The altered metabolic pathways of diffuse large B-cell lymphoma not otherwise specified.

Altered metabolic fingerprints of Diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS) may offer novel opportunities to identify new biomarkers and improve the understanding of its pathogenesis. This study aimed to investigate the modified metabolic pathways in extranodal, germinal center B-cell (GCB) and non-GCB DLBCL NOS from the head and neck. Formalin-fixed paraffin-embedded (FFPE) tissues from eleven DLBCL NOS classified according to Hans' algorithm using immunohistochemistry, and five normal lymphoid tissues (LT) were analyzed by high-performance liquid chromatography-mass spectrometry-based untargeted metabolomics. Partial Least Squares Discriminant Analysis showed that GCB and non-GCB DLBCL NOS have a distinct metabolomics profile, being the former more similar to normal lymphoid tissues. Metabolite pathway enrichment analysis indicated the following altered pathways: arachidonic acid, tyrosine, xenobiotics, vitamin E metabolism, and vitamin A. Our findings support that GCB and non-GCB DLBCL NOS has a distinct metabolomic profile, in which GCB possibly shares more metabolic similarities with LT than non-GCB DLBCL NOS.

Integrated proteomics, phosphoproteomics and metabolomics analyses reveal similarities among giant cell granulomas of the jaws with different genetic mutations.

BACKGROUND: Giant cell granuloma of the jaws are benign osteolytic lesions of the jaws. These lesions are genetically characterized by mutually exclusive somatic mutations at TRPV4, KRAS, and FGFR1, and a fourth molecular subgroup which is wild-type for the three mutations. Irrespective of the molecular background, giant cell granulomas show MAPK/ERK activation. However, it remains unclear if these mutations lead to differences in their molecular signaling in giant cell granulomas. METHODS: Metabolomics, proteomics, and phosphoproteomics analyses were carried out in formalin-fixed paraffin-embedded samples of giant cell granuloma of the jaws. The study cohort consisted of five lesions harboring mutations in FGFR1, six in KRAS, five in TRPV4, and five that were wild-type for these mutations. RESULTS: Lesions harboring KRAS or FGFR1 mutations showed overall similar proteomics and metabolomics profiles. In all four groups, metabolic pathways showed similarity in apoptosis, cell signaling, gene expression, cell differentiation, and erythrocyte activity. Lesions harboring TRPV4 mutations showed a greater number of enriched pathways related to tissue architecture. On the other hand, the wild-type group presented increased number of enriched pathways related to protein metabolism compared to the other groups. CONCLUSION: Despite some minor differences, our results revealed an overall similar molecular profile among the groups with different mutational profile at the metabolic, proteic, and phosphopeptidic levels.

Unveiling metabolic changes in marsupialized odontogenic keratocyst: A pilot study.

OBJECTIVE: We aimed to assess which metabolic pathways would be implicated in the phenotypic changes of the epithelial lining of odontogenic keratocyst after marsupialization, comparing pre- and post-marsupialized lesions with adjacent oral mucosa. MATERIALS AND METHODS: Eighteen formalin-fixed and paraffin-embedded tissues from six subjects were divided into three paired groups: odontogenic keratocyst pre- (n = 6) and post-marsupialization (n = 6), and adjacent oral mucosa (n = 6). The metabolic pathways found in these groups were obtained by high-performance liquid chromatography-mass spectrometry-based untargeted metabolomics performed. RESULTS: Through putative metabolite annotation followed by pathway enrichment and predictive analysis with automated algorithms (Mummichog and Gene Set Enrichment Analysis), we found differences in many cellular processes that may be involved in inflammation, oxidative stress response, keratinocyte-basal membrane attachment, differentiation, and proliferation functions, all relevant to odontogenic keratocyst pathobiology and the phenotype acquired after marsupialization. CONCLUSION: Our study was able to identify several metabolic pathways potentially involved in the metaplastic changes induced by marsupialization of odontogenic keratocysts. An improved comprehension of this process could pave the way for the development of targeted therapies.

A survey on experiences in leachate treatment: Common practices, differences worldwide and future perspectives.

The necessity for landfill leachate treatment is a requisite to reduce the environmental impact related to municipal solid waste landfills and different aspects must be considered while deciding for an appropriate treatment process. For example, it was demonstrated that the landfill leachate stabilization in tropical regions is achieved right after its first year of operation, requiring technologies capable of treating leachates of a higher recalcitrant character if compared to those leachates from temperate regions and same landfill age. In view of its complexity and variability, stand-alone processes (either biological or physicochemical) are often ineffective in attaining the threshold values for its discharge in receiving bodies. Due to that fact, full-scale facilities have adopted integrated routes, harvesting the benefits of both biological and physicochemical processes. The implementation of membrane bioreactors followed by polishing membrane separation process (nanofiltration and reverse osmosis) seems to be a trend in leachate treatment by full-scale treatment plants. This technology is widely employed in China, European countries, and tropical countries as Brazil, generally with a treatment cost lower than the costs related to its disposal in domestic effluent collection systems. From the technologies already employed by full-scale facilities, four integrated routes were proposed for a sensitive analysis considering the treatment of a landfill leachate of different physicochemical characteristics. From all routes, those employing the membrane separation process as a polishing step had a better efficacy in attaining the threshold values for leachate disposal, being that an interesting alternative for leachate polishing by full-scale facilities.

Age-Related Metabolic Pathways Changes in Dental Follicles: A Pilot Study.

Aging is not a matter of choice; it is our fate. The "time-dependent functional decline that affects most living organisms" is coupled with several alterations in cellular processes, such as cell senescence, epigenetic alterations, genomic instability, stem cell exhaustion, among others. Age-related morphological changes in dental follicles have been investigated for decades, mainly motivated by the fact that cysts and tumors may arise in association with unerupted and/or impacted teeth. The more we understand the physiology of dental follicles, the more we are able to contextualize biological events that can be associated with the occurrence of odontogenic lesions, whose incidence increases with age. Thus, our objective was to assess age-related changes in metabolic pathways of dental follicles associated with unerupted/impacted mandibular third molars from young and adult individuals. For this purpose, a convenience sample of formalin-fixed paraffin-embedded (FFPE) dental follicles from young (<16 y.o., n = 13) and adult (>26 y.o., n = 7) individuals was selected. Samples were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS)-based untargeted metabolomics. Multivariate and univariate analyses were conducted, and the prediction of altered pathways was performed by mummichog and Gene Set Enrichment Analysis (GSEA) approaches. Dental follicles from young and older individuals showed differences in pathways related to C21-steroid hormone biosynthesis, bile acid biosynthesis, galactose metabolism, androgen and estrogen biosynthesis, starch and sucrose metabolism, and lipoate metabolism. We conclude that metabolic pathways differences related to aging were observed between dental follicles from young and adult individuals. Our findings support that similar to other human tissues, dental follicles associated with unerupted tooth show alterations at a metabolic level with aging, which can pave the way for further studies on oral pathology, oral biology, and physiology.

The environmental risks of pharmaceuticals beyond traditional toxic effects: Chemical differences that can repel or entrap aquatic organisms.

The aim of the present study was to assess the risks of four different pharmaceutical active compounds (PhACs; diazepam, metformin, omeprazole and simvastatin). Acute and chronic toxicities were studied using the bacterium Aliivibrio fischeri and the microalgae Pseudokirchneriella subcapitata; while the repellency and attractiveness were assessed by avoidance tests with juvenile Cypirinus carpio using a multi-compartmented exposure system. Omeprazole was found to be an acutely toxic drug (EC50: 0.015 mg/L), while the other PhACs, except simvastatin, showed some chronic toxicity. Regarding avoidance, simvastatin and omeprazole induced an escape response for 50% of the fish population at 0.032 and 0.144 mg/L, respectively; contrarily, diazepam was attractive, even at lethal concentrations, representing a dangerous trap for organisms. The toxicity of the PhACs seemed not to be directly related to their repellency; and the mode of action seems to determine the repellency or attractiveness of the chemicals. Contamination by PhACs is of concern due to the environmental disturbance they might cause, either due to their acute and chronic toxicity (at the individual level), repellency (at the ecosystem level: loss of local biodiversity) or attraction to potentially lethal levels.

Occurrence and risk assessment of pharmaceutically active compounds in water supply systems in Brazil.

The presence of pharmaceutically active compounds (PhACs) in water supply systems has been generating great concern about their effects on the environment and human health. Twenty-eight PhACs were monitored during one year in four Brazilian water sources, aiming to understand the factors that influence their occurrence and removal in conventional drinking water treatment plants (DWTPs) and to assess the environmental and human health risks. Trace levels of PhACs were detected in surface and drinking water in all assessed water sources. Effects of seasonality and socioeconomic aspects were observed in PhACs occurrence, like their higher concentrations during winter and in locales with higher values of gross domestic product per capita and human development index. Betamethasone, prednisone, and fluconazole were the most commonly detected PhACs, and also presented the highest concentrations. However, they were not related to toxicological risks. Nonetheless, all surface waters were subject to toxicological risk owing to at least one PhAC. PhACs related to the highest toxicological risks were loratadine, atorvastatin, norfloxacin, caffeine, and ranitidine, however, all these PhACs presented low quantification frequency. DWTPs capacity to remove PhACs was only partial, so treated water was still contaminated with these compounds. Furthermore, atorvastatin presented a margin of exposure below 100, indicating possible risk for public health. Thus, additional advanced treatment steps should be considered to improve PhACs removal during drinking water treatment.

Estudo da biodegradabilidade de fluoroquinolona por meio da utilização de biomassas aeróbias e anaeróbias / Study of fluoroquinolone biodegradability by using aerobic and anaerobic biomass

RESUMO Os antibióticos como o norfloxacino constituem os fármacos mais utilizados na Medicina, com consumos expressivos no mundo todo. Por ser quimicamente estável, após sua administração a maior parte do fármaco é excretada de forma inalterada e, geralmente, é removida apenas parcialmente nas estações de tratamento de esgoto (ETEs). Assim, o presente trabalho buscou avaliar a eficiência dos processos biológicos na remediação de norfloxacino investigando os mecanismos de remoção envolvidos. O objetivo foi verificar a biodegradabilidade do fármaco e sua toxicidade. Para realização dos ensaios de biodegradabilidade, coletaram-se lodos na ETE Arrudas (Sabará, Minas Gerais) dos processos de tratamento com lodos ativados, reatores upflow anaerobic sludge blanket (UASB) e biodigestor anaeróbio. Reatores em escala de bancada foram montados com lodo aclimatado e não aclimatado. Amostras tiveram a biodegradabilidade acompanhada por meio da determinação do carbono orgânico total e da absortividade molar do norfloxacino por espectrofotometria de UV/Vis. Determinou-se a toxicidade por intermédio de ensaios com a bactéria Aliivibrio fischeri. Entre as biomassas utilizadas, a mais eficiente na remoção do norfloxacino foi advinda dos reatores UASB (23%), seguida do biodigestor anaeróbio (18%) e, então, dos lodos ativados (13%). Quanto à ecotoxicidade, a degradação anaeróbia promoveu a eliminação da toxicidade do antibiótico, enquanto com relação à degradação aeróbia os efluentes gerados permanecem tóxicos.

ABSTRACT Antibiotics, such as norfloxacin, are the most widely used drugs in medicine, with significant consumption in the world. By being chