Cytarabine Research Articles

Heterogeneous catalysts for electro-Fenton degradation of cytostatic drug cytarabine

In the present work, a reduced graphene oxide (rGO) modified-Fe3O4 doped bifunctional carbon felt cathode (rGO-Fe3O4/CF) that is capable of generating and converting H2O2 into hydroxyl radicals (•OH) on-site was fabricated, thus removing the need for an external catalyst. In addition, an rGO-modified cathode (rGO/CF) with high H2O2 production efficiency and a heterogeneous Fenton catalyst (CNT-Fe3O4) with magnetic properties were fabricated. The study examined the degradation and mineralization of the cytostatic drug cytarabine (CYT) using two HEF configurations: (i) a bifunctional cathode rGO-Fe3O4/CF and (ii) a combination of the rGO/CF cathode with CNT-Fe3O4 catalyst. The effects of parameters such as catalyst concentration, initial pH, and applied current were studied. HPLC and ion chromatography analyses were used to identify carboxylic acids and inorganic end-products, respectively. The results show that 0.1 mM CYT was completely degraded within 18 min at an applied current of 300 mA in the HEF system with the rGO-Fe3O4/CF bifunctional cathode. Total organic carbon (TOC) analysis revealed that the bifunctional cathode system achieved 98.2% mineralization of CYT after 4 h of treatment at 300 mA. Using the rGO/CF cathode and CNT-Fe3O4 catalyst cell, total degradation of 0.1 mM CYT occurred within 7 min, and nearly total mineralization (97.3% TOC removal) was achieved at 300 mA after 4 h.

Bilosomes and Niosomes for Enhanced Intestinal Absorption and In Vivo Efficacy of Cytarabine in Treatment of Acute Myeloid Leukemia

Cytarabine (CTR) is a hydrophilic anticancer drug used to treat leukemia. It suffers from poor permeability and intestinal metabolism, diminishing its oral bioavailability. Background/Objectives: The objective was to develop and evaluate niosomes and bilosomes for enhanced intestinal absorption; hence, oral bioavailability. Results: CTR-loaded niosomes and bilosomes with vesicle sizes of 152 and 204.3 nm were successfully prepared with acceptable properties. The presence of bile salts increased the zeta potential of bilosomes. The recorded entrapment efficiency of cytarabine was acceptable for such a hydrophilic drug. CTR-bilosomes showed a pH-dependent drug release pattern with preferred release in pH 6.8. Intestinal absorption behavior indicated a site-dependent CTR absorption pattern with unfavorable absorption in the distal intestine. Niosomal and bilosomal formulations enhanced intestinal absorption parameters with evidence for a predominant paracellular absorption mechanism that bypasses intestinal barriers. The investigation of the anti-leukemic effect of niosomal and bilosomal formulations indicated that both formulations ameliorated the blood parameters, reflecting significant improvement in leukemia treatment compared with the drug solution. Pathological examination of blood films revealed decreased blast cells in peripheral blood in groups treated with tested formulations. Methods: Tested formulations were prepared according to the pro-concentrate method and characterized for particle size, zeta potential, entrapment efficiency, and in vitro release. CTR-loaded niosomes and bilosomes were evaluated for enhanced intestinal absorption utilizing the single-pass in situ intestinal perfusion method in rabbits, and the anti-leukemic effect was assessed using the benzene-induced leukemia model in rats. Conclusions: This study introduced surfactant vesicles for enhanced oral bioavailability of CTR.

Molecular Design of Phthalocyanine-Based Drug Coassembly with Tailored Function.

Coassemblies with tailored functions, such as drug loading, tissue targeting and releasing, therapeutic and/or imaging purposes, and so on, have been widely studied and applied in biomedicine. De novo design of these coassemblies hinges on an integrated approach involving synergy between various design strategies, ranging from structure screening of combinations of "phthalocyanine-chemotherapeutic drug" molecules for molecular scaffolds, exploration of related fabrication principles to verification of intended activity of specific designs. Here, we propose an integrated approach combining computation and experiments to design from scratch coassembled nanoparticles. This nanocoassembly, termed NanoPC here, consists of phthalocyanine-based scaffolds hosting chemotherapeutic drugs, aimed at hypersensitive chemotherapy guided by photoimaging for targeting tumors. Our design starts from the selection of phthalocyanine derivatives that are not aggregation-prone, followed by computational screening of coassembled molecules covering various categories of chemotherapy drugs. To facilitate an efficient and accurate assessment of coassembly capabilities, we utilize small systems as surrogates to enable free-energy calculations at all-atom levels facilitated with enhanced sampling and statistical mechanics for efficient and accurate evaluation of coassembly ability. The final top NanoPC candidate, comprised of phthalocyanine PcL and cytarabine (CYT), can greatly increase the fluorescence intensity ratio of tumor/liver by 21.5 times and achieve higher antitumor efficiency in a pH-dependent manner. Therefore, the designing approach proposed here has a potential pattern, which can provide ideas and references for the design and development of coassembled nanodrugs with tailored functions and applications in biomedicine.

Neurodevelopmental Process Monitoring of Cytosine Arabinoside-Exposed Neurons Using Raman Spectroscopy.

Raman spectroscopy is used to monitor the development of live neurons exposed to cytosine arabinoside (ara-C). Ara-C is widely used to culture neurons and exclude non-neuronal cells. In this study, Raman spectra obtained from neurons exposed to ara-C were plotted using an analytical model of neuronal development to evaluate the impact of ara-C on neuronal development. After two days of culturing, neurons were exposed to ara-C for 24 h at final concentrations of 0 (control), 5, and 25 μM. Principal component analysis (PCA) was performed to build an analytical model for evaluating neurodevelopmental disorders caused by ara-C treatment. We projected the Raman spectra obtained from ara-C-treated cells onto the control group dataset. The distribution of PC1 scores for neurons exposed to ara-C at a final concentration of 5 μM was not significantly different from that of the control group. In contrast, under a final concentration of 25 μM, the data population at 10 and 15 days of culturing overlapped significantly with that of neurons at 4 days of normal culturing. These results suggest that Raman spectroscopy can detect very small physiological alterations in the neurons even after a short-term exposure (24 h) of ara-C. Our analytical method has high potential to evaluate the developmental stages for living neurons under exposure to chemicals.

Poxin-deficient poxviruses are sensed by cGAS prior to genome replication.

Poxviruses are dsDNA viruses infecting a wide range of cell types, where they need to contend with multiple host antiviral pathways, including DNA and RNA sensing. Accordingly, poxviruses encode a variety of immune antagonists, most of which are expressed early during infection from within virus cores before uncoating and genome release take place. Amongst these antagonists, the poxvirus immune nuclease (poxin) counteracts the cyclic 2'3'-GMP-AMP (2'3'-cGAMP) synthase (cGAS)/stimulator of interferon genes DNA sensing pathway by degrading the immunomodulatory cyclic dinucleotide 2'3'-cGAMP, the product of activated cGAS. Here, we use poxviruses engineered to lack poxin to investigate how virus infection triggers the activation of STING and its downstream transcription factor interferon-responsive factor 3 (IRF3). Our results demonstrate that poxin-deficient vaccinia virus (VACV) and ectromelia virus (ECTV) induce IRF3 activation in primary fibroblasts and differentiated macrophages, although to a lower extent in VACV compared to ECTV. In fibroblasts, IRF3 activation was detectable at 10 h post-infection (hpi) and was abolished by the DNA replication inhibitor cytosine arabinoside (AraC), indicating that the sensing was mediated by replicated genomes. In macrophages, IRF3 activation was detectable at 4 hpi, and this was not affected by AraC, suggesting that the sensing in this cell type was induced by genomes released from incoming virions. In agreement with this, macrophages expressing short hairpin RNA (shRNA) against the virus uncoating factor D5 showed reduced IRF3 activation upon infection. Collectively, our data show that the viral genome is sensed by cGAS prior to and during genome replication, but immune activation downstream of it is effectively suppressed by poxin. Our data also support the model where virus uncoating acts as an immune evasion strategy to simultaneously cloak the viral genome and allow the expression of early immune antagonists.

Empowering the NSC-34 cell line as a motor neuron model: cytosine arabinoside's action.

The NSC-34 cell line is a widely recognized motor neuron model and various neuronal differentiation protocols have been exploited. Under previously reported experimental conditions, only part of the cells resemble differentiated neurons; however, they do not exhibit extensive and time-prolonged neuritogenesis, and maintain their duplication capacity in culture. The aim of the present work was to facilitate long-term and more homogeneous neuronal differentiation in motor neuron-like NSC-34 cells. We found that the antimitotic drug cytosine arabinoside promoted robust and persistent neuronal differentiation in the entire cell population. Long and interconnecting neuronal processes with abundant growth cones were homogeneously induced and were durable for up to at least 6 weeks in culture. Moreover, cytosine arabinoside was permissive, dispensable, and mostly irreversible in priming NSC-34 cells for neurite initiation and regeneration after mechanical dislodgement. Finally, the expression of the cell proliferation antigen Ki67 was inhibited by cytosine arabinoside, whereas the expression levels of neuronal growth associated protein 43, vimentin, and motor neuron-specific p75, Islet2, homeobox 9 markers were upregulated, as confirmed by western blot and/or confocal immunofluorescence analysis. Overall, these findings support the use of NSC-34 cells as a motor neuron model for properly investigating neurodegenerative mechanisms and prospectively identifying neuroprotective strategies.

Differential functionality of fluoropyrimidine nucleosides for safe cancer therapy.

Chemotherapies are standard care for most cancer types. Pyrimidine analogs including 5-fluorouracil, cytosine arabinoside, 5-azacytidine, and gemcitabine are effective drugs that are utilized as part of a number of anticancer regimens. However, their lack of cell-specificity results in severe side effects. Therefore, there is a capacity to improve the efficacy of such therapies, while decreasing unwanted side effects. Here, we report that while 5-fluorocytosine is not chemotherapeutic in itself, incorporated into a ribonucleoside and more importantly into an RNA oligonucleotide, it induces cytotoxic effects on cancer cells in vitro . Interestingly, these effects are rescued by both uridine and thymidine. Similarly, in-vitro 2'-deoxy-5-fluorocytidine inhibits the growth of tumor cells but has the advantage of being less toxic to human primary cells compared with 5-fluorocytidine, suggesting that the deoxyribonucleoside could exhibit less side-effects in vivo . Thus, this work indicates that the potency of 5-fluorocytidine and 2'-deoxy-5-fluorocytidine should be further explored. In particular, oligonucleotides incorporating 5-fluorocytosine could be novel chemotherapeutic drugs that could be formulated in cancer-specific particles for safe and efficacious cancer treatments.

Synergistic anticancer effect of polymersome‐encapsulated curcumin and cytarabine: A spectroscopic and theoretical approach

AbstractCytarabine, also known as cytosine arabinoside is an anticancer drug, and it is widely used to treat acute myeloid leukemia (AML). But, clinical efficacy of highly hydrophilic cytarabine is often limited due to its rapid degradation and high biodistribution. Hence, this study aims to enhance the anticancer effect of cytarabine with the help of a naturally occurring polyphenol, curcumin. The interaction between cytarabine and curcumin was established by different spectroscopic techniques like UV–Visible, fluorescence, and Fourier transform infrared (FT‐IR). Molecular interactions were also studied using isothermal calorimetric titrations (ITC) followed by theoretical docking. The involvement of the amine group of cytarabine with the interaction of curcumin has been supported by FT‐IR and docking study. However, the major challenge with curcumin is that, in spite of its several medicinal benefits, poor solubility and bioavailability restricts its potential clinical applications. Hence, polymersome‐encapsulated curcumin (PEC) was prepared for the intravenous application. A two‐fold decrease in IC50 value of cytarabine against HeLa cell line was found in presence of encapsulated curcumin. This was justified on the basis of observed reactive oxygen species enhancement in serum in presence of cytarabine and PEC together, determined using absorption spectroscopy. The enhanced affinity of cytarabine toward DNA‐curcumin complex as compared to free DNA, supported by theoretical study, also validates the increased cytotoxicity of cytarabine in presence of PEC.

GPS2 promotes erythroid differentiation in K562 erythroleukemia cells primarily via NCOR1.

G protein pathway suppressor 2 (GPS2) has been shown to play a pivotal role in human and mouse definitive erythropoiesis in an EKLF-dependent manner. However, whether GPS2 affects human primitive erythropoiesis is still unknown. This study demonstrated that GPS2 positively regulates erythroid differentiation in K562 cells, which have a primitive erythroid phenotype. Overexpression of GPS2 promoted hemin-induced hemoglobin synthesis in K562 cells as assessed by the increased percentage of benzidine-positive cells and the deeper red coloration of the cell pellets. In contrast, knockdown of GPS2 inhibited hemin-induced erythroid differentiation of K562 cells. GPS2 overexpression also enhanced erythroid differentiation of K562 cells induced by cytosine arabinoside (Ara-C). GPS2 induced hemoglobin synthesis by increasing the expression of globin and ALAS2 genes, either under steady state or upon hemin treatment. Promotion of erythroid differentiation of K562 cells by GPS2 mainly relies on NCOR1, as knockdown of NCOR1 or lack of the NCOR1-binding domain of GPS2 potently diminished the promotive effect. Thus, our study revealed a previously unknown role of GPS2 in regulating human primitive erythropoiesis in K562 cells.

Novel coumarin-piperazine-2(5H)-furanone hybrids as potential anti-lung cancer agents: Synthesis, biological evaluation and molecular docking studies

Novel coumarin-piperazine-2(5H)-furanone hybrids 5a–l were efficiently synthesized by introducing a furanone scaffold into coumarin using piperazine as a linker. The cytotoxicity of all hybrids 5a–l were evaluated by MTT assay on human lung cancer A549 cells and normal human lung fibroblast WI-38 cells with cytarabine (CAR) as a positive control. Hybrid 5l (IC50 = 11.28 μM) was the most toxic to A549 cells, 18-fold more toxic than the reference CAR (IC50 = 202.57 μM). Moreover, hybrid 5l (IC50 = 411.93 μM) was less toxic to WI-38 cells, with a much higher selectivity (5l, SI ≈ 37, WI-38/A549) than CAR (SI ≈ 2). Structure–activity relationship analysis showed that both the cytotoxicity against A549 cells and selectivity (WI-38/A549) were greatly improved when the bornyl group was incorporated in the hybrids (5c, 5f, 5i and 5l). Further, hybrid 5l was more toxic and selective against four types of human lung cancer cells (A549, Calu-1, PC-9 and H460; IC50 = 5.72–45.46 μM; SI ≈ 9–72) than three other types of human cancer cells (SK-BR-3, 786-O and SK-OV-3, IC50 = 39.07–130.82 μM; SI ≈ 0–2), showing remarkable specificity. In particular, hybrid 5l (IC50 = 5.72 μM) showed the highest cytotoxicity against H460 cells with the highest selectivity of up to 72 (WI-38/H460). Flow cytometric analysis showed that hybrid 5l induced apoptosis in H460 cells in a concentration-dependent manner. Molecular docking studies revealed a high binding affinity of hybrid 5l with CDK2 protein. Hybrid 5l is expected to be a leading candidate for anti-lung cancer agents.

Suspected cytosine arabinoside induced interstitial lung disease in a dog with meningoencephalitis

Suspected cytosine arabinoside induced interstitial lung disease in a dog with meningoencephalitis

THE MANAGEMENT OF LYMPHOPROLIFERATIVE NEOPLASIA IN FOUR NORTHERN SEA OTTERS (ENHYDRA LUTRIS KENYONI).

Lymphoproliferative neoplasia has been reported in both free-ranging sea otters and those in managed care, but little information is available on the management of this neoplastic disease in this species. This case series describes clinical lymphoma in four northern sea otters (Enhydra lutris kenyoni) in managed care. Two otters presented with Stage 5 lymphoma with evidence of hematologic spread resulting in leukemia. Two additional otters presented with Stage 3 disease. Immunophenotypes in these cases included disseminated large B-cell lymphoma and lymphoblastic lymphoma of potential T-cell origin. Cases were managed with multiagent chemotherapy protocols including prednisone, L-asparaginase, cyclophosphamide, vincristine, cytosine arabinoside, lomustine, and doxorubicin. Unique approaches included the use of a vascular access port in one case and development of an autologous vaccine in another. Survival time ranged from 81 to 409 days. Diagnosis, staging, and treatment with multiagent protocols is recommended for the management of lymphoma in sea otters.

Marine-Derived Cytosine Arabinoside (Ara-C) Inhibits Biofilm Formation by Inhibiting PEL Operon Proteins (Pel A and Pel B) of Pseudomonas aeruginosa: An In Silico Approach.

Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative biofilm-forming opportunistic human pathogen whose vital mechanism is biofilm formation for better survival. PelA and PelB proteins of the PEL operon are essential for bacterial-synthesized pellicle polysaccharide (PEL), which is a vital structural component of the biofilm. It helps in adherence of biofilm on the surface and maintenance of cell-to-cell interactions and with other matrix components. Here, in-silico molecular docking and simulation studies were performed against PelA and PelB using ten natural bioactive compounds, individually [podocarpic acids, ferruginol, scopadulcic acid B, pisiferic acid, metachromin A, Cytarabine (cytosine arabinoside; Ara-C), ursolic acid, oleanolic acid, maslinic acid, and betulinic acid], those have already been established as anti-infectious compounds. The results obtained from AutoDock and Glide-Schordinger stated that a marine-derived cytosine arabinoside(Ara-C) among the ten compounds binds active sites of PelA and PelB, exhibiting strong binding affinity [Trp224 (hydrogen), Ser219 (polar), Val234 (hydrophobic) for PelA; Leu365 and Glu389 (hydrogen), Gln366 (polar) for PelB] with high negative binding energy -5.518kcal/mol and -6.056kcal/mol, respectively. The molecular dynamic and simulation studies for 100ns showed the MMGBSA binding energy scores are -16.4kcal/mol (Ara-C with PelA), and -22.25kcal/mol (Ara-C with PelB). Further, ADME/T studies indicate the IC50 values of AraC are 6.10mM for PelA and 18.78mM for PelB, which is a comparatively very low dose. The zero violation of Lipinski's Rule of Five further established that Ara-C is a good candidate for drug development. Thus, Ara-C could be considered a potent anti-biofilm compound against PEL operon-dependent biofilm formation of P. aeruginosa.

Diagnosis and treatment of metastatic uterine lymphoma in a chinchilla (Chinchilla lanigera)

AbstractA 4‐year‐old, entire, female chinchilla (Chinchilla lanigera) presented to an emergency veterinary hospital for laboured breathing, lethargy and hyporexia. Physical exam findings and diagnostic imaging were supportive of uterine disease. An ovariohysterectomy was performed, and histopathology diagnosed incompletely resected uterine lymphoma. A rotating outpatient chemotherapy protocol containing oral prednisolone (0.5 mg/kg), subcutaneous L‐asparaginase (400 iu/kg), oral cyclophosphamide (200 mg/m2) and subcutaneous cytosine arabinoside (50 mg/kg) was initiated. The patient tolerated chemotherapeutics well based on normal behaviour, appetite, exam findings and serial bloodwork values. One hundred two days after initial presentation, the patient was euthanased due to a decline in clinical condition. Postmortem examination and histopathology confirmed metastasis of lymphoma to the brain, mediastinum, mesentery, liver and spleen. No evidence of organ damage due to chemotherapeutics was noted histologically. Postmortem immunohistochemistry confirmed the diagnosis of lymphoma. Further studies are needed to guide chemotherapeutic dosing and treatment of lymphoma in chinchillas.

Corticosteroid monotherapy versus combined cytarabine continuous rate infusion and corticosteroid therapy in dogs with meningoencephalitis of unknown origin: A blinded, randomized, controlled trial.

