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PURPOSE: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)–fused tumors, emphasizing access, responses, side effects, and outcomes. PATIENTS AND METHODS: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. RESULTS: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. CONCLUSION: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil. [ABSTRACT FROM AUTHOR]

Polymethylmethacrylate (PMMA)‐based cements are used for bone reparation due to their biocompatibility, suitable mechanical properties, and mouldability. However, these materials suffer from high exothermic polymerization and poor bioactivity, which can cause the formation of fibrous tissue around the implant and aseptic loosening. Herein, we tackled these problems by adding Sr2+‐substituted hydroxyapatite nanoparticles (NPs) and a porogenic compound to the formulations, thus creating a microenvironment suitable for the proliferation of osteoblasts. The NPs resembled the structure of the bone's apatite and enabled the controlled release of Sr2+. Trends in the X‐ray patterns and infrared spectra confirmed that Sr2+ replaced Ca2+ in the whole composition range of the NPs. The inclusion of an effervescent additive reduced the polymerization temperature and lead to the formation of highly porous cement exhibiting mechanical properties comparable to the trabecular bone. The formation of an opened and interconnected matrix allowed osteoblasts to penetrate the cement structure. Most importantly, the gas formation confined the NPs at the surface of the pores, guaranteeing the controlled delivery of Sr2+ within a concentration sufficient to maintain osteoblast viability. Additionally, the cement was able to form apatite when immersed into simulated body fluids, further increasing its bioactivity. Therefore, we offer a formulation of PMMA cement with improved in vitro performance supported by enhanced bioactivity, increased osteoblast viability and deposition of mineralized matrix assigned to the loading with Sr2+‐substituted hydroxyapatite NPs and the creation of an interconnected porous structure. Altogether, our results hold promise for enhanced bone reparation guided by PMMA cements. [ABSTRACT FROM AUTHOR]

HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all‐trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA‐induced differentiation in APL. We observed higher (5‐ to 40‐fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short‐hairpin RNA led to cell death in ATRA‐sensitive NB4 and resistant NB4‐R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4‐R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis‐specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4‐R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4‐R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance. [ABSTRACT FROM AUTHOR]

The main objective of this work is to use soybean hull (SBH) waste as an adsorbent for the removal of two industrial textile dyes: Reactive Blue 21 (RB21) and Reactive Yellow 145 (RY145). Physical characterization of SBH and kinetic and equilibrium experiments were performed to determine the adsorption conditions. The best adsorption condition was pH 2.0 because the zero electrical charge of soybean hulls (pHZ = 0) is 5.27; thus, in an acidic pH, the adsorbent is positively charged, and the dyes keep their anionic charges due to the –SO3− and –OSO3− groups. Kinetic data were better represented by the Elovich kinetic model, evidencing two well-differentiated mass transfer regions, which agrees with a pseudo-second-order kinetic mechanism. The experimental data showed that RB21 and RY145 were fitted with Hill and Redlich–Peterson isotherm models, respectively. Consequently, the maximum adsorption capacities of SBH for RB21 and RY145 dyes were 149 mg/g and 87 mg/g, respectively. Dye adsorption in packed bed column was also assayed at different bed heights, flow rates, and inlet concentration of dyes. The Thomas, Yoon–Nelson, and modified dose-response (MDR) models fitted well to the breakthrough curves, the MDR model being the one with the highest correlation coefficients, with 96.5% and 94.4% removal of RY145 and RB21 dyes, respectively. [ABSTRACT FROM AUTHOR]

Current cure rates for retinoblastoma (RB) are very high in developed countries. Nonetheless, in less privileged places worldwide, delayed diagnosis and refusal to adhere to treatment still endure an obstacle to improve overall patient survival. Thus, the access to consistent biomarkers for diagnosis at an earlier stage may facilitate treatment and improve outcomes. Over recent years, much attention has been focused on miRNAs, key post-transcriptional regulators that when altered, largely contribute to carcinogenesis and tumor progression. Many of the ~ 2500 microRNAs described in humans have shown differential expression profiles in tumors. In this review, we summarize current data about the roles of miRNAs in RB along with their value as diagnostic/prognostic factors using electronic databases such as PubMed. We reviewed the importance of miRNA in RB biology and discussed their implications in clinic intervention. Several miRNAs have pointed out reliable diagnostic and prognostic molecular biomarkers. The emergence of targeted therapies has significantly improved cancer treatment. In the near future, the modulation of miRNAs will represent a good treatment strategy. [ABSTRACT FROM AUTHOR]

The adsorption of commercial trypsin (Try) onto epichlorohydrin cross‐linked alginate–guar gum matrix has been studied at equilibrium in batch and in fixed bed column. Experiments were conducted to study the effect of ionic strength, temperature and to obtain a thermodynamic characterization of the adsorption process. The resulting adsorption isotherm fitted the Hill equation. Experimental breakthrough curve profiles were compared with the theoretical breakthrough profiles obtained from the mathematical model, bed depth service time. At pH 5.0, 1.0 g hydrated matrix adsorbed 480.0 milligram of Try per gram of dried bed. The desorption process showed 80% of Try recovery in 50 mM phosphate buffer, pH 7.00—500 mM NaCl—20% propylene glycol. The obtained results were applied to an adsorption/washing/desorption process with fresh pancreas homogenate yielded 20% of recovery and 5.7 purification factor of Try. The matrix remained functional until the fifth cycle of repeated batch enzyme adsorption. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018 [ABSTRACT FROM AUTHOR]

Introduction: Medulloblastoma (MB) is an embryonal tumour that originates from genetic deregulation of cerebellar developmental pathways and is classified into 4 molecular subgroups: SHH, WNT, group 3, and group 4. Hydroxymethylation levels progressively increases during cerebellum development suggesting a possibility of deregulation in MB pathogenesis. The aim of this study was to investigate global hydroxymethylation levels and changes in TET and IDH gene expression in MB samples compared to control cerebellum samples.Methods: The methods utilized were qRT-PCR for gene expression, dot-blot and immunohistochemistry for global hydroxymethylation levels and sequencing for the investigation of IDH mutations.Results: Our results show that global hydroxymethylation level was decreased in MB, and low 5hmC level was associated with the presence of metastasis. TET1 expression levels were decreased in the WNT subgroup, while TET3 expression levels were decreased in the SHH subgroup. Reduced TET3 expression levels were associated with the presence of events such as relapse and death. Higher expression of IDH1 was observed in MB group 3 samples, whereas no mutations were detected in exon 4 of IDH1 and IDH2.Conclusion: These findings suggest that reduction of global hydroxymethylation levels, an epigenetic event, may be important for MB development and/or maintenance, representing a possible target in this tumour and indicating a possible interaction of TET and IDH genes with the developmental pathways specifically activated in the MB subgroups. These genes could be specific targets and markers for each subgroup. [ABSTRACT FROM AUTHOR]

Bone defects created after curettage of benign bone tumors are customarily filled with solid poly(methyl methacrylate) (PMMA) or other bone substitutes. In this study, we depicted a porous PMMA-based cement (produced by mixing sodium bicarbonate and citric acid) and evaluated the prospect of its clinic application. Cement samples were characterized by high-performance liquid chromatography (HPLC) coupled to mass spectrometry and its cytotoxicity evaluated in fibroblast cultures. Implantation in rabbits allowed the histologic analysis of bone, kidneys, and liver for toxicity and coagulation tests, and MRI images for hemostasis evaluation. Osseointegration was analyzed through radiography, microtomography (micro-CT), SEM, and histology of sheep specimens. Rabbit specimens were analyzed 1, 4, and 7 days after implantation of porous or solid bone cement in 6.0 mm femoral defects. Sheep specimens were analyzed 3 and 6 months after implantation or not of porous or solid cement in 15.0 mm subchondral tibial defects. The production process did not release any detectable toxic substance but slightly reduced fibroblast proliferation in vitro. Until 7 days after surgery, no local or systemic alterations could be detected in histology, or hematoma formation in histology or MRI. Sheep implants showed 6 mm linear ingrowth from the bone-cement interface and 20% bone ingrowth considering the whole defect area. Radiography, micro-CT, SEM, and histology confirmed these findings. We conclude that our porous PMMA-based cement is an attractive alternative treatment for bone defect filling that combines osseointegration and early weight bearing. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 649-658, 2018. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the impact of gross total resection of giant supratentorial brain tumors (GSBT) on survival and neurological outcome in a consecutive single-center pediatric series. Methods: Clinical data of 23 patients under 18 years of age operated with GSBT (≥5 cm in diameter) were reviewed to determine epidemiological aspects, clinical presentation, associated factors, histopathological features, and outcome. Volumetric measurements were performed on magnetic resonance imaging or computed tomography scans obtained at the time of the initial surgical procedure. Results: The group included 23 patients (mean age 4.5 years). Signs and symptoms of raised intracranial pressure were present in 19 patients (82.6 %). The most frequent tumor location was the parietal lobe in 19 patients (82.6 %), and the mean tumor volume was 208 cm. Gross total or radical resection was achieved in all patients. Histopathological analysis revealed malignant brain tumors in 18 cases (78.2 %). The most common neoplasm was choroid plexus carcinoma in seven (30.4 %). Mean intraoperative blood transfusion volume was 51.2 ml/kg. Chemotherapy and/or radiotherapy were performed as adjuvant treatment in 16 patients (69.5 %). Mean length of follow-up was 36.7 months. Tumor malignancy grade significantly correlated with recurrence of the disease ( P = 0.03) and death ( P = 0.01), as opposed to tumor location, size, and extension to the ventricles. Conclusions: Our clinical experience suggests that tumor mass reduction by en bloc surgery seems to be an effective approach in pediatric patients with GSBT, relieving symptoms related to raised intracranial pressure and providing a better response to adjuvant treatment. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study was to determine the epidemiology, clinical presentation, associated factors, pathological features, and treatment outcome of pediatric meningiomas in a single-center institution. Methods: Clinical data of 15 patients under 18 years of age operated on for meningiomas from January 1994 to December 2010 were reviewed. Results: The study group included nine males and six females (mean age of 13 years at surgery). The most common symptoms at presentation were headaches in 6 out of 15 (40 %), raised intracranial pressure in 3 out of 15 (20 %), and seizures in 3 out of 15 (20 %). Sole operated tumors were found in 12 out of 15 (80 %), whose location is as follows: parasagittal in 4 out of 12 (33.3 %), 2 in the convexity (16.6 %), 2 at the skull base (16.6 %), and 4 in other sites (33.3 %). Six children presented with radiation-induced (RT) meningiomas and five had evidence of neurofibromatosis type 2 (NF2). Three patients had multiple meningiomas (all of them had NF2). Simpson's grade I excision was achieved in 12 out of 15 (80 %). On histopathology, 11 out of 15 (73.3 %) were grade I and 4 out of 15 (26.6 %) were grade II (all of them atypical). Five tumors (33.3 %) recurred, four of which had RT or NF2. During the mean follow-up period of 5 years, 12 out of 15 (80 %) had a good outcome (GOS = 5). Conclusions: Childhood meningiomas are uncommon lesions with a slight male predominance. Absence of large series with long follow-up precludes any definite conclusions on the clinical course and outcome of these tumors. Associated factors (such as RT and NF2), location, and extent of excision appear to be more important than histopathological grade in predicting outcome. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma remains one of the most devastating human malignancies, and despite therapeutic advances, there are no drugs that significantly improve the patient survival. Altered expression of the Aurora kinases was found in different malignancies, and their inhibition has been studied in cancer therapy. In this study, we analyzed the expression of Aurora A and Aurora B in glioblastoma samples and also analyzed whether the effects of Aurora kinase inhibition were associated with temozolomide or not on cell lines and primary cultures of glioblastoma. Materials and methods: RT-PCR assays were used to determine the mRNA expression in glioblastoma tumor samples and in the cell lines. Cell proliferation was measured by XTT assay, and apoptosis was determined by flow cytometry. Drug combination analyses were made based in Chou-Talalay method. Gamma radiation for clonogenic survival used the doses of 2, 4 and 6 Gy. Changes in Aurora B level were assessed by Western blot analysis. Results: Aurora A and B were expressed in glioblastoma samples as well as in the glioblastoma cell lines ( n = 6). Moreover, ZM447439, a selective Aurora kinase inhibitor, decreased the proliferation separately and synergistically with temozolomide in primary cultures and cell lines of glioblastoma. ZM also enhanced the effects of radiation on the two cell lines studied (U343 and U251), mainly when associated with TMZ in U343 cells. Treatment with ZM induced apoptotic cell death and diminished Aurora B protein level. Conclusions: These data suggest that Aurora kinase inhibition may be a target for glioblastoma treatment and could be used as adjuvant to chemo- and radiotherapy. [ABSTRACT FROM AUTHOR]

Valonea tannin is a natural product readily extracted from acorn shells that has been suggested to have potential skin whitening properties. This study investigated the tyrosinase inhibition activity of extracted valonea tannin and the associated structure–function activity. Nuclear magnetic resonance spectroscopy and molecular weight analysis with gel permeation chromatography revealed that valonea tannin could be characterized as a hydrolysable tannin with galloyl, hexahydroxydiphenoyl and open formed-glucose moieties and an average molecular weight of 3042 ± 15 Da. Tyrosinase inhibition assays demonstrated that valonea tannin was 334 times more effective than gallic acid and 3.4 times more effective than tannic acid, which may relate to the larger molecular size. Kinetic studies of the inhibition reactions indicated that valonea tannin provided tyrosinase inhibition through mixed competitive–uncompetitive way. Stern–Volmer fitted fluorescence quenching analysis, isothermal titration calorimetry analysis and in silico molecule docking showed valonea tannin non-selectively bound to the surface of tyrosinase via hydrogen bonds and hydrophobic interactions. Inductively coupled plasma-optical emission spectroscopy and free radical scavenging assays indicated the valonea tannin had copper ion chelating and antioxidant ability, which may also contribute to inhibition activity. These results demonstrated the structure–function activity of valonea tannin as a highly effective natural tyrosinase inhibitor that may have commercial application in dermatological medicines or cosmetic products. [ABSTRACT FROM AUTHOR]

Lactobacillus bulgaricus is a LAB strain which is capable of producing bacteriocin substances to inhibit Staphylococcus aureus. The aim of this study was to purify a bacteriocin-like inhibitory substance (BLIS) produced by L. bulgaricus FTDC 1211 using an aqueous impregnated resins system consisting of polyethylene-glycol (PEG) impregnated on Amberlite XAD4. Important parameters influencing on purification of BLIS, such as the molecular weight and concentration of PEG, the concentration and pH of sodium citrate and the concentration of sodium chloride, were optimized using a response surface methodology. Under optimum conditions of 11% (w/w) of PEG 4000 impregnated Amberlite XAD4 resins and 2% (w/w) of sodium citrate at pH 6, the maximum purification factor (3.26) and recovery yield (82.69% ± 0.06) were obtained. These results demonstrate that AIRS could be used as an alternate purification system in the primary recovery step. [ABSTRACT FROM AUTHOR]

This review is focused on the study of the effects of grape seed and skin extract (GSSE) on human health. GSSE contains high concentrations of important polyphenolic substances with high biological activity. This review is a summary of studies that investigate the effects of GSSE on diabetes mellitus, cardiovascular disease and cancer, its neuroprotective effect, and its effects on the gastrointestinal tract and other health complications related to these diseases. The results of the studies confirm that the anti-inflammatory, antiapoptotic, and pro-proliferative effects of "Vitis vinifera L." seed extract reduce the level of oxidative stress and improve the overall lipid metabolism. [ABSTRACT FROM AUTHOR]