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Klinička imunoterapija raka blokadom molekularnih interakcija negativne povratne sprege [Tumor immunotherapy in clinical setting based on the blockade of molecular interactions of the negative feedback mechanism]
Get PDFThe recent successful results of several relatively new immunotherapeutic anti-cancer strategies such as the blockade of immune inhibitory pathways by monoclonal antibodies against checkpoint molecules can be considered as a medical breakthrough in clinical cancer immunotherapy. This paper presents a basic overview of cancer immunoediting and the clinical application of monoclonal antibodies against checkpoint molecules in cancer patients. Interactions between the immune system and the malignancy are complex, but the results obtained by using the above mentioned therapeutic approaches indicate acceptable clinical utility, efficacy and safety against several types of cancer. Clinical application of monoclonal antibodies against checkpoint molecules CTLA-4, PD-1, and PD-L1, depending on which tumors these antibodies are tested and applied against, ranges from their already usage having been approved by regulatory agencies for patients with particular metastatic tumors to their testing in clinical studies with the aim of demonstrating their efficiency and consequently obtaining approval
Scintigrafija somatostatinskih receptora pomoću oktreotida obilježenoga Tehnecijem-99m u bolesnika s neuroendokrinim tumorima [Somatostatin receptor scintigraphy in neuroendocrine tumour patients using Technetium-99m octreotide]
Get PDFObjective: The aim of this study was to evaluate the additional value of 99mTc-HYNIC-TOC SPECT/CT over planar whole-body (WB) scintigraphy and SPECT alone in the detection and accurate localisation of neuroendocrine tumour (NET) lesions.
Methods: This study included 65 patients with a definitive histological diagnosis of NET prior to scintigraphy. Planar WB scintigraphy, SPECT, and SPECT/CT images were acquired at 4 h post-administration of 670 MBq 99mTc-HYNIC-TOC. Additional SPECT images at 10 min after tracer administration were also acquired. Clinical and imaging follow-up findings were considered as the reference standards.
Results: The sensitivity and specificity of SPECT/CT were found to be 88.9% and 79.3%, respectively. The diagnostic accuracies of WB scintigraphy, 4h-SPECT, and SPECT/CT were 72.3, 73.8, and 84.6%, respectively. The area under curve (AUC) value for SPECT/CT (0.84) was the highest, followed by those for 4h-SPECT (0.75) and WB scintigraphy (0.74). The accuracy and AUC values of SPECT/CT were significantly better compared to those of WB scintigraphy (P < 0.001), 10 min-SPECT (P < 0.001), and 4h-SPECT (P = 0.001).
Conclusion: The sensitivity and diagnostic accuracy of SPECT/CT in the evaluation of NET lesions are higher compared to those of other tested imaging modalities
Utjecaj imunosupresiva na brzinu agregacije trombocita u bolesnika s transplantiranim bubregom [Effect of immunosupressive agents on platelet aggregation in renal transplant patients]
Get PDFIntroductionRenal transplantation is the treatment of choice for patients with end stage renal disease meaning better survival and quality of life. The success of transplantation depends largely on immunosupressive therapy. The major immunosupressive agents that are currently being used in various combination regimens are corticosteroids, azathioprine, mycophenolate mofetil (MMF), cyclosporine, tacrolimus, everolimus, and sirolimus. Immunosuppressive therapy is associated with an increase risk of thromboembolic complications and overall increased riks of morbidity and mortality from cardiovascular disease. Main goal of the study was to investigate the effect of different immunosupressive agents on platelet aggregation in renal transplant patients with stable graft function. Materials and methods The study included renal transplant patients which were controlled in the Department of Nephrology, Hyperthension, Dialysis and Renal Transplantation in Clinical Hospital Center Zagreb, during 3 months period, after providing the informed consent. During the regular visit, together with blood sampling for standard laboratory parameters, an aditional 2 ml of blood was taken for testing platelet aggregation, from all patients who met the inclusion criteria. Platelet function testing was performed on platelet function analyzer (PFA-200) that „in vitro“ simulates the process of aggregation and platelet activation. The test simulates primary hemostasis through interaction of platelets with the aperture of a membrane at the end of the capillary which is coated with collagen and either adenosine diphosphate (COL-ADP) or epinephrine (COL-EPI). Results are reported as the closure time (CT) in seconds for COL-EPI and COL-ADP cartridges. The ranges for control subjects were 85–165 s for the COL - EPI closure time, and 71–118 s for the COL -ADP closure time. Data for analysis for renal transplant patients were taken from the medical records. Control group included healty individuals. Results The study included 85 renal transplant patients (50 male and 35 female, median age 54 (29-76). Patients were divided into four groups based on the type of different immunosuppressive agent (cyclosporine, tacrolimus, everolimus, and sirolimus). All values of „in vitro“ closure times (s) with COL-EPI test were within the reference range, but patients in tacrolimus group had significantly lower values compared to controls (98,5 (IQR:89,0-122,8) : (129(IQR: 107,0-147,3); p=0,006), and compared to cyclosporine group (98,5(IQR:89,0-122,8) : (123,5 (IQR:98,3-166,0); p=0,031). With COL/ADP test, patients in sirolimus group had
significantly lower values compared to controls (77 (67,25-87,5) : (96,5 (85,8 – 105,3); p=0,010). Discussion and conclusion Although, all the values of „in vitro“ closure times with both tests (COL-EPI and COL-ADP) were within reference range, tacrolimus group of patients showed significantly lower values compared to cyclosporine and to controls, while sirolimus group of patients showed significantly lower values compared only to controls. Platelet aggregation values in everolimus patient group did not show any significant differences. These findings could have a certain clinical value. The sensitivity and clinical relevance of this test findings should be further investigated
Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME
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To counteract/reveal celecoxib-induced toxicity and NO system involvement. -----
METHODS:
Celecoxib (1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157 (known to inhibit these lesions, 10 μg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine (100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L-arginine methyl ester (L-NAME)] (5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter. -----
RESULTS:
This high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization (L-arginine) and NO system antagonization (L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157 (at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups (L-arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition (counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade (equally counteracting the noxious effects of celecoxib + L-NAME). -----
CONCLUSION:
BPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs' post-surgery application and NO system involvement
Involvement of substance P in the antinociceptive effect of botulinum toxin type A: evidence from knockout mice
Get PDFThe antinociceptive action of botulinum toxin type A (BoNT/A) has been demonstrated in behavioral animal studies and clinical settings. It was shown that this effect is associated with toxin activity in CNS, however, the mechanism is not fully understood. Substance P (SP) is one of the dominant neurotransmitters in primary afferent neurons transmitting pain and itch. Thus, here we examined association of SP-mediated transmission and BoNT/A antinociceptive action by employing gene knockouts. Antinociceptive activity of intraplantarly (i.pl.) injected BoNT/A was examined in mice lacking the gene encoding for SP/neurokinin A (tac1-/-) or SP-preferred receptor neurokinin 1 (tac1r-/-), compared to control C57Bl/6J wild type animals. BoNT/A action was assessed in inflammatory pain induced by formalin and CFA, and neuropathic pain induced by partial sciatic nerve ligation. BoNT/A activity in CNS was examined by c-Fos and BoNT/A-cleaved SNAP-25 immunohistochemistry. In wild type mice, acute (formalin-evoked) and chronic pain (neuropathic and inflammatory) was reduced by peripherally injected BoNT/A. In tac1-/- and tac1r-/- knockout mice, BoNT/A exerted no analgesic effect. In control animals BoNT/A reduced the formalin-evoked c-Fos expression in lumbar dorsal horn, while in knockout mice the c-Fos expression was not reduced. After peripheral toxin injection, cleaved SNAP-25 occurred in lumbar dorsal horn in all animal genotypes. BoNT/A antinociceptive activity is absent in animals lacking the SP and neurokinin 1 receptor encoding genes, in spite of presence of toxin's enzymatic activity in central sensory regions. Thus, we conclude that the integrity of SP-ergic system is necessary for the antinociceptive activity of BoNT/A
Neuroplastin deletion in glutamatergic neurons impairs selective brain functions and calcium regulation: implication for cognitive deterioration
Get PDFThe cell adhesion molecule neuroplastin (Np) is a novel candidate to influence human intelligence. Np-deficient mice display complex cognitive deficits and reduced levels of Plasma Membrane Ca2+ ATPases (PMCAs), an essential regulator of the intracellular Ca2+ concentration ([iCa2+]) and neuronal activity. We show abundant expression and conserved cellular and molecular features of Np in glutamatergic neurons in human hippocampal-cortical pathways as characterized for the rodent brain. In Nptn lox/loxEmx1Cre mice, glutamatergic neuron-selective Np ablation resulted in behavioral deficits indicating hippocampal, striatal, and sensorimotor dysfunction paralleled by highly altered activities in hippocampal CA1 area, sensorimotor cortex layers I-III/IV, and the striatal sensorimotor domain detected by single-photon emission computed tomography. Altered hippocampal and cortical activities correlated with reduction of distinct PMCA paralogs in Nptn lox/loxEmx1Cre mice and increased [iCa2+] in cultured mutant neurons. Human and rodent Np enhanced the post-transcriptional expression of and co-localized with PMCA paralogs in the plasma membrane of transfected cells. Our results indicate Np as essential for PMCA expression in glutamatergic neurons allowing proper [iCa2+] regulation and normal circuit activity. Neuron-type-specific Np ablation empowers the investigation of circuit-coded learning and memory and identification of causal mechanisms leading to cognitive deterioration
IgM as a novel predictor of disease progression in secondary focal segmental glomerulosclerosis
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To determine the role of immunoglobulin M (IgM) deposits in clinical manifestations, disease outcome, and treatment response of idiopathic and secondary focal segmental glomerulosclerosis (FSGS). -----
METHODS:
Kidney biopsy specimens of 171 patients diagnosed with FSGS (primary and secondary) and 50 control patients were retrospectively included in the study. For each patient, clinical and outcome data were obtained and compared to morphological parameters, including immunofluorescence analysis of mesangial IgM and complement 3 (C3) deposits analyzed on kidney biopsy samples. -----
RESULTS:
There were significant positive correlations between IgM and C3 deposition in secondary FSGS (P<0.001) and between IgM and mesangial deposits detected by electron microscopy in secondary FSGS (P=0.015), which indicated that higher IgM deposition correlated with higher C3 deposition and mesangial deposits only in secondary FSGS. Patients with secondary FSGS and the deposition of IgM showed inferior renal outcomes at earlier time points in comparison with patients with negative IgM expression (P=0.022). -----
CONCLUSIONS:
We detected a positive correlation between IgM and C3 in secondary FSGS. The association between IgM deposition and worse renal outcome in secondary FSGS indicates that IgM may play a role in the progression of this disease