ALBERT

Description: Although cardiac tumors are not common they may vary in terms of race and surgical approach in different countries. Method. Patients data of 20 years was collected and evaluated in the “Shahid Modarres Hospital”—a tertiary university hospital—Tehran, Iran. Results. 42 patients with cardiac myxoma (all cases in 20 years) were included in study, 17 males and 25 females, age difference: 13 to 76 years (mean 50.6). Most of patients were in functional classes I, II. 35 patients complained of dyspnea and 3 patients had embolic events. 97.6% of tumors were primary (41 patients) and one tumor was recurrent (2.4%), 85.7% of tumors (36 cases) were located in LA, and 88.1% of tumors (37 cases) were pediculated. 40 patients (95%) had one tumor. In 22 patients (52.3%) after tumor resection septal defects were repaired primarily while in 18 patients (42.8%) the defects were repaired with pericardial patch and In one patient, tumor resected without any septal defect. Mean tumor size was about 5.22 cm (range of 2.2 to 8.2 cm). Postoperatively, 33 patients discharged from hospital without any complication. Discussion. The research reveals that patients’ age and gender were similar to that of other studies in other countries while tumor’s incidence seems to be higher. 3 patients were diagnosed after remote embolic event and one patient was diagnosed after MI reflecting relatively high tumor complications and late diagnosis. Conclusion. In our study mean time from diagnosis to operation was too long. The patients had more preoperative embolic events and complication. However, size of myxoma and location of that was as same as its rate in the other literature. As recommendation we suggested that in all patients with vague chest pain or remote embolic events cardiac myxomas should be ruled out.

Description: Background and Objective. This study aimed to compare the effects of different local anesthetic solutions on postoperative pain of anal surgery in adult patients. Method. In this randomized double-blind prospective clinical trial, 60 adult patients (18 to 60 years old) with physical status class I and class II that had been brought to a university hospital operating room for fistula anal surgery with spinal anesthesia were selected. Patients were randomly divided into 4 equal groups according to table of random numbers (created by Random Allocation Software 1). Group 1 received 3 mL of normal saline, group 2, 1 mL of normal saline plus 2 mL of bupivacaine 0.5%, group 3, 1 mL of ketamine plus 2 mL of bupivacaine 0.5%, and group 4, no infiltration. Intensity of pain in patients was measured using visual analogue scale (VAS) at 0 (transfer to ward), 2, 6, 12, and 24 hours after surgery. Time interval to administration of drugs and overall dose of drugs were measured in 4 groups. Results. Mean level of pain was the lowest in group 3 at all occasions with a significant difference, followed by groups 2, 4, and lastly 1 (). Furthermore, groups 2 and 3 compared to groups 1 and 4 had the least overall dose of analgesics and requested them the latest, with a significant difference (). Conclusion. Local anesthesia (1 mL of ketamine plus 2 mL of bupivacaine 0.5% or 1 mL of normal saline plus 2 mL of bupivacaine 0.5%) combined with spinal anesthesia reduces postoperative pain and leads to greater comfort in recovering patients.

Description: Valvular heart disease is the common cardiac manifestation of systemic lupus erythematosus (SLE) with a tendency for mitral valve regurgitation. In this study we report a case of mitral valve replacement for mitral stenosis caused by Libman-Sacks endocarditis in the setting of SLE. In addition, we provide a systematic review of the literature on mitral valve surgery in the presence of Libman-Sacks endocarditis because its challenge on surgical options continues. Surgical decision depends on structural involvement of mitral valve and presence of active lupus nephritis and antiphospholipid antibody syndrome. Review of the literature has also shown that outcome is good in most SLE patients who have undergone valvular surgery, but association of antiphospholipid antibody syndrome with SLE has negative impact on the outcome.

Description: Background: Receptor tyrosine kinase (RTK) (ROR1) is normally expressed during embryogenesis but absent in most normal tissues. However, ROR1 is overexpressed in several cancers (onco-fetal RTK) and of importance for various tumor cell functions such as proliferation and survival. In patients with diffuse large B-cell lymphomas (DLBCL) there is a great medical need to develop new treatment alternatives for those not responding to primary treatment as well as for patients with relapse as effective treatments are warranted. Inhibition of ROR1 by a small molecule ROR1 inhibitor (KAN0439834) abrogated downstream kinase activities as well as induced apoptosis of various tumor cells as CLL and pancreatic carcinoma (Leukemia, Oct;32(10):2291-2295, 2018) (PLoS One. 13(6): e0198038, 2018). A 2nd generation of ROR1 inhibitor (KAN0441571C) has been synthesized with the aim to bind to the ROR1-TK domain and inhibit ROR1 signaling. Aim: To examine the expression of ROR1 in DLBCL cell lines (RC-KB, SUDHL4, MS, OCL-LY3, U2932) and in patients´ samples at different stages of DLBCL as well as effects of KAN0441571C on survival of DLBCL cells and ROR1 signaling. Methods: Flow cytometry, tissue microarray and immunohistochemistry assays were used to check ROR1 expression. MTT and Annexin V/PI assays were applied to analyse cytotoxicity and apoptosis of KAN0441571C alone or in combination with ibrutinib (BTK inhibitor) and venetoclax (BCL-2 inhibitor) on DLBCL cell lines. Western blot was performed to evaluate ROR1 phosphorylation and associated signaling pathways. DLBCL cells were also cultured with HS-5 stromal cells (ROR1 neg.) to evaluate the apoptosis inhibitory effects of stromal cells. Results: ROR1 expression was significantly more frequently noted in patients with advanced disease (Richter´s, transformation, transformed follicular lymphoma and refractory DLBCL) compared to less advanced disease (recurrent or de novo DLBCL) (p=0.0001). In primary refractory and relapsing DLBCL 5-years survival was 45% in ROR1- patients (n=17) while in ROR1+ patients (n=16) the corresponding figure was 10000 nM). EC50 for venetoclax in the ROR1+ DLBCL cell lines varied between 100 and 500 and 5000 - 10000 nM for ibrutinib. In comparison to venetoclax, KAN0441571C induced a similar or significantly higher cytotoxic effect. KAN0441571C and venetoclax seemed to be the most promising drug combination approaching 100% killing at the EC50 dose for each drug. Apoptosis was confirmed by Annexin V/PI staining as well as by downregulation of BCL-2 and MCL-1 as well as cleavage of PARP and caspase 3. KAN0441571C dephosphorylated ROR1 as well as the co-receptor LRP6 and the SRC protein which binds to phosphorylated ROR1. The downstream molecules PI3Kδ/AKT/mTOR was also dephosphorylated and the transcription factor CREB. CK1δ and GSK3B were also dephosphorylated and β-catenin downregulated indicating involvement of both the non-canonical and canonical Wnt pathways. When DLBCL and HS-5 cells (ROR1 neg.) were co-cultured, HS-5 cells could partially prevent induction of apoptosis of DLBCL cells at low concentrations of KAN0441571C, while at higher concentrations the presence of stromal cells was less effective. Zebrafish embryos transplanted with the OCI-Ly3 cell line were treated for 3 days with KAN0441571C (25-1000 nM). No toxic effects of the drug could be noted. A significant dose and time-dependent decrease in the tumor area were noted. Conclusion: KAN0441571C is the 2nd generation of a novel class of ROR1-inhibiting small molecule drugs. The molecule was more effective in inducing apoptosis of DCBCL cells than venetoclax or ibrutinib. New anti-cancer drugs with other mechanisms of action than those clinically available for DLBCL are warranted to improve the prognosis. ROR1 inhibitors in combination with other targeted drugs as venetoclax and ibrutinib might improve the therapeutic effects. KAN0441571C may be a novel drug candidate which needs further exploration in DLBCL. Disclosures Lehto: Kancera AB: Employment. Vågberg:Kancera AB: Employment. Olsson:Kancera AB: Employment. Löfberg:Kancera AB: Employment. Norström:Kancera AB: Employment. Schultz:Kancera AB: Employment, Equity Ownership. Norin:Kancera AB: Employment. Olin:Kancera AB: Employment, Equity Ownership. Österborg:Kancera AB: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; BeiGene: Research Funding. Mellstedt:Kancera AB: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: ROR1 - a receptor tyrosine kinase (RTK) - is essential for normal embryonic development, but is absent on most normal adult tissues. ROR1 is of importance of cell proliferation, differentiation, survival and metabolism. However, ROR1 is overexpressed in several types of cancer (onco-fetal RTK). MCL is an aggressive and incurable non-Hodgkin lymphoma characterized by translocation (11;14) (q13;q32) and cyclin D overexpression. ROR1 has been described to be highly expressed in MCL cells. We have previously presented results on a small molecule ROR1 inhibitor in CLL (KAN0439834) (Leukemia 32(10):2291, 2018). A second generation ROR1 inhibitor, KAN0441571C, has been developed with improved killing of tumor cells and with longer half-life time (〉10h) (PK studies in mice/rats/dogs) compared to KAN0439834. Aim: In this study we examined effects of the ROR1 small molecule inhibitor KAN0441571C in human MCL cells (Granta-519, Jeko-1, JVM-2, Z138, Mino) as part of a pre-clinical evaluation. Methods: ROR1 expression was evaluated by flow cytometry and WB. Cytotoxicity was analysed by MTT and apoptosis by Annexin V/P staining and Western Blot for apoptotic proteins. Cytotoxicity (MTT) was also analysed by combining the ROR1 inhibitor with ibrutinib, acalabrutinib, venetoclax and bendamustine. Effects of KAN0441571C on ROR1 inactivation (dephosphorylation) and signaling pathways were evaluated by WB. Results: All five cell-lines expressed phosphorylated ROR1 (130 kDa) with a varying intensity. Surface expression (flow-cytometry) varied from 0% (JVM-2) to 100% (Mino and JeKo-1). The data indicate expression of also splice variants lacking the extracellular domain. KAN0441571C induced time and dose dependent apoptosis of the five MCL cell-lines which was p53 independent. EC50 varied between 100-250 nM (24h). Apoptosis was confirmed by cleavage of caspase 3 and PARP as well as down-regulation of the MCL-1 and BCL-2 proteins. Moreover, ROR1 was dephosphorylated by KAN0441571C. Downstream of ROR1 both the Wnt canonical and non-canonical pathways were inactivated depending on the cell line. KAN0441571C had in most cell lines a similar cytotoxic effect as ibrutinib, acalabrutinib and venetoclax while bendamustine was inferior. KAN0441571C had an additive effect to ibrutinib, acalabrutinib and venetoclax respectively and KAN0441571C in combination with either of these three agents induced a complete killing of the cell lines. Conclusions: KAN0441571C is a second generation of a novel class of ROR1-tyrosine kinase inhibitor. This small molecule was effective in inducing apoptosis of MCL cells with other mechanisms of action than for drugs in clinical use for MCL. Combination of KAN0441571C with other MCL targeting drugs induced a complete killing of the tumor cell population in a preclinical in vitro model. Our results support the further development of ROR1 small molecule inhibitors as a new therapeutic principle in MCL as well as in other B-cell malignancies with an additive effect to existing targeted therapeutics. Disclosures Schultz: Kancera AB: Employment, Equity Ownership. Norin:Kancera AB: Employment. Olin:Kancera AB: Employment, Equity Ownership. Österborg:Janssen: Research Funding; Kancera AB: Research Funding; BeiGene: Research Funding; Abbvie: Research Funding; Gilead: Research Funding.

Description: Bulk-carbonate carbon isotope ratios are a widely applied proxy for investigating the ancient biogeochemical carbon cycle. Temporal carbon isotope trends serve as a prime stratigraphic tool, with the inherent assumption that bulk micritic carbonate rock is a faithful geochemical recorder of the isotopic composition of seawater dissolved inorganic carbon. However, bulk-carbonate rock is also prone to incorporate diagenetic signals. The aim of the present study is to disentangle primary trends from diagenetic signals in carbon isotope records which traverse the Permian–Triassic boundary in the marine carbonate-bearing sequences of Iran and South China. By pooling newly produced and published carbon isotope data, we confirm that a global first-order trend towards depleted values exists. However, a large amount of scatter is superimposed on this geochemical record. In addition, we observe a temporal trend in the amplitude of this residual δ13C variability, which is reproducible for the two studied regions. We suggest that (sub-)sea-floor microbial communities and their control on calcite nucleation and ambient porewater dissolved inorganic carbon δ13C pose a viable mechanism to induce bulk-rock δ13C variability. Numerical model calculations highlight that early diagenetic carbonate rock stabilization and linked carbon isotope alteration can be controlled by organic matter supply and subsequent microbial remineralization. A major biotic decline among Late Permian bottom-dwelling organisms facilitated a spatial increase in heterogeneous organic carbon accumulation. Combined with low marine sulfate, this resulted in varying degrees of carbon isotope overprinting. A simulated time series suggests that a 50 % increase in the spatial scatter of organic carbon relative to the average, in addition to an imposed increase in the likelihood of sampling cements formed by microbial calcite nucleation to 1 out of 10 samples, is sufficient to induce the observed signal of carbon isotope variability. These findings put constraints on the application of Permian–Triassic carbon isotope chemostratigraphy based on whole-rock samples, which appears less refined than classical biozonation dating schemes. On the other hand, this signal of increased carbon isotope variability concurrent with the largest mass extinction of the Phanerozoic may provide information about local carbon cycling mediated by spatially heterogeneous (sub-)sea-floor microbial communities under suppressed bioturbation.

Description: Bulk-carbonate carbon isotope measurements are a widely applied proxy for investigating the ancient biogeochemical carbon cycle. Temporal carbon isotope trends serve as a prime stratigraphic tool, with the inherent assumption that bulk micritic carbonate rock is a faithful geochemical recorder of the isotopic composition of seawater dissolved inorganic carbon. However, bulk-carbonate rock is also prone to incorporate diagenetic signals. The aim of the present study is to disentangle primary trends from diagenetic signals in carbon isotope records which traverse the Permian–Triassic boundary in marine carbonate-bearing sequences of Iran and South China. By pooling newly produced and published carbon isotope data we confirm that a global first-order trend towards depleted values exists. However, a large amount of scatter is superimposed on this geochemical record. In addition, we observe a temporal trend in the amplitude of this residual δ13C variability, which is reproducible for the two studied regions. We suggest that (sub)seafloor microbial communities and their control on calcite nucleation as well as on ambient porewater dissolved inorganic carbon-δ13C pose a viable mechanism to induce bulk-rock δ13C variability. Numerical model calculations highlight that early diagenetic carbonate rock stabilization, and linked carbon isotope alteration, can be controlled by organic matter supply and subsequent microbial remineralization. Low marine sulfate and a major biotic decline among late Permian bottom-dwelling organisms facilitated a spatial increase in heterogeneous organic carbon accumulation, causing varying degrees of carbon isotope overprint. A simulated time series suggests that a 50 % increase in the spatial scatter of organic carbon relative to the average, in addition to an imposed increase in the likelihood of sampling cements formed by microbial calcite nucleation to one out of 10 samples, is sufficient to induce the observed signal of carbon isotope variability. These findings put constraints on the application of Permian–Triassic carbon isotope chemostratigraphy based on whole-rock samples, which appears less refined than classical biozonation dating schemes. On the other hand, this signal of increased carbon isotope variability concurrent with the largest mass extinction of the Phanerozoic may inform about local carbon cycling mediated by spatially heterogeneous (sub)-seafloor microbial communities under suppressed bioturbation.

Description: Valvular heart disease is the common cardiac manifestation of systemic lupus erythematosus (SLE) with a tendency for mitral valve regurgitation. In this study we report a case of mitral valve replacement for mitral stenosis caused by Libman-Sacks endocarditis in the setting of SLE. In addition, we provide a systematic review of the literature on mitral valve surgery in the presence of Libman-Sacks endocarditis because its challenge on surgical options continues. Surgical decision depends on structural involvement of mitral valve and presence of active lupus nephritis and antiphospholipid antibody syndrome. Review of the literature has also shown that outcome is good in most SLE patients who have undergone valvular surgery, but association of antiphospholipid antibody syndrome with SLE has negative impact on the outcome.

Description: Background and Objective. This study aimed to compare the effects of different local anesthetic solutions on postoperative pain of anal surgery in adult patients.Method. In this randomized double-blind prospective clinical trial, 60 adult patients (18 to 60 years old) with physical status class I and class II that had been brought to a university hospital operating room for fistula anal surgery with spinal anesthesia were selected. Patients were randomly divided into 4 equal groups according to table of random numbers (created by Random Allocation Software 1). Group 1 received 3 mL of normal saline, group 2, 1 mL of normal saline plus 2 mL of bupivacaine 0.5%, group 3, 1 mL of ketamine plus 2 mL of bupivacaine 0.5%, and group 4, no infiltration. Intensity of pain in patients was measured using visual analogue scale (VAS) at 0 (transfer to ward), 2, 6, 12, and 24 hours after surgery. Time interval to administration of drugs and overall dose of drugs were measured in 4 groups.Results. Mean level of pain was the lowest in group 3 at all occasions with a significant difference, followed by groups 2, 4, and lastly 1 (P

Description: Fractional calculus techniques and methods started to be applied successfully during the last decades in several fields of science and engineering. In this paper we studied the stability of fractional-order nonlinear time-delay systems for Riemann-Liouville and Caputo derivatives and we extended Razumikhin theorem for the fractional nonlinear time-delay systems.