Treatment options available for meningoencephalitis of unknown origin (MUO) in dogs are suboptimal, and currently, no single treatment protocol appears to be superior. Compare neurological deterioration rates at 7 days between dogs with MUO treated with corticosteroids alone or combined with cytosine arabinoside (CA) continuous rate infusion (CRI) and compare clinical deterioration and survival at 30 and 100 days. Sixty-nine dogs with magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) features or both compatible with MUO. Parallel, blinded, randomized controlled trial. Simple randomization into 2 treatment groups: 4 mg/kg/day prednisolone (or dexamethasone equivalent) for 2 days or 200 mg/m2 CA CRI over 8 hours plus 2 mg/kg/day prednisolone. Blinding of the treatment protocol was carried out using reversible redaction of clinical records, and treatment failure was defined as deterioration of neurological assessment or death. Using intention-to-treat analysis, proportions failing treatment at 7, 30, and 100 days were compared using Fisher's exact test. All-cause mortality at 100 days was compared using Kaplan-Meier survival curves. Thirty-five dogs were allocated to corticosteroid only, and 34 dogs were allocated to combined CA CRI and corticosteroid. Proportions failing treatment at 7, 30, and 100 days were 7/35 (20%), 9/35 (26%), and 15/35 (43%) in the corticosteroid-only group and 8/34 (24%), 11/34 (32%), and 23/34 (68%) in the corticosteroid and CA CRI group. All-cause mortality at 100 days was not significantly different between groups (P = .62). Clinically relevant treatment-related adverse effects were not observed. We foundno difference in outcome between corticosteroid monotherapy and combined cytarabine CRI and corticosteroid therapy at 7, 30, and 100 days after diagnosis in dogs with MUO.

High Dose Cytosine Arabinoside- Induced Asymptomatic Bradycardia A Rare Case of Concurrent Pneumoretroperitoneum, Pneumomediastinum, Pneumothorax and Subcutaneous Emphysema Seen After Colonoscopy

Coexistence of pneumoretroperitoneum, pneumomediastinum, pneumothorax and subcutaneous emphysema after colonoscopy is a rarely seen condition. We present this rare clinical condition seen after colonoscopy to contribute to the literature. A 62-year-old male patient, who was operated for acute abdomen two years ago, underwent colonoscopy due to colon stenosis. He applied with the complaints of swelling in the neck and subcutaneous swelling in the chest and abdomen after the procedure. Pneumoretroperitoneum, pneumomediastinum and subcutaneous emphysema were detected in the patient In case of subcutaneous emphysema to be seen after colonoscopy, the possibility of pneumomediastinum and pneumothorax should also be considered.

High Dose Cytosine Arabinoside- Induced Asymptomatic Bradycardia

Cytosine Arabinoside (Cytarabine) is commonly used agents in acute myeloid leukemia (AML). Cardiovascular side effects are not common during treatment. We aimed to present asymptomatic bradycardia developed during the first consolidation treatment in a patient with acute myeloid leukemia. A 34-year-old male patient was diagnosed with AML in February. After induction chemotherapy, high dose cytarabine treatment was started at 2x1.5 grams/m² for consolidation treatment. On the 11th day of the treatment, his pulse decreased to 39 beats/min. On the 12th day after the initiation of high dose cytosine arabinoside treatment (6 days after chemotherapy treatment ends), the patient's pulse rate was above 50/min, and there was no bradycardia in the following days. Other causes of other causes of bradycardia were excluded. It was reported that the patient had sinus bradycardia with an ejection fraction of 65% and his heart rate was rhythmic. There are seven patients with acute myeloid leukemia, one patient with acute lymphoblastic leukemia, one patient with non-Hodgkin's lymphoma, and one patient with Hodgkin's lymphoma who reported high dose cytosine arabinoside associated bradycardia. In addition, one patient with acute myeloid leukemia developed bradycardia with low dose cytosine arabinoside. Our case is the 11th case in the literature that develops bradycardia due to cytarabine.

Clinical features, treatment, and outcome of juvenile dogs with meningoencephalitis of unknown etiology.

The information relating to the outcome specifically for juvenile dogs with meningoencephalitis of unknown etiology (MUE) is lacking. To describe the clinical presentation, diagnostic findings, treatment, and outcome in a cohort of dogs with MUE <52 weeks old. Thirty-four client-owned dogs. Multicenter retrospective case series. Records from 5 referral centers were searched. Data was extracted from the medical records and referring veterinarians were contacted for survival data if this was not available from the record. The mean age was 31 weeks; the youngest dog was 11 weeks and 3 dogs were <16 weeks old. Altered mentation (71%), ataxia (44%), seizures (29%), and circling (26%) were the most common presenting complaints. Neuroanatomical localization was to the forebrain (38%), multifocal (35%), brainstem (18%), and cerebellum (12%). Corticosteroid monotherapy (n = 15) and corticosteroid plus cytosine arabinoside (n = 15) were used in equal proportions. Outcome data was available for 26 dogs, 8 (31%) were alive at the time of data collection with a follow-up range of 135 to 2944 days. Death or euthanasia was related to MUE in 17/18 dogs that died during the study period. Kaplan-Meier survival analysis demonstrated a median survival time for all-cause death of 84 days. The prognosis for MUE in this subset of dogs was considered poor.

The use of BRAF-inhibitors as monotherapy and in combination with cytosine arabinoside and 2-chloro-2’deoxyadenosine in pediatric patients with different forms of Langerhans cell histiocytosis

Background. Langerhans cell histiocytosis (LCH) is a rare disease that occurs due to abnormal proliferation and expansion of myeloid precursors. The occurrence of mutations in genes that encode key kinases of MAPK-signaling pathway leads to its pathological activation and has been shown the cause of disease. Mutations in BRAF and MAP2K1 genes are the most frequent among LCH patients. The effectiveness of BRAF-inhibitors in LCH patients has been shown in numerous studies.The purpose of the study – analyze the experience of BRAF-inhibitor vemurafenib administration as monotherapy and in combination with cytosine arabinoside (ARA-C) and 2-chloro-2'-deoxyadenosine (2-CdA) in pediatric patients with different forms of LCH.Materials and methods. Fifteen patients with various forms of LCH were enrolled in the study. BRAF mutations were detected in 14 patients, mutation in the MAP2K1 gene was detected in one case. Patients with “risk organ” (RO) involvement were included in the first group (n = 9). These patients received combined therapy with vemurafenib and ARA-C/2-CdA. Patients without RO involvement, included in group 2 (n = 6), received vemurafenib as monotherapy. The assessment of the response to the therapy in group 1 was carried out in accordance with the DAS scale, in group 2 in accordance with the RECIST v1.1. The toxicity assessment in both groups was carried out in accordance with the CTCAE v5.0.Results. All patients in group 1 achieved non-active disease status with a median of 35 (28–61) days. In group 2 partial response to vemurafenib was achieved in 5 cases. Relapse after targeted therapy termination was diagnosed in two patients. Photodermatitis was the most common side effect of targeted therapy.Conclusions. The use of vemurafenib was effective in both groups. There were no cases of grade III–IV toxicity according to CTCAE v5.0 associated with vemurafenib administration in this study. The combination of vemurafenib and ARA-C/2-CdA showed high efficacy and good tolerability in group 1. Two cases of disease relapse after targeted therapy cessation in group 2 show that the monotherapy approach does not always allow to achieve long-term remission in LCH patients.

Oxidation of Allura Red AC Using the NaHCO3-activated H2O2 System Catalyzed with Cobalt Supported on Al-PILC

The oxidation of aqueous solutions containing Allura Red AC (AR–AC) using bicarbonate-activated peroxide (BAP) and cobalt-impregnated pillared clay (Co/Al–PILC) as the catalyst was investigated. Using the CCD-RMS approach (central composite design–response surface methodology), the effects of dye, H2O2, and NaHCO3 concentrations on AR–AC degradation were studied. The decolorization, total nitrogen (TN), and total carbon (TC) removals were the analyzed responses, and the experimental data were fitted to empirical quadratic equations for these responses, obtaining coefficients of determination R2 and adjusted-R2 higher than 0.9528. The multi-objective optimization conditions were [dye] = 21.25 mg/L, [H2O2] = 2.59 mM, [NaHCO3] = 1.25 mM, and a catalyst loading of 2 g/L. Under these conditions, a decolorization greater than 99.43% was obtained, as well as TN and TC removals of 72.82 and 18.74%, respectively, with the added advantage of showing cobalt leaching below 0.01 mg/L. Chromatographic analyses (GC–MS and HPLC) were used to identify some reaction intermediates and by-products. This research showed that wastewater containing azo dyes may be treated using the cobalt-catalyzed BAP system in heterogeneous media.