Hospital Acquired MRSA Penumonia

Background: Antibiotic resistance is a growing problem and particularly of concern in nosocomial infections. Nosocomial pneumonia occurs in 0.4—1.1% of hospitalized patients. It is the most common infection in intensive care units. Bacterial colonization of the upper airway followed by micro aspiration or macro inspiration into the lungs is considered the primary mechanism for development of nosocomial pneumonia. More than 90% of cases of nosocomial pneumonia are caused by bacteria, 15—30% represented with staphylococcus aureus. Following the data of a 4-year long period the resistance to methicillin was identified in ≈32% with a tendency of increasing percentage of MRSA isolates up to 35%, originated from samples taken among patients from ICU in the Clinical Center of Skopje

Prostate cancer theranostics using GRPR antagonist RM26

The malignant transformation of cells is often associated with an alteration of their molecular phenotype, resulting in overexpression of several cell surface proteins. Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are examples of such pro-teins that are expressed at a high density in prostate cancer. GRPR is primarily expressed in earlier stages of prostate cancer and tends to decrease with disease progression. This expression pattern indicates that GRPR could be a promising target for imaging and treatment of oligometa-static prostate cancer, an early step in prostate cancer progression characterized by limited meta-static spread. In contrast, the expression of PSMA increases with cancer progression and is significantly upregulated as tumors dedifferentiate into higher grade, in androgen-insensitive and metastatic lesions. This thesis is based on five original articles (papers I-V) and focuses on the preclinical de-velopment of radiotracers for imaging and treatment of prostate cancer. The work can be divided into three distinct parts: (1) the development and optimization of GRPR-antagonist RM26 for high contrast PET and SPECT imaging of oligometastatic prostate cancer (papers I-III), (2) the preclinical evaluation of 177Lu-labeled RM26 as a potential candidate for peptide receptor radionuclide therapy (PRRT) in GRPR-expressing tumors, alone or in combination with anti-HER2 antibody trastuzumab (paper IV), and (3) the development of a bispecific heterodimer targeting both PSMA and GRPR in prostate cancer (paper V). We have demonstrated that the in vitro and in vivo properties of GRPR antagonist RM26 are strongly influenced by the choice of chelator-radionuclide complex and that long-lived radionuclides are desirable for high-contrast imaging. Furthermore, our data indicate that 55Co-NOTA-PEG2-RM26 has remarkable potential for next-day high-contrast PET imaging of GRPR-expressing tumors. Experimental PRRT using 177Lu-DOTAGA-PEG2-RM26 resulted in a pronounced inhibition of tumor growth and a significantly longer median survival. Interestingly, survival was further improved when trastuzumab was co-injected with 177Lu-DOTAGA-PEG2-RM26. These data indicate that blocking HER2 with trastuzumab decreased the repairing ability of irradiated cells. Finally, we developed a heterodimer (NOTA-DUPA-RM26) for imaging GRPR and PSMA expression in prostate cancer shortly after administration. In conclusion, we have successfully developed and preclinically evaluated radioconjugates for GRPR-directed theranostics in oligometastatic prostate cancer using the bombesin antagonistic analog RM26

Prostate cancer theranostics using GRPR antagonist RM26

The malignant transformation of cells is often associated with an alteration of their molecular phenotype, resulting in overexpression of several cell surface proteins. Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are examples of such pro-teins that are expressed at a high density in prostate cancer. GRPR is primarily expressed in earlier stages of prostate cancer and tends to decrease with disease progression. This expression pattern indicates that GRPR could be a promising target for imaging and treatment of oligometa-static prostate cancer, an early step in prostate cancer progression characterized by limited meta-static spread. In contrast, the expression of PSMA increases with cancer progression and is significantly upregulated as tumors dedifferentiate into higher grade, in androgen-insensitive and metastatic lesions. This thesis is based on five original articles (papers I-V) and focuses on the preclinical de-velopment of radiotracers for imaging and treatment of prostate cancer. The work can be divided into three distinct parts: (1) the development and optimization of GRPR-antagonist RM26 for high contrast PET and SPECT imaging of oligometastatic prostate cancer (papers I-III), (2) the preclinical evaluation of 177Lu-labeled RM26 as a potential candidate for peptide receptor radionuclide therapy (PRRT) in GRPR-expressing tumors, alone or in combination with anti-HER2 antibody trastuzumab (paper IV), and (3) the development of a bispecific heterodimer targeting both PSMA and GRPR in prostate cancer (paper V). We have demonstrated that the in vitro and in vivo properties of GRPR antagonist RM26 are strongly influenced by the choice of chelator-radionuclide complex and that long-lived radionuclides are desirable for high-contrast imaging. Furthermore, our data indicate that 55Co-NOTA-PEG2-RM26 has remarkable potential for next-day high-contrast PET imaging of GRPR-expressing tumors. Experimental PRRT using 177Lu-DOTAGA-PEG2-RM26 resulted in a pronounced inhibition of tumor growth and a significantly longer median survival. Interestingly, survival was further improved when trastuzumab was co-injected with 177Lu-DOTAGA-PEG2-RM26. These data indicate that blocking HER2 with trastuzumab decreased the repairing ability of irradiated cells. Finally, we developed a heterodimer (NOTA-DUPA-RM26) for imaging GRPR and PSMA expression in prostate cancer shortly after administration. In conclusion, we have successfully developed and preclinically evaluated radioconjugates for GRPR-directed theranostics in oligometastatic prostate cancer using the bombesin antagonistic analog RM26

Research Regarding the Development of the Combustion Chamber of Internal Combustion Engines with Opposite Pistons

The reduction in environment pollutant emissions is one of the main challenges regarding ground transportation. Internal combustion engines, used especially in hybrid propulsion systems, may be a solution in the transition to fully electric cars. Therefore, more efficient engines in terms of fuel consumption, emission generation and power density must be developed. This paper presents research regarding the architecture of the combustion chamber of an internal combustion engine with opposed pistons. The aim of this research was to find a combustion chamber architecture that would enable the engine to perform close to the program target of: NOx < 3.5 g/kWh, smoke (FSN) < 1, specific fuel consumption (bsfc) < 198 g/kWh. Three variants of the combustion chamber’s architecture have been studied. After the experimental research, the conclusion was that none of them fully reached the target; however, significant improvements have been achieved compared with the starting point. As a result, further research needs to be carried out in order to reach and even exceed the target

Driver Drowsiness Multi-Method Detection for Vehicles with Autonomous Driving Functions

The article outlines various approaches to developing a fuzzy decision algorithm designed for monitoring and issuing warnings about driver drowsiness. This algorithm is based on analyzing EOG (electrooculography) signals and eye state images with the aim of preventing accidents. The drowsiness warning system comprises key components that learn about, analyze and make decisions regarding the driver’s alertness status. The outcomes of this analysis can then trigger warnings if the driver is identified as being in a drowsy state. Driver drowsiness is characterized by a gradual decline in attention to the road and traffic, diminishing driving skills and an increase in reaction time, all contributing to a higher risk of accidents. In cases where the driver does not respond to the warnings, the ADAS (advanced driver assistance systems) system should intervene, assuming control of the vehicle’s commands

Moderate Alcohol Consumption Increases the Risk of Clinical Relapse in Male Depressed Patients Treated with Serotonin-Norepinephrine Reuptake Inhibitors

Background: While depression can be associated with multiple comorbidities, the association between depression and liver injury significantly increases the mortality risk. The aim of this study was to evaluate if moderate alcohol intake affects the rate of clinical relapses in patients treated with antidepressants as monotherapy. Methods: We assessed, over a period of 30 months, the clinical records of 254 patients with depressive disorder, of either gender, without additional pathologies, receiving monotherapy treatment with antidepressants. Thirty-three patients with alcohol abuse, alcoholism or significant cognitive impairment were excluded. The medical and psychiatric history, medication and liver enzyme values were collected and analyzed. Results: Out of the 221 patients who met the inclusion criteria, 78 experienced relapses of depression. The rate of relapse did not correlate with the levels of liver enzymes. Alcohol consumption, as objectified based on GGT levels and the AST/ALT ratio, suggested that men had higher alcohol intake compared to women. Patients treated with serotonin-norepinephrine reuptake inhibitors (SNRIs) with elevated AST levels were approximately 9 times more likely to relapse, while the ones with elevated GGT had a 5.34 times higher risk. While GGT levels remained a marker for relapse in men with elevated GGT, ALT and not AST proved to be a better risk indicator for relapses in male patients. Conclusion: The use of SNRIs in depressed male patients with moderate alcohol intake should be carefully considered, as they might be susceptible to higher risks of relapse compared to alternative antidepressant therapies

Evaluation of Tumor-Targeting Properties of an Antagonistic Bombesin Analogue RM26 Conjugated with a Non-Residualizing Radioiodine Label Comparison with a Radiometal-Labelled Counterpart

Radiolabelled antagonistic bombesin analogues are successfully used for targeting of gastrin-releasing peptide receptors (GRPR) that are overexpressed in prostate cancer. Internalization of antagonistic bombesin analogues is slow. We hypothesized that the use of a non-residualizing radioiodine label might not affect the tumour uptake but would reduce the retention in normal organs, where radiopharmaceutical would be internalized. To test this hypothesis, tyrosine was conjugated via diethylene glycol linker to N-terminus of an antagonistic bombesin analogue RM26 to form Tyr-PEG(2)-RM26. [In-111]In-DOTA-PEG(2)-RM26 was used as a control with a residualizing label. Tyr-PEG(2)-RM26 was labelled with I-125 with 95% radiochemical purity and retained binding specificity to GRPR. The IC50 values for Tyr-PEG(2)-RM26 and DOTA-PEG(2)-RM26 were 1.7 +/- 0.3 nM and 3.3 +/- 0.5 nM, respectively. The cellular processing of [I-125]I-Tyr-PEG(2)-RM26 by PC-3 cells showed unusually fast internalization. Biodistribution showed that uptake in pancreas and tumour was GRPR-specific for both radioconjugates. Blood clearance of [I-125]I-Tyr-PEG(2)-RM26 was appreciably slower and activity accumulation in all organs was significantly higher than for [In-111]In-DOTA-PEG(2)-RM26. Tumor uptake of [In-111]In-DOTA-PEG(2)-RM26 was significantly higher than for [I-125]I-Tyr-PEG(2)-RM26, resulting in higher tumour-to-organ ratio for [In-111]In-DOTA-PEG(2)-RM26 at studied time points. Incorporation of amino acids with hydrophilic side-chains next to tyrosine might overcome the problems associated with the use of tyrosine as a prosthetic group for radioiodination