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Nanomedicine has emerged as a novel cancer treatment and diagnostic modality, whose design constantly evolves towards increasing the safety and efficacy of the chemotherapeutic and diagnostic protocols. Molecular diagnostics, which create a great amount of data related to the unique molecular signatures of each tumor subtype, have emerged as an important tool for detailed profiling of tumors. They provide an opportunity to develop targeting agents for early detection and diagnosis, and to select the most effective combinatorial treatment options. Alongside, the design of the nanoscale carriers needs to cope with novel trends of molecular screening. Also, multiple targeting ligands needed for robust and specific interactions with the targeted cell populations have to be introduced, which should result in substantial improvements in safety and efficacy of the cancer treatment. This article will focus on novel design strategies for nanoscale drug delivery systems, based on the unique molecular signatures of myeloid leukemia and EGFR/CD44-positive solid tumors, and the impact of novel discoveries in molecular tumor profiles on future chemotherapeutic protocols.

Cervical cancer (CCa) is one of the most common malign diseases in women associated with human papillomavirus (HPV). The virus is an initiating factor, but not sufficient for the development of cervical intraepithelial lesions (CIN) and CCa. The disease might be a result of the influence of host's genetic factors and polymorphisms in inflammatory-related genes that modify the immune response to HPV and attribute to cancer susceptibility. We carried out a study to determine the association between TNF-a-238G/A and TNF-a-308 G/T polymorphisms with HPV-positive CIN and CCa in women living in the Republic of North Macedonia. Using multiplex SNaPshot analysis for single nucleotide polymorphisms (SNPs), we analysed the genotype and allele distributions of TNF-a-238G/A and TNF-a-308 G/T in 134 cases (HPV-positive and histologically confirmed CIN and CCa) and in 113 controls (cytological and HPV-negative women). For further analysis, the case group was stratified in three subgroups (all cases: CINs+ CCa- group; CIN2+ -group and CIN1- group). Data analysed using the odds ratio (OR) and chi-square test showed the frequency of AA genotypes and A alleles are not significantly higher in cases compared to the controls for both SNPs: AA of TNF-a-238 (0.7% versus 0%) and TNF-a-308 (1.5% versus 0.9%) as well as A allelic frequency (3.0% versus 1.7%) and (13.1% versus 10.6), respectively. The comparison of the case's subgroups with the control group did not show a statistically significant difference. Compared to controls, TNF-a-238G/A and TNF-a-308 G/T are not associated with the risk of HPV associated CIN or CCa in the studied women.

BACKGROUND:: There is a growing interest in the possible role of inflammatory biomarkers, such as interleukins, chemokines, growth factors, and acute-phase proteins, in cardiovascular risk-stratification. AIM: The aim of the study was to determine a possible correlation between the subjects’ cardiovascular risk profile and various inflammatory markers and to assess the sole use of IL-6 in CVD risk prediction. MATERIALS AND METHODS: Seventy-five healthy subjects participated. EUROSCORE, lipid, glycemic, and inflammatory markers were analyzed. Сhi-square test, t-test, one-way ANOVA, Mann–Whitney, and Kruskal–Wallis tests were used. Significance was determined at 1 pg/ml were positively correlated with female gender, age > 55 years, EUROSCORE ≥ 3, risk age, SBP, hsCRP > 2 mg/L, and IL-2 (p = 0.025, p = 0.013, p = 0.025, p = 0.011, p = 0.026, p = 0.046, and p = 0.018). Except for total CVD risk and risk age, the same variables were identified to be independently associated with IL-6. CONCLUSION: Inflammatory biomarkers, especially hsCRP and IL-6, have a statistically significant, added predictive power in cardiovascular risk stratification.

The aim of the study was to get detailed insight into the antibiotic consumption trends in the three year period (2016-2018) in Kocani Hospital, to identify the most often prescribed antibiotics and to determine whether the treatment of given diagnosis was in accordance with the official guidelines. The survey covered all pediatric and infant patients admitted to the pediatric ward. Patients’ data included gender, age, diagnosis, antibiotic used and doses. The majority of admitted patients were in the age group of 0-1 (27.48%, 25.94% and 30.77% for 2016, 2017 and 2018, accordingly) followed by age group of 1-2 years (20.86%, 22,0% and 23.83% for 2016, 2017 and 2018, consequently) and 2-3 years (16.06%, 16.1% and 14.63% for 2016, 2017 and 2018, consequently) .The most frequent diagnosis was acute tonsillitis which was determined in ~21% of patients, pneumonia without complications in ~18% and acute bronchitis in ~16% of patients in the period 2016-2018. Results from conducted survey identified high prescription rate and use of antibiotics predominantly ceftriaxone (82.58%, 81.05% and 50.85% in 2016, 2017 and 2018, respectively) contrary to official recommendations and evidences based on clinical data for treatment of the diagnoses in question. So, it is foreseeable to conclude that there is urgent need for restrictive and educational measures i.e. to strength the surveillance and monitoring of antibiotic prescription and usage and hence to promote awareness for rational use of antibiotics on all health-care levels. Key words: antibiotic prescription, antibiotic consumption, pediatric wards, annual report

Airway infections are a key component of cystic fibrosis (CF) lung disease. The approach to common pathogens such as Pseudomonas aeruginosa or Staphilococcus aureus is guided by a significant evidence base, but the treatment of other infections is significant challenge to pharmacotherapy teams. Here we present a specific approach to treatment of chronic infections with non-tuberculous mycobacteria (NTM) anaerobic bacteria and fungi in a 25 year old patient with CF and severely decreased lung function. Also, allergic bronchopulmonary aspegillosis (ABPA) was diagnosed in the patient. Key words: cystic fibrosis, non-tuberculous mycobacteria, allergic bronchopulmonary aspegillosis, antibiotics, systemic steroids

Recent advances in understanding the etiology and pathogenesis of periodontal disease and polymicrobial synergy in the dysbiotic oral microbial community endorsed novel therapeutic targets and assured further improvement in periodontal disease treatment. Moreover, understanding of the events at the molecular level inspired the researchers to alleviate the stress from the disease by applying the bottom-up approach and delivering the drugs at the site of action, using nanoscale medicines. This review is focused on promising strategies for rational design of nanopaharmaceuticals for periodontal disease treatment based on novel therapeutic targets and the potential of advanced concepts for inflammation cascade targeting. Due to their size, nanomedicines are capable to interact with the elements of the immune system through cell receptor binding and to subsequently influence specific intracellular signaling pathways activation. They might also interfere with different signaling molecules continuously involved in the disease progression, in order to abolish cell activation and block the production of proinflammatory substances. Different biomacromolecules can be trafficked to the site of action using nanomedicines for gene targeting: i) decoy oligodeoxynucleotide (ODN) for suppression of NF-κB transcription activity, ii) DNA therapeutics for modulation of cell inflammatory response and iii) siRNA for cytokine production silencing. However, despite the potential of the nanotechnology for improvement of periodontal disease treatment, the translation of nano-drug delivery systems to clinical therapy is hindered by the lack of standard procedures for proper safety and efficacy profile evaluation.

Hyperphosphatemia (HP) in patients with chronic kidney disease (CKD) leads to complications such as renal osteodistrophy, cardiovascular calcification and hemodynamic abnormalities, all of them having a serious impact on the survival rate and quality of life. Also, HP is a key pathogenic factor in the development of secondary hyperparathyroidism (SHPT) in CKD. Having in regard the significance of controlling serum phosphorus levels (Pi), in this paper, the needs and obstacles to successful pharmacological management of HP in CKD are presented, with an overview of major classes of phosphate binders (PBs) and other drugs affecting Pi level, such as active vitamin D sterols and calcimimetics (CMs). In addition, their effects on progression of cardiovascular calcification and bone health are elaborated. In this regard, a PubMed search was carried out to capture all abstracts and articles relevant to the topic of CKD, HP and mineral metabolism, bone disorders and vascular/valvular calcification (VC), published from January 2007 to August 2017. The search was limited to English language, with the search terms including drug name AND hyperphosphatemia or cardiovascular calcification or bone disorder. Comparative studies, clinical studies/trials and meta-analyses related to different classes/representatives of PBs, vitamin D analogues and CMs were reviewed and research data related to their efficacy and safety compared. Keywords: chronic kidney disease, hyperphosphatemia, phosphate binders, active vitamin D sterols, calcimimetics, bone disorders, cardiovascular calcification

Herein synchronous occurrence of Hodgkin lymphoma and secondary myelodysplastic syndrome in a 60 year old male patient with small cell lung cancer treated with combined chemotherapy (carboplatin and paclitaxel) and radiotherapy is presented. The objective of this report is to stress the importance of documenting and monitoring adverse drug reactions that arise from chemotherapy. After four years of treatment with the combined chemotherapy, the patient presented inguinal lymphadenopathy and enlarged lymph nodes and histopathology rapport was suggestive for plasmacytoid variant of Castleman disease. Three years later, biopsy of lymph node was performed and diagnosis of Hodgkin lymphoma – mixed cellularity has been established. Molecular analyses revealed presence of dominant monoclonal population of the immunoglobulin genes in the oligo/monoclonal background. Bone marrow biopsy findings suggested secondary myelodysplasia and revealed signs of hematopoietic cells dismaturation with signs of megaloblastic maturation of the erytropoetic lineage, appearance of ALIP (abnormal localization of immature precursors) in the myeloid lineage and dysplastic megakaryocytes. In addition, an increased level of polyclonal plasmacytes (lambda vs kappa was 60%:40%) was found. Hodgkin lymphoma and MDS occurring after 4 years of carboplatin/paclitaxel therapy might be contributed to the accumulation of alkylator-related DNA damage. This emphasize the need of outlining a monitoring plan regarding development of secondary leukemia and other malignant hematological proliferations should be outlined in the protocols.

Probiotics, prebiotics, and synbiotics are functional components able to exert positive effects on human health. Numerous medical conditions lack effective and safe approaches for prevention or treatment, thus usage of probiotics, prebiotics, and synbiotics is an alternative. Further, the benefit related to the consumption of these compounds is associated with lower morbidity of chronic diseases and reduced health-care costs. Various types of mediums to deliver probiotics/synbiotics to the human GIT are used. Although capsules and tablets are frequently applied as delivery systems for probiotics, the major challenge of the commercial sector is to market new functional foods containing probiotics and/or prebiotics. Discovering of new probiotic/synbiotic functional foods is connected to the interest of the food industry to revitalize continuously through introduction of products with improved nutritional value and pleasant taste, but also with health benefit for the consumers. The review provides insights and new perspectives in respect to usage of functional components and foods in prevention and treatment of inflammatory bowel diseases (IBD) that are highly correlated with the modern lifestyle. The therapeutic and safety properties of probiotics and prebiotics, their role in pathogenesis of IBD, potential to prevent and treat these diseases as well as postulated mechanisms of action will be discussed, highlighting the main areas in which further research is an emergence.

Possible synergistic effect of tamoxifen (2 μM) and hydrazinyldiene-chroman-2,4-diones (10-100 μM) was examined with an aim to create more effective treatment for ER+ breast cancer. Anti-breast cancer effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells using MTT and alamarBlue assays. Cell viability was evaluated after 48h-treatment and the ICs50 of the coumarin derivatives were determined. The apoptotic effect was evaluated by detection of PARP cleavage and reduced activity of the survival kinase Akt. The results demonstrated dose-dependent activity, with a percent of growth inhibition after combination treatment being significantly higher (53% to 79%, 10 μM and 100 μM, respectively) than the one in the cell lines treated with tamoxifen (29% to 37%) and the synthesized coumarin derivatives alone (11% to 68%, 10 μM and 100 μM, respectively). The ICs50 of the synthesized compounds significantly decreased in synergy with tamoxifen (33% to 51%). Coumarin derivative having thiazole moiety with additional methyl groups attached to the carbons at positions 5 and 4 in the thiazole ring showed to be the most potent, with IC50 20 µM when administered alone and 10 µM in synergy with tamoxifen. The levels of phospho-Thr308 Akt were down-regulated by the combination treatment, pointing to tyrosine kinase phosphorylation inhibition. In conclusion, the novel coumarin derivatives enhance the activity of tamoxifen and this combination may be suitable for prevention of ER+ breast cancer or development of related compounds. Further studies are needed to elucidate precisely the type of receptor involved in the activity and the mechanism of action.

Background: Elevated lipoprotein (a) [Lp(a)] is an independent risk factor for coronary artery disease (CAD). However, there is little evidence about the therapeutic efficacy of different lipid-lowering agents in reducing Lp(a). Objective: The primary objective of our study was to test the effect of different therapeutic treatment strategies on elevated Lp(a) levels, specifically to compare rosuvastatin versus atorvastatin alone or in combination with niacin or fibrates. The secondary objective was to analyze the occurrence of potential adverse effects. Methods: It was a prospective, single-center, interventional study. Patients with CAD, or high CAD risk, with increased Lp(a), >50 mg/dL, were included in the study. Lp(a), total cholesterol (C), triglycerides (TGs), high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1, Apo B, and enzymes of myocyte and hepatic injury were comparatively analyzed between 4 lipid-lowering treatment strategies: rosuvastatin (R group) 40 mg, atorvastatin (A group) 80 mg, atorvastatin 40 mg add-on micronized fenofibrate (A+F group), and atorvastatin 40 mg add-on 1 g extended-release niacin (A+ERN group). Comparison was made for their lipid lowering therapeutic efficacy, primarily on Lp(a), and their safety profile. Results: A total of 87 patients, 61 ± 12 years old, were analyzed. The main risk factors were obesity (64.7%) and hypertension (64.6%). Men were more often smokers (odds ratio [OR] = 5.1) and had CAD (OR = 2.8), but lower total C (206.9 ± 32.9 vs 238.6 ± 47.9 mg/dL, P = 0.002) and LDL-C (136.5 ± 18.2 vs 160.9 ± 30.9 mg/dL, P = 0.000). Mean Lp(a) was 94.6 ± 39.6 mg/dL, without significant gender difference. There were 25 patients in the R group, 22 in the A group, and 20 each in the A+F and A+ERN groups. Significant reduction in all lipid fractions in all treatment groups was reported after 6 months. The average reduction of Lp(a) was 15.9 ± 21.0 mg/dL, with 18.2 ± 24.8 (P = 0.001) in the R group and similar values in the A+F and A+ERN groups (17.3 ± 10.4, P = 0.001, and 19.5 ± 10.9, P = 0.001, respectively), and the lowest in the A group (11.24 ± 22.91, P = 0.032). No adverse effects were observed in any of the treatment groups. Conclusions: When compared with atorvastatin, it seems that rosuvastatin can achieve a statistically more significant decrease of Lp(a). The efficacy of atorvastatin on the Lp(a) optimization can be increased by adding either fibrate or ERN. Given in recommended doses, all agents were well tolerated.

The term colitis describes variety of inflammatory diseases of the colon which can be differentiated according to their etiology, clinical, endoscopic and histological characteristics. In general, they can be classified as inflammatory bowel diseases (IBD) and infectious colitis (Hemstreet & Diprio, 2008; Novaneethan & Giannella, 2011), and non-IBD and non-infectious colitis, including ischemic colitis, chemical colitis, microscopic colitis, segmental colitis, radiation colitis, diversion colitis, eosinophilic colitis and Behcet’s colitis (Koutroubakis, 2008). The two forms of idiopathic IBD, ulcerative colitis (UC), a mucosal inflammatory condition restricted to the rectum and colon, and Crohn’s disease (CD), a transmural inflammation of the GIT affecting any part from the mouth to anus, are the most prevalent, especially in the western countries and in areas of northern latitude. Other forms, such as diversion colitis, eosinophilic colitis and Behcet’s colitis are rare, with unknown ethiopathogenesis and limited epidemiological data. Clinical presentation of all forms is very similar and includes mild, moderate or severe local complications, such as diarrhea, abdominal pain or cramping, rectal bleeding and weight loss, and systemic ones, including hepatobiliary, joint, ocular, renal, dermatologic and mucosal complications.