Targeting Burkitt Lymphoma with a Tumor Cell–specific Heptamethine Carbocyanine-cisplatin Conjugate

BACKGROUND: Burkitt lymphoma is a fast-growing mature B cell malignancy, whose genetic hallmark is translocation and activation of the c-myc gene. Prompt multiagent immunochemotherapy regimens can have favorable outcomes, but prognosis is poor in refractory or relapsed disease. We previously identified a novel family of near-infrared heptamethine carbocyanine fluorescent dyes (HMCD or DZ) with tumor-homing properties via organic anion-transporting peptides. These membrane carriers have uptake in tumor cells but not normal cells in cell culture, mouse and dog tumor models, patient-derived xenografts, and perfused kidney cancers in human patients. METHODS: Here we report the cytotoxic effects of a synthesized conjugate of DZ with cisplatin (CIS) on B cell lymphoma CA46, Daudi, Namalwa, Raji, and Ramos cell lines in cell culture and in xenograft tumor formation. Impaired mitochondrial membrane permeability was examined as the mechanism of DZ-CIS-induced lymphoma cell death. RESULTS: The new conjugate, DZ-CIS, is cytotoxic against Burkitt lymphoma cell lines and tumor models. DZ-CIS retains tumor-homing properties to mitochondrial and lysosomal compartments, does not accumulate in normal cells and tissues, and has no nephrotoxicity in mice. DZ-CIS accumulated in Burkitt lymphoma cells and tumors induces apoptosis and retards tumor cell growth in culture and xenograft tumor growth in mice. CONCLUSION: DZ-CIS downregulated c-myc and overcame CIS resistance in myc-driven TP53-mutated aggressive B cell Burkitt lymphoma. We propose that DZ-CIS could be used to treat relapsed/refractory aggressive Burkitt lymphomas

Nutritional Considerations of Cardiovascular Diseases and Treatments

Nutritional considerations of many chronic diseases are not fully understood or taken into consideration in everyday clinical practice. Therefore, it is not surprising that high proportion of hospitalized patients with cardiovascular diseases remains underdiagnosed with malnutrition. Malnourished patients have increased risk of poor clinical outcomes, complications rate, prolonged hospital stay, more frequent rehospitalizations, and lower quality of life. The purpose of this review is to recapitulate recent data on nutritional considerations in cardiovascular medicine

Targeting Burkitt Lymphoma with a Tumor Cell-specific Heptamethine Carbocyanine-cisplatin Conjugate

BACKGROUND: Burkitt lymphoma is a fast-growing mature B cell malignancy, whose genetic hallmark is translocation and activation of the c-myc gene. Prompt multiagent immunochemotherapy regimens can have favorable outcomes, but prognosis is poor in refractory or relapsed disease. We previously identified a novel family of near-infrared heptamethine carbocyanine fluorescent dyes (HMCD or DZ) with tumor-homing properties via organic anion-transporting peptides. These membrane carriers have uptake in tumor cells but not normal cells in cell culture, mouse and dog tumor models, patient-derived xenografts, and perfused kidney cancers in human patients. METHODS: Here we report the cytotoxic effects of a synthesized conjugate of DZ with cisplatin (CIS) on B cell lymphoma CA46, Daudi, Namalwa, Raji, and Ramos cell lines in cell culture and in xenograft tumor formation. Impaired mitochondrial membrane permeability was examined as the mechanism of DZ-CIS-induced lymphoma cell death. RESULTS: The new conjugate, DZ-CIS, is cytotoxic against Burkitt lymphoma cell lines and tumor models. DZ-CIS retains tumor-homing properties to mitochondrial and lysosomal compartments, does not accumulate in normal cells and tissues, and has no nephrotoxicity in mice. DZ-CIS accumulated in Burkitt lymphoma cells and tumors induces apoptosis and retards tumor cell growth in culture and xenograft tumor growth in mice. CONCLUSION: DZ-CIS downregulated c-myc and overcame CIS resistance in myc-driven TP53-mutated aggressive B cell Burkitt lymphoma. We propose that DZ-CIS could be used to treat relapsed/refractory aggressive Burkitt lymphomas

Spinal Cord Stimulation for the Treatment of Chronic Pain – The Initial Osijek Experience

Stimulacija kralježnične moždine (engl. spinal cord stimulation - SCS) je postupak kojim se ugrađuju jedna ili dvije elektrode u epiduralni prostor torakalne i lumbalne kralježnice te se elektrode spoje na bateriju koja isporučuje stimulaciju programiranu za tog bolesnika. SCS je indiciran kod bolesnika s jakom kroničnom boli koja se ne smanjuje primjenom ostalih oblika liječenja. Ovaj zahvat se radi kod bolesnika koji imaju bolove u lumbalnom dijelu kralježnice nakon neurokirurških zahvata na lumbalnoj kralježnici s posljedičnim stvaranjem priraslica, sa širenjem boli u donje ekstremitete ili bez širenja boli, kod bolesnika s bolovima nakon amputacije donjih ekstremiteta, te boli koja je posljedica kompleksnih regionalnih bolnih sindroma. U KBC-u Osijek tijekom 2017. g. postupak perkutane ugradnje elektroda za stimulator kralježnične moždine učinjen je kod 5 bolesnika. Prema našim saznanjima sve dosadašnje ugradnje stimulatora kralježnične moždine u Republici Hrvatskoj učinjene su kirurškim, a ne perkutanim pristupom. Bolesnike se procjenjivalo putem numeričke ljestvice za procjenu boli, Oswestry upitnika za procjenu stupnja invalidnosti, SF-36 upitnika za procjenu kvalitete života. Upitnici su ispunjavani prije zahvata, na kontrolnom pregledu prije ugradnje trajne stimulacije, te mjesec i tri mjeseca nakon ugradnje trajnog stimulatora. U ukupnim vrijednostima opaženo je značajno poboljšanje ocjene tjelesnog zdravlja, smanjenje stupnja invalidnosti kao i trenutni, prosječni i najjači intenzitet boli proteklih četiri tjedana u odnosu na prvu vizitu.Spinal cord stimulation (SCS) is a procedure of incorporating one or two electrodes into the epidural space of the thoracic and lumbar spine. The epidural space is located above the dura that covers the spinal cord. This procedure is performed in patients with pain in the lumbar spine with or without pain spreading to lower extremities, in patients with lower extremity amputation, and pain resulting from complex regional pain syndromes. SCS is indicated in patients with severe chronic pain that cannot be alleviated by other modes of treatment. Total SCS was performed in fi ve patients. Patients fi lled out a numerical scale assessing the intensity of pain, the Oswestry questionnaire assessing the degree of disability, and the SF36 questionnaire assessing the quality of life. The above-mentioned questionnaires were completed by the patients before implantation of permanent SCS, then one month after permanent SCS and 3 months of permanent SCS. The results showed signifi cant improvement in the quality of life at the 4th visit in almost all SF-36 items except for limiting the activity for physical health, emotional problems, and mental health. In the overall values, the improvement in physical health assessment with a median 33 (interquartile range from 30 to 59) was signifi cantly better as compared to the 15 (interquartile range from 11 to 16) on the fi rst visit (Friedman’s test, p=0.007). There was also a signifi cant reduction in the degree of disability, as well as in the current, average and most severe pain intensity lasting for four weeks compared to the fi rst visit

The Soluble Fms-like Tyrosin Kinase-1 (sFLT-1) to Placental Growth Factor (PIGF) Ratio as a Possible Indicator for the Severity of Preeclampsia - Single Institution Experience

Aim To investigate a potential of the clinical use of the soluble fms-like tyrosine kinase 1 (sFLT-1) to placental growth factor (PlGF) ratio from the perspective of a small hospital centre. Methods Maternal serum samples were analysed at 241/7-28 0/7, and 281/7-320/7 weeks of gestation. The level of sFLT-1 and PIGF was determined by immunoassay platform and used to calculate the sFLT-1/PIGF ratio in 35 pregnant women, and divided into subgroups according to preeclampsia occurrence at the time of delivery: preterm (≤37 weeks) or term (37-42 weeks'), and matched a control group. Results Patients in the preterm delivery group had a significantly higher incidence of intrauterine growth restriction, lower gestational age at the time of delivery, and lower infant birth weight compared to the other two groups. There was a negative correlation between the sFLT-1/PlGF ratio and GA and between the sFLT-1/ PlGF ratio and birth weight at the time of delivery. The value of the sFLT-1/PlGF ratio was significantly higher in the preterm delivery PE group. All the PE group pregnancies ended with caesarean delivery compared to 25% in the control group. However, none of the patients from the PE group had any of the possible complications of preeclampsia nor did they require additional therapy such as blood transfusion or additional non-standard hypertensive therapy. Conclusion The sFLT-1/PlGF ratio could be used as an indicator for the development and estimation of the severity of PE to provide objective evidence for the management of preeclampsia patients, and as a predictive marker of preeclampsia at low cost

The Physiological Effect of n-3 Polyunsaturated Fatty Acids (n-3 PUFAs) Intake and Exercise on Hemorheology, Microvascular Function, and Physical Performance in Health and Cardiovascular Diseases; Is There an Interaction of Exercise and Dietary n-3 PUFA Intake?

Physical activity has a beneficial effect on systemic hemodynamics, physical strength, and cardiac function in cardiovascular (CV) patients. Potential beneficial effects of dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs), such as α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid on hemorheology, vascular function, inflammation and potential to improve physical performance as well as other CV parameters are currently investigated. Recent meta-analysis suggests no effect of n-3 PUFA supplementation on CV function and outcomes of CV diseases. On the other hand, some studies support beneficial effects of n-3 PUFAs dietary intake on CV and muscular system, as well as on immune responses in healthy and in CV patients. Furthermore, the interaction of exercise and dietary n-3 PUFA intake is understudied. Supplementation of n-3 PUFAs has been shown to have antithrombotic effects (by decreasing blood viscosity, decreasing coagulation factor and PAI-1 levels and platelet aggregation/reactivity, enhancing fibrinolysis, but without effects on erythrocyte deformability). They decrease inflammation by decreasing IL-6, MCP-1, TNFα and hsCRP levels, expression of endothelial cell adhesion molecules and significantly affect blood composition of fatty acids. Treatment with n-3 PUFAs enhances brachial artery blood flow and conductance during exercise and enhances microvascular post-occlusive hyperemic response in healthy humans, however, the effects are unknown in cardiovascular patients. Supplementation of n-3 PUFAs may improve anaerobic endurance and may modulate oxygen consumption during intense exercise, may increase metabolic capacity, enhance endurance capacity delaying the onset of fatigue, and improving muscle hypertrophy and neuromuscular function in humans and animal models. In addition, n-3 PUFAs have anti-inflammatory and anti-nociceptive effects and may attenuate delayed-onset muscle soreness and muscle stiffness, and preserve joint mobility. On the other hand, effects of n-3 PUFAs were variably observed in men and women and they vary depending on dietary protocol, type of supplementation and type of sports activity undertaken, both in healthy and cardiovascular patients. In this review we will discuss the physiological effects of n-3 PUFA intake and exercise on hemorheology, microvascular function, immunomodulation and inflammation and physical performance in healthy persons and in cardiovascular diseases; elucidating if there is an interaction of exercise and diet

Preživljenje do otpusta iz bolnice novorođenčadi vrlo niske porođajne težine u dvije hrvatske perinatalne regije: retrospektivna studija vremena i uzroka smrti

We investigated mortality, causes, timing and risk factors for death until hospital discharge in very-low-birth-weight (VLBW) infants born in two Croatian perinatal care regions. This retrospective study included 252 live born VLBW infants. The mortality rate until hospital discharge was 30.5% (77/252). VLBW in-fants who died had by 4 weeks lower gestational age (GA) than surviving infants (median GA, 25 vs. 29 weeks), lower birth weight (BW) (mean BW, 756.4 vs. 1126.4 g), lower 5-minute Apgar score (median 5 vs. 8) and were more often resuscitated at birth (41.6 vs. 19.4%; p12 hours to necrotizing enterocolitis.Istraživali smo smrtnost, uzroke, vrijeme i rizične čimbenike za smrt do otpusta iz bolnice u novorođenčadi vrlo niske porođajne težine (VNPT) rođene u dvije hrvatske perinatalne regije. Ova retrospektivna studija je uključila 252 živo-rođena novorođenčeta VNPT. Smrtnost do otpusta iz bolnice bila je 30.5% (77/252). Novorođenčad VNPT koja su umrla bila su 4 tjedna manje gestacijske dobi od novorođenčadi koja je preživjela (medijan gestacijske dobi 25 prema 29 tjedana; p12 sati glavni uzrok smrti je nekrotizirajući enterokolitis

Short-Term High-NaCl Dietary Intake Changes Leukocyte Expression of VLA-4, LFA-1, and Mac-1 Integrins in Both Healthy Humans and Sprague-Dawley Rats: a Comparative Study

This study is aimed at assessing the effects of a short-term high-salt (HS) diet on the peripheral blood leukocyte (PBL) activation status in healthy rats and young human individuals. Distribution of PBL subpopulations and surface expression of integrins were determined using flow cytometry in 36 men and women on a 7-day low-salt diet (<3.2 g salt/day) immediately followed by a 7-day HS diet (~14 g salt/day) or in Sprague-Dawley (SD) rats (n = 24) on a 0.4% NaCl diet (aLS group) or a 4% NaCl diet (aHS group) for 7 days. The aHS group presented with an increased frequency of granulocytes, while the frequency of lymphocytes was reduced. Although in humans HS diet reduced the expression of CD11b(act) integrin on lymphocytes, the frequency of CD11b(act)-bearing cells among all PBL subsets was increased. The aHS group of rats exhibited increased expression of total CD11b/c in granulocytes and CD3 lymphocytes. The expression of CD11a was significantly reduced in all PBL subsets from human subjects and increased in the aHS group. CD49d expression on all PBL subsets was significantly decreased in both humans and rats. In human subjects, we found reduced frequencies of intermediate monocytes accompanied by a reciprocal increase in classical monocytes. Present results suggest that a short-term HS diet can alter leukocytes' activation status and promote vascular low-grade inflammation

Serum Levels of the High-mobility Group box 1 Protein (HMGB1) in Children with Type 1 Diabetes Mellitus: Case-control Study

INTRODUCTION: The involvement of the high-mobility group box 1 protein (HMGB1) in various autoimmune and inflammatory diseases has been documented; however, the role of this proinflammatory molecule in children with diabetes type 1 (T1DM) has not been addressed. The aim of this case-control study is to compare the serum level of HMGB1 in children with newly diagnosed T1DM (group 1) and a control group composed of healthy children. MATERIAL AND METHODS: This case-control study included 136 children: group 1 (n = 96) and a control group (n = 40). Measurements were taken from serum for the following: HMGB1, white blood cell count, C-reactive protein, glucose, haemoglobin A1C, and β-cell autoantibodies (GADA-65, IA-2, ICA). HMGB1 was determined using enzyme-linked immunosorbent assay on a Labsystems iEMS Reader MF analyser (Labsystems Diagnostics Oy, Helsinki, Finland). RESULTS: The level (median and interquartile range) of HMGB1 was statistically higher (p < 0.001) in children with T1DM: 8.7 (5.0-9.8) µg/l, in comparison with the control group: 1.0 (0.6-1.4) µg/l. No correlation was found between HMGB1 and HbA1c in group 1, or between HMGB1 and BMI. A statistically higher percentage of positive children for autoantibodies were present in group 1 compared to the control group (p ≤ 0.001). HMGB1 serum levels were also tested and the presence of autoantibodies, and none of those antibodies correlated with the level of HMGB1. CONCLUSIONS: The higher level of HMGB1 in children with T1DM, compared to the control group, indicates that this proinflammatory molecule is a good candidate marker of inflammation in children with T1DM

Promoter Methylation Status of ASC/TMS1/PYCARD is Associated with Decreased Overall Survival and TNM Status in Patients with Early Stage Non-small Cell Lung Cancer (NSCLC).

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide, with 5-year overall survival less than 15%. Therefore, it is essential to find biomarkers for early detection and prognosis. Aberrant DNA methylation is a common feature of human cancers and its utility is already recognized in cancer management. The aim of this study was to explore the diagnostic and prognostic value of the promoter methylation status of the ASC/TMS1/PYCARD and MyD88 genes, key adaptor molecules in the activation of the innate immune response and apoptosis pathways. METHODS: A total of 50 non-small cell lung cancer (NSCLC) patients were enrolled in the study. Methylation of bisulphite converted DNA was quantified by pyrosequencing in fresh frozen malignant tissues and adjacent non-malignant tissues. Associations between methylation and lung function, tumor grade and overall survival were evaluated using receiver-operating characteristics (ROC) analysis and statistical tests of hypothesis. RESULTS: Methylation level of tested genes is generally low but significantly decreased in tumor tissues (ASC/TMS1/PYCARD, P<0.0001; MyD88, P<0.0002), which correlates with increased protein expression. Three CpG sites were identified as promising diagnostic marker candidates; CpG11 (-63 position) in ASC/TMS1/PYCARD and CpG1 (-253 position) and 2 (-265 position) in MyD88. The association study showed that the methylation status of the ASC/TMS1 CpG4 site (-34 position) in malignant and non-malignant tissues is associated with the overall survival (P=0.019) and the methylation status of CpG8 site (-92 position) is associated with TNM-stage (P=0.011). CONCLUSIONS: The methylation status of the ASC/TMS1/PYCARD and MyD88 promoters are promising prognostic biomarker candidates. However, presented results should be considered as a preliminary and should be confirmed on the larger number of the samples