Ecotoxicological Estimation of 4-Cumylphenol, 4-t-Octylphenol, Nonylphenol, and Volatile Leachate Phenol Degradation by the Microscopic Fungus Umbelopsis isabellina Using a Battery of Biotests.

The phenolic xenobiotics nonylphenol (NP), 4-tert-octylphenol (4-t-OP), and 4-cumylphenol (4-CP) have the potential to seriously disrupt the endocrine system. Volatile phenols (VPs), especially those present in landfill leachate, also adversely affect the health of numerous organisms. Microbial degradation of xenobiotics can result in the formation of intermediates with higher toxicity than the precursor substrates. Therefore, the main aim of this study was to assess the changes in environmental ecotoxicity during the biotransformation of nonylphenol, 4-tert-octylphenol, 4-cumylphenol and volatile phenols by Umbelopsis isabellina using a battery of biotests. The application of bioindicators belonging to different taxonomic groups and diverse trophic levels (producers, consumers, and reducers) indicated a significant reduction in toxicity during the cultivation of fungus cultures both for nonylphenol, 4-tert-octylphenol, 4-cumylphenol and volatile phenols. The rate of toxicity decline was correlated with the degree of xenobiotic biotransformation. Removal of 4-cumylphenol and 4-tert-octylphenol also led to a decrease in the anti-androgenic potential. Moreover, this is the first report demonstrating the anti-androgenic properties of 4-cumylphenol. The results showed that U. isabellina is an attractive tool for the bioremediation and detoxification of contaminated environments.

An investigation into the cutting efficiency of a novel degradable glass as an alternative to alumina powder in air abrasion cutting of enamel.

OBJECTIVES: To develop and test the cutting efficiency of a novel degradable glass as an alternative media to alumina powder for air abrasion. MATERIALS AND METHODS: A zinc-based glass (QMZK2) was designed, produced, and evaluated with a multi-modality imaging analysis. The glass dissolution study was carried out in three acids, using ICP-OES (inductively coupled plasma optical emission spectroscopy) at 5 different time points: 2.5, 5, 10, 60, and 240 min. The cutting efficiency of both materials was tested under the same parameters on slabs of elephant enamel. A stained fissure of a molar tooth was air abraded with the glass and evaluated with X-ray micro-tomography before and after air abrasion. RESULTS: The particle size distribution of the glass was similar to that of alumina 53 µm but with a slightly greater dispersion of particle size. The shape of the particles was angular, appropriate for cutting purposes. The dissolution study showed that the glass dissolved rapidly in acidic conditions at all time points. Between the two variables, pressure and powder flow, pressure was found to influence the cutting speed to a greater extent than powder flow. CONCLUSIONS: Alumina powder was found to perform significantly better in 4 of the 9 conditions tested on elephant enamel, QMZK2 in one, and no significant differences were found for the rest of the 4 conditions. The QMZK2 seems to offer promising results as an alternative material to alumina. CLINICAL RELEVANCE: QMZK2 glass has the potential for replacing aluminum oxide as a degradable material in air abrasion technology.

Detoxification and simultaneous removal of phenolic xenobiotics and heavy metals with endocrine-disrupting activity by the non-ligninolytic fungus Umbelopsis isabellina.

Organic and inorganic pollutants well known to interfere with the major functions of the endocrine system co-occur widely in contaminated ecosystems. The aim of the study was to evaluate the ability of Umbelopsis isabellina fungus to simultaneously remove and detoxify multiple environmentally significant endocrine disruptors: the heavy metals Cd(II), Zn(II), Mn(II), Pb(II) and Ni(II) and the phenolic xenobiotics nonylphenol (t-NP), 4-cumylphenol (CP) and 4-tert-octylphenol (4-t-OP). The effects of the metals on fungal growth and efficiency of single-metal uptake were also investigated. U. isabellina exhibited considerable tolerance to Zn(II), Mn(II), Pb(II) and Ni(II), with IC50/24 values ranging from 5.08 for Ni(II) to 13.1 mM for Zn(II). In the presence of CP, the maximum efficiency of Pb(II) removal increased 25% relative to that of the control. Supplementation with Mn(II) or Zn(II) enhanced the 4-t-OP degradation by 18 or 9%, respectively, after 6 h of cultivation. Ecotoxicological assays monitoring bioindicators from different aquatic ecosystems revealed detoxification coinciding with the removal of metals and organic xenobiotics from binary mixtures. This work indicates the potential of a single microorganism, U. isabellina, to remove both heavy metals and organic xenobiotics from co-contaminated sites, making it a suitable candidate for the development of bioremediation strategies.

Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has a bidirectional association with metabolic syndrome. It affects up to 30% of the general population, 70% of individuals with diabetes and 90% with obesity. The main histological hallmark of progressive NAFLD is fibrosis. There is a bidirectional epidemiological link between periodontitis and metabolic syndrome. NAFLD, periodontitis and diabetes share common risk factors, are characterised by inflammation and associated with changes in commensal bacteria. Therefore we tested the hypothesis that periodontitis is associated with NAFLD and with significant fibrosis in two study groups. METHODS: We analyzed data from a population-based survey and a patient-based study. NHANES III participants with abdominal ultrasound and sociodemographic, clinical, and oral examination data were extracted and appropriate weighting applied. In a separate patient-based study, consenting patients with biopsy-proved NAFLD (or with liver indices too mild to justify biopsy) underwent dental examination. Basic Periodontal Examination score was recorded. RESULTS: In NHANES, periodontitis was significantly associated with steatosis in 8172 adults even after adjusting for sociodemographic factors. However, associations were fully explained after accounting for features of metabolic syndrome. In the patient-based study, periodontitis was significantly more common in patients with biopsy-proven NASH and any fibrosis (F0-F4) than without NASH (p = 0.009). Periodontitis was more common in patients with NASH and significant fibrosis (F2-4) than mild or no fibrosis (F0-1, p = 0.04). CONCLUSIONS: Complementary evidence from an epidemiological survey and a clinical study show that NAFLD is associated with periodontitis and that the association is stronger with significant liver fibrosis.

Degradation and toxicity reduction of the endocrine disruptors nonylphenol, 4-tert-octylphenol and 4-cumylphenol by the non-ligninolytic fungus Umbelopsis isabellina.

Nonylphenol (NP), 4-tert-octylphenol (4-t-OP) and 4-cumylphenol (4-CP) are pollutants that are known as endocrine disruptors mainly due to their estrogen-mimicking activity. These phenolic substances are used in a wide range of industrial and commercial applications. In the present study, biodegradation of tNP, 4-t-OP and 4-CP using the non-ligninolytic fungus Umbelopsis isabellina was investigated. After 12h of incubation, more than 90% of initially applied tNP, 4-t-OP and 4-CP (25mgL(-1)) were eliminated. GC-MS analysis revealed several derivatives mainly (hydroxyalkyl)phenols. Moreover, xenobiotic biotransformation led to the formation of intermediates with less harmful effects than the parent compounds. For all xenobiotics, a decrease in growth medium toxicity was observed, using Artemia franciscana and Daphnia magna as bioindicators. The results indicate that U. isabellina has potential in the degradation and detoxification of contaminants with endocrine activity. Moreover, this is the first report demonstrating that a microorganism is capable of effective 4-CP elimination.

Complete response and long-term survival (>20 years) of a child with tectal glioma: a case report.

Tectal glioma is a midbrain tumor. The patient generally presents with symptoms related to increased intracranial pressure and requires treatment for hydrocephalus. No effective pharmacological treatments have yet been introduced. This report discusses a case of a 13-year-old male diagnosed with tectal glioma who obtained a complete response and long-term survival after the treatment with antineoplastons (ANP) in phase II trial. Prior treatment consisted of placement of a ventriculoperitoneal shunt. After 6 years of stabilization there had been an increase in tumor size with signs of malignant transformation. The patient received treatment with ANP A10 and AS2-1 infusions for 20 months, obtained a complete response, and was switched to maintenance with ANP capsules. All treatments were discontinued in December 2003. Adverse events according to CTCAE v3.0 included: hypernatremia (two events of grade 3, one event of grade 2, four events of grade 1), one case of fatigue (grade 2), and one allergic reaction (grade 1). Currently, over 20 years from his diagnosis and over 13 years from treatment start he is symptom-free and leads a normal life. This report indicates that it is possible to obtain long-term survival of a child with tectal glioma with currently available investigational treatment.

Biodegradation and utilization of 4-n-nonylphenol by Aspergillus versicolor as a sole carbon and energy source.

4-n-Nonylphenol (4-n-NP) is an environmental pollutant with endocrine-disrupting activities that is formed during the degradation of nonylphenol polyethoxylates, which are widely used as surfactants. Utilization of 4-n-NP by the filamentous fungus Aspergillus versicolor as the sole carbon and energy source was investigated. By means of gas chromatography-mass spectrometry, we showed that in the absence of any carbon source other than 4-n-NP in the medium, A. versicolor completely removed the xenobiotic (100 mg L(-1)) after 3 d of cultivation. Moreover, mass spectrometric analysis of intracellular extracts led to the identification of eight intermediates. The mineralization of the xenobiotic in cultures supplemented with 4-n-NP [ring-(14)C(U)] as a growth substrate was also assessed. After 3 d of incubation, approximately 50% of the initially applied radioactivity was recovered in the form of (14)CO2, proving that this xenobiotic was completely metabolized and utilized by A. versicolor as a carbon source. Based on microscopic analysis, A. versicolor is capable of germinating spores under such conditions. To confirm these observations, a microcalorimetric method was used. The results show that even the highest amount of 4-n-NP initiates heat production in the fungal samples, proving that metabolic processes were affected by the use of 4-n-NP as an energetic substrate.

The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma.

BACKGROUND: Brainstem gliomas (BSG) are relatively rare tumors of which recurrent pediatric diffuse intrinsic pontine gliomas (RPDIPG) comprise a distinct group. Numerous trials have been conducted on RPDIPG, none of which have resulted in identifying any proven pharmacological treatment benefit. This study included 40 patients diagnosed with different types of BSG, but it was decided to describe first the encouraging results in the most challenging group of RPDIPG. MATERIALS AND METHODS: This single-arm phase II study evaluated the efficacy and safety of the combination of antineoplastons A10 and AS2-1 (ANP) in patients with RPDIPG. Seventeen patients (median age 8.8 years) were enrolled, and all were diagnosed with RPDIPG. ANP was administered intravenously daily. Efficacy analyses were conducted in this group of patients. RESULTS: In this group, complete responses were observed in 6 % of patients, partial responses in 23.5 %, and stable disease in 11.8 %. Six-month progression-free survival was 35.3 %. One-year overall survival was 29.4 %, 2 years 11.8 %, and 5, 10, and 15 years 5.9 %. One patient with DIPG is alive over 15 years post-treatment. Grade 3 and higher toxicities including hypokalemia and fatigue occurred in 6 %, hypernatremia in 18 %, fatigue and urinary incontinence in 6 %, and somnolence in 12 %. In a single patient, grade 4 hypernatremia occurred when he was on mechanical ventilation. He was disconnected from the ventilator and died from brain tumor according to the attending physician. Responding patients experienced improved quality of life. CONCLUSION: The results suggest that ANP shows efficacy and acceptable tolerability profile in patients with RPDIPG.

Long-term survival (>13 years) in a child with recurrent diffuse pontine gliosarcoma: a case report.

Pediatric gliosarcoma (GS) is a rare variant of glioblastoma multiforme. The authors describe the case of an unusual pontine location of GS in a 9-year-old boy who was initially diagnosed with low-grade astrocytoma (LGA) that was successfully controlled for 4 years. Subsequently, his brain tumor transformed into a GS. Prior treatment of his LGA included subtotal tumor resection 3 times, standard radiation therapy, and Gamma Knife procedure twice. His LGA was also treated with a standard chemotherapy regimen of carboplatin and vincristine, and his GS with subtotal resection, high-dose cyclophosphamide, and thiotepa with stem cell rescue and temozolomide. Unfortunately, he developed disseminated disease with multiple lesions and leptomeningeal involvement including a tumor occupying 80% of the pons. Upon presentation at our clinic, he had rapidly progressing disease. He received treatment with antineoplastons (ANP) A10 and AS2-1 for 6 years and 10 months under special exception to our phase II protocol BT-22. During his treatment with ANP his tumor stabilized, then decreased, and, ultimately, did not show any metabolic activity. The patient's response was evaluated by magnetic resonance imaging and positron emission tomography scans. His pathology diagnosis was confirmed by external neuropathologists, and his response to the treatment was determined by central radiology review. He experienced the following treatment-related, reversible toxicities with ANP: fatigue, xerostomia and urinary frequency (grade 1), diarrhea, incontinence and urine color change (grade 2), and grade 4 hypernatremia. His condition continued to improve after treatment with ANP and, currently, he complains only of residual neurological deficit from his previous surgery. He achieved a complete response, and his overall and progression-free survival is in excess of 13 years. This report indicates that it is possible to obtain long-term survival of a child with a highly aggressive recurrent GS with diffuse pontine involvement with a currently available investigational treatment.

Influence of sodium content on the properties of bioactive glasses for use in air abrasion.

Air abrasion is used in minimally invasive dentistry for preparing cavities, while removing no or little sound dentine or enamel, and the use of bioactive glass (rather than alumina) as an abrasive could aid in tooth remineralization. Melt-derived bioactive glasses (SiO2-P2O5-CaO-CaF2-Na2O) with low sodium content (0 to 10 mol% Na2O in exchange for CaO) for increased hardness, high phosphate content for high bioactivity and fluoride content for release of fluoride and formation of fluorapatite were produced, and particles between 38 and 80 µm in size were used for cutting soda-lime silicate glass microscope slides and human enamel. Vickers hardness increased with decreasing Na2O content, owing to a more compact silicate network in low sodium content glasses, resulting in shorter cutting times. Cutting times using bioactive glass were significantly longer than using the alumina control (29 µm) when tested on microscope slides; however, glasses showed more comparable results when cutting human enamel. The bioactive glasses formed apatite in Tris buffer within 6 h, which was significantly faster than Bioglass® 45S5 (24 h), suggesting that the hardness of the glasses makes them suitable for air abrasion application, while their high bioactivity and fluoride content make them of interest for tooth remineralization.

Surface of root cementum following air-polishing with bioactive hydroxyapatite (Ca and P mapping). A pilot study.

Air-polishing is a well-known and common technique to remove plaque, tartar and different kind of stains from teeth, using abrasive materials. Commonly used cleaning powders contain Al (aluminium) which is still controversial in terms of its inertness and harmfulness for human body. Nowadays, new air-polishing materials, including biomaterials, are being introduced. In particular, biomaterials the structure of which imitates that of natural tissue are very promising materials of reparative and reconstructive features. The purpose of the study was to assess in vitro the influence of natural hydroxyapatite on cementum surface and to assess superficial qualitative distribution of such elements as calcium and phosphorus before and after air-polishing. Four teeth extracted for periodontal reasons were airpolished. Bioactive hydroxyapatite (prepared in the Cracow Institute of Technology) was a cleaning powder with particle size of up to 10 µm. Bioactive natural hydroxyapatite is a very effective cleaning powder, which removes efficiently tartar from cementum surface and does not cause any damage. The qualitative analysis of cementum images after air-polishing with natural hydroxyapatite showed that the cementum surface was fully saturated with such elements as calcium and phosphorus, which was not observed on control cementum images.

Targeted therapy with antineoplastons A10 and AS2-1 of high-grade, recurrent, and progressive brainstem glioma.

BACKGROUND: Brainstem glioma carries the worst prognosis of all malignancies of the brain. Most patients with brainstem glioma fail standard radiation therapy and chemotherapy and do not survive longer than 2 years. Treatment is even more challenging when an inoperable tumor is of high-grade pathology (HBSG). The objective of this report is to summarize the outcome of patients with HBSG treated with antineoplastons in 4 phase 2 trials. PATIENTS: The following group of 18 patients was evaluable: 4 patients with glioblastomas and 14 patients with anaplastic HBSG. Fourteen patients had diffuse intrinsic tumors. Twelve patients suffered from recurrence, and 6 patients did not have radiation therapy or chemotherapy. METHODS: Antineoplastons, which consist of antineoplaston A10 (A10I) and AS2-1 injections, were given in escalating doses by intravenous injections. The median duration of antineoplaston administration was 5 months, and the average dosage of A10I was 9.22 g/kg/d and of AS2-1 was 0.31 g/kg/d. Responses were assessed by gadolinium-enhanced magnetic resonance imaging and positron emission tomography. RESULTS: The overall survival at 2 and 5 years was 39% and 22%, respectively, and maximum survival was more than 17 years for a patient with anaplastic astrocytoma and more than 5 years for a patient with glioblastoma. Progression-free survival at 6 months was 39%. Complete response was achieved in 11%, partial response in 11%, stable disease in 39%, and progressive disease in 39% of patients. Antineoplastons were tolerated very well with 1 case of grade 4 toxicity (reversible anemia). CONCLUSION: Antineoplastons contributed to more than a 5-year survival in recurrent diffuse intrinsic glioblastomas and anaplastic astrocytomas of the brainstem in a small group of patients.

Long-term survival of high-risk pediatric patients with primitive neuroectodermal tumors treated with antineoplastons A10 and AS2-1.

Primitive neuroectodermal tumors (PNETs) are usually successfully treated with craniospinal radiation and chemotherapy; however, difficulties with standard treatment can be encountered in very young children, in adult patients at high risk of complication from standard treatment, and in patients with recurrent tumors. Thirteen children, either with recurrent disease or high risk, were treated in phase II studies with antineoplastons (ANP). The median age of patients was 5 years, 7 months (range, 1-11). Medulloblastoma was diagnosed in 8 patients, pineoblastoma in 3 patients, and other PNET in 2 patients. Previous treatments included surgery in 12 patients (1 had biopsy only, suboccipital craniotomy), chemotherapy in 6 patients, and radiation therapy in 6 patients. Six patients had not received prior chemotherapy or radiation. The treatment consisted of intravenous infusions of 2 formulations of ANP, A10 and AS2-1, and was administered for an average of 20 months. The average dosage of A10 was 10.3 g/kg/d and of AS2-1 was 0.38 g/kg/d. Complete response was accomplished in 23%, partial response in 8%, stable disease in 31%, and progressive disease in 38% of cases. Six patients (46%) survived more than 5 years from initiation of ANP; 5 were not treated earlier with radiation therapy or chemotherapy. The serious side effects included single occurrences of fever, granulocytopenia, and anemia. The study is ongoing and accruing additional patients. The percentage of patients' response is lower than for standard treatment of favorable PNET, but long-term survival in poor-risk cases and reduced toxicity makes ANP promising for very young children, patients at high risk of complication of standard therapy, and patients with recurrent tumors.

Phase II study of antineoplaston A10 and AS2-1 in children with recurrent and progressive multicentric glioma : a preliminary report.

OBJECTIVE: To evaluate the response rates, survival and toxicity of treatment with antineoplaston A10 and AS2-1 (ANP) in the first 12 children enrolled in our studies diagnosed with incurable recurrent and progressive multicentric glioma. PATIENTS AND METHODS: The patients' median age was 9 years. Six patients were diagnosed with pilocytic astrocytoma, four with low-grade astrocytoma and one with astrocytoma grade 2. In one case of visual pathway glioma, a biopsy was not performed due to a dangerous location. Patients received ANP intravenously initially and subsequently orally. The average duration of intravenous ANP therapy was 16 months and the average dosage of A10 was 7.95 g/kg/day and of AS2-1 was 0.33 g/kg/day. The average duration of oral ANP was 19 months and the average dosage of A10 and AS2-1 was 0.28 g/kg/day. Responses were assessed by MRI according to the National Cancer Institute's criteria and confirmed by PET scans in some cases. RESULTS: Complete response was accomplished in 33%, partial response in 25%, and stable disease in 33% of patients, and there was no progressive disease. One patient was non-evaluable due to only 4 weeks of ANP and lack of follow-up scans. One patient who had stable disease discontinued ANP against medical advice and died 4.5 years later. Ten patients are alive and well from 2 to >14 years post-diagnosis. Only one case of serious toxicity of reversible tinnitus, of one day's duration, was described. The study continues with accrual of additional patients. CONCLUSION: The results of the present study are favourable in comparison with radiation therapy and chemotherapy. We believe that confirmation of these results through further studies may introduce a new promising treatment for incurable paediatric brain tumours.

Long-term survival and complete response of a patient with recurrent diffuse intrinsic brain stem glioblastoma multiforme.

Recurrent diffuse intrinsic brain stem glioblastoma multiforme carries an extremely poor prognosis and a median survival of less than 7 months. In this article, the authors report good results in a 40-year-old man diagnosed with glioblastoma multiforme who received antineoplastons. The patient's brain tumor was diagnosed in May 1999, and he subsequently underwent subtotal tumor resection and standard radiation therapy. Magnetic resonance imaging and positron emission tomography scans documented his tumor recurrence. Approximately 2 months after completion of radiation therapy, he was admitted for administration of intravenous antineoplastons A10 and AS2-1 through a subclavian venous catheter by intermittent bolus injections 6 times per day using a portable pump. Administration of antineoplastons A10 and AS2-1 was over 655 consecutive days with the exception of a few short interruptions. The maximum dosage of A10 was 8.15 g/kg/d and AS2-1 0.35 g/kg/d. Antineoplastons A10 and AS2-1 administration was very well tolerated with only mild reversible side effects. Follow-up magnetic resonance imaging and positron emission tomography scans revealed decrease and eventually disappearance of the tumor. A complete response was documented after approximately 1 year of antineoplastons A10 and AS2-1 administration. More than 4 years later, off antineoplastons A10 and AS2-1, the patient is tumor free, able to carry on normal activities, and works full-time, and his Karnofsky Performance Status increased from 50 to 100. Extensive phase II trials with antineoplastons A10 and AS2-1 in patients with glioblastoma multiforme are nearing completion. These trials may provide more data regarding the efficacy of antineoplastons A10 and AS2-1 in the treatment of glioblastoma multiforme in untreated patients compared to the results in those patients with tumor recurrence after radiation therapy.

Phase II study of antineoplaston A10 and AS2-1 in patients with recurrent diffuse intrinsic brain stem glioma: a preliminary report.

OBJECTIVE: A phase II study of antineoplaston A10 and AS2-1 was conducted to evaluate the antineoplastic activity in patients with recurrent diffuse intrinsic brain stem glioma. PATIENTS AND METHODS: This report describes the results of treatment of the first 12 patients admitted to the study. Patients received escalating doses of antineoplaston A10 and AS2-1 by intravenous bolus injections. The median duration of treatment was 6 months and the average dosage of antineoplaston A10 was 11.3 g/kg/day and of antineoplaston AS2-1 0.4 g/kg/day. Responses were assessed by gadolinium-enhanced magnetic resonance imaging of the head. RESULTS: Of ten evaluable patients, complete response was determined in two cases (20%), partial response in three (30%), stable disease in three (30%) and progressive disease in two (20%). Survival at 2 years was 33.3%. Currently, of all 12 patients, two (17%) were alive and tumour free for over 5 years since initial diagnosis; one was alive for more than 5 years, and another for more than 4 years from the start of treatment. Only mild and moderate toxicities were observed, which included three cases of skin allergy, two cases of anaemia, fever and hypernatraemia, and single cases of agranulocytosis, hypoglycaemia, numbness, tiredness, myalgia and vomiting. CONCLUSION: The results of this study compared favourably with the responses of patients treated with radiation therapy and chemotherapy. The study continues with accrual of additional patients.