters and patient characteristics was detected, and the estimated interindividual and inter-occasion variability for clearance was small. This suggests that a universal dose is sufficient to achieve homogeneous drug exposure in critically ill patients. The pharmacokinetics of caspofungin was described in critically ill patients. The clearance and volume of central compartment showed systematic increase over time that was not explained by the covariates. The estimated increase in clearance values for three consecutive doses results in a clinically relevant reduction in drug exposure. The developed population models extend the knowledge of the pharmacokinetics of sufentanyl, tigecycline, and caspofungin. Simulations based on these models can aid the dosing decision-making process.

Risk factors of colorectal cancer after screening colonoscopy

In the era of populational screening programs for colorectal cancer, evaluation of their quality and efficacy becomes an important issue. One of the main criteria taken into account when assessing the quality of a screening program is related to the risk of colorectal cancer developing in the period between the screening colonoscopy and the control examination. The objective of this article consists in presenting the results of the doctoral research carried out by dr. Paulina Wieszcza, a beneficient of the Polpharma Scientific Foundation scholarship. The objective of the doctoral dissertation was to investigate and discuss the relationship between the definition of risk groups as well as the quality of the study and the risk of colorectal cancer developing after the screening colonoscopy. The risk of colorectal cancer developing following adenomas being removed during the screening colonoscopy procedure was assessed using data obtained from the Colorectal Cancer Screening Program and the National Cancer Registry databases. The quality of the study was assessed on the basis of literature evidence regarding the adenoma detection rates (ADR). A total of 236.089 patients were included in colorectal cancer risk analyses, with at least one adenoma being detected in a screening study in 17.7% of cases. Over the follow-up period (median of 7 years, maximum duration of 14 years), colorectal cancer was detected in 439 patients. It was demonstrated that when the high-risk group was defined as patients presenting with adenomas ≥ 20 mm in diameter or high grade dysplasia rather than patients with ≥ 3 adenomas or adenomas ≥10 mm in diameter with high grade dysplasia or villous component (current definition), the number of patients requiring intensive surveillance can be reduced by 74% without any impact on the risk in the low-risk group. The literature review revealed a total of three studies which clearly showed that the risk of colorectal cancer significantly decreased with the increase in the endoscopist’s ADR. Restricting the high-risk group to patients with adenomas ≥ 20 mm in diameter or high-grade dysplasia facilitates optimized care being delivered to patients with a significantly increased risk of colorectal cancer. Scientific evidence is available for the important role of endoscopist’s ADR as the key parameter of the quality of colonoscopic examination.

The impact of compliance with Enhanced Recovery After Surgery (ERAS) protocol on short and long-term outcomes in patients after laparoscopic colorectal cancer surgery

Patients undergoing surgery for colorectal cancer are a special group of patients. Not only performed resections are extensive, but also the underlying disease significantly depletes regenerative capacities of the body. It is well known that every surgical procedure is associated with an injury, the size of which is proportional to the type and extent of the intervention. The size of surgical trauma in postoperative period is proportional to the increase in insulin resistance which delays convalescence and increases the risk of postoperative complications. Hence, for several years, a specific program had been developed and introduced to reduce trauma associated with the surgery and its adverse consequences. The use of a modern multimodal care protocol for Enhanced Recovery After Surgery(ERAS) served this purpose. The aim of the study was to determine the impact of compliance to ERAS protocol on short-term results in a group of patients operated for colorectal cancer. In the next stage, it was checked whether it is possible to maintain high compliance of the protocol for a long time. Finally, I tried to determine the relationship between the compliance and distant oncological results. Consecutive patients with colon or rectal cancer undergoing laparoscopic resection were included in the study. In all patients the 16-item ERAS protocol was applied. The use of ERAS protocol improves short-term results: accelerates convalescence, reduces morbidity and reduces the length of hospital stay. However, its impact on short-term results correlates with the level of protocol implementation. The higher compliance with the protocol, the better the short-term results. Maintaining a high level of implementation of the protocol is possible despite the slight decrease over time. However, this has no adverse effect on short-term results. The compliance with ERAS protocol seems to also affect long-term results. Low compliance with ERAS protocol, along with the higher stage of cancer and postoperative complications, is an independent factor worsening long-term survival.

Metabolomic profiling of acute diabetes complications in children with type 1 diabetes mellitus

Acute type 1 diabetes mellitus (T1DM) complications – diabetes ketoacidosis (DKA) and hypoglycemia (HG) – are dangerous not only as a threat to patients’ life but also because of their long-term sequelae. Aim: Evaluation of serum metabolic changes caused by episode of DKA and HG, that can be detected despite restoring parameters typically changed during the episodes. Selection of putative long-standing biomarkers of past episodes of DKA and HG. Materials and methods: Four groups of children with T1DM were recruited: patients after episode of DKA and HG, children with established T1DM (EDM) and patients with newly diagnosed diabetes without diabetes ketoacidosis (NDM). Serum samples were collected in three group-specific time points (since the hospital admission): 0h – 24h – 72h for DKA and NDM group and 0h – 12h – 48h for HG group. From EDM patients only one sample was collected during running routine laboratory tests. Patients were assigned to two batches: DKA-NDM-EDM (N = 20x3, N = 10x3, N = 10) and HG-EDM- -NDM (N = 10x3, N = 25, N = 15x3). All patients within the batches were matched based on age and sex. Metabolic fingerprinting was performed with LC- -QTOF-MS (Agilent 6550 iFunnel). Results: In DKA batch after technical filtering 248 metabolomic features out of 712 (in positive ionization) and 295 out of 652 (in negative ionization) were suitable for between-group comparisons. Statistical analysis selected 22 metabolic features as putative biomarkers of episodes of DKA occurrence in nearest 72h. Decision tree to diagnose past DKA episode, based on two best metabolites, achieved sensitivity of 95% (CI (confidence interval): 81.79–99.13%) and specificity of 80% (CI: 67.30–88.81%). In HG batch after technical filtering 359 metabolomic features out of 1006 (in positive ionization) and 374 out of 763 (in negative ionization) were suitable for between-group comparisons. Statistical analysis selected 9 metabolic features as putative biomarkers of episodes of DKA occurrence in nearest 48h. Decision tree to diagnose past HG episode, based on two best metabolites, achieved sensitivity of 90% (CI: 72.32–97.38%) and specificity 80% (CI: 68.39–88.26%). Conclusions: Metabolic disturbances caused by DKA may be traced in serum up to 72h after the episode and for hypoglycemia up to 48h.

Crosstalk between TGF-β1 signalling pathway and microRNAs in renal cancer

Alterations in TGF-β1 signalling in renal cancer are accompanied by disturbed expression of microRNAs (miRNAs). TGF-β1 is an important regulator of key cellular processes and contributes to the development of many diseases, including cancer. At early cancer stages, TGF-β1 inhibits proliferation and tumour growth, while as the disease progresses, TGF-β1 stimulates metastasis. This dual TGF-β1 effect in cancers is called the “TGF-β1 paradox”. miRNAs – small, noncoding RNAs which regulate genes expression may contribute to the switching of TGF-β1 from suppressor to oncogenic function. The article presents the latest information regarding mutual regulation between miRNAs and the TGF-β1 signalling pathway as well as its potential role in the treatment of kidney cancer.

The TLRs and IFNs in patients with connective tissue diseases

Autoimmune connective tissue diseases (ACTD) are characterized by spontaneous stimulation of the immune system and the production of autoantibodies. Some autoantibodies may create an immune complex with DNA and/or RNA and promote tissue inflammation. Immune complexes that contain nucleic acids can act as ligands for endosomal Toll-like receptors (TLR), which activation induces secretion of the type I and type III interferons. The present study aimed to determine whether TLRs and IFNs genes could be considered as potential ACTD biomarkers. IFN-A and IFN-G showed a relationship with a predisposition to the development of SLE and MCTD, and IFN-B with a predisposition to the development of SLE. The TLR7 rs5743305 T allele and rs5743316 A allele may play a protective role against the development of MCTD, and the TLR7 rs1731479 T allele and TLR8 rs17256081 C allele may be predictors of MCTD development. mRNA expression of the IFN-α, IFN-β, IFN-γ, TLR3, TLR8 and TLR7 was significantly higher in patients with SLE compared to patients with MCTD and SSc. MCTD patients with anti-U1-70k (+) had higher IFN-γ and lower IFN-β serum levels than patients without this antibody. In patients with SLE, serum levels of IFN-α and IFN-γ correlate with the concentration of complement components, and serum levels of IFN-α with disease activity. The study confirmed that the TLR-IFN pathway may be considered as an important pathogenic mechanism for ACTD.

The role of the endothelium in selected diseases of the cardiovascular system

In recent years, the role of endothelial function assessment in the recognition of preclinical forms of cardiovascular disease has increased. At the same time, there are tools to assess endothelial function that are fully objective and automated, which significantly affects the ease of assessment. It seems that they can displace the most commonly used method of measuring endothelial function, which is dilatation of the artery in response to ischemia. In addition to the diagnostic value, the improvement of endothelial function may be the goal of treatment of patients with known cardiovascular diseases. The beneficial effect of physical activity in patients after ST segment elevation myocardial infarction on endothelial function has been demonstrated. Patients with more severe, baseline endothelial diffusion experienced the greatest benefits. Similarly, a positive effect of beta-blockers on endothelial function has been demonstrated. Other antihypertensive drugs also have this effect. Endothelial dysfunction also affects the occurrence of arrhythmias, including atrial fibrillation. However, it has been shown that the longer duration of the arrhythmia episode decreases the degree of endothelial dysfunction as assessed by measuring serum biomarkers’ levels. The situation may be related to the adaptation of the body to the occurrence of arrhythmias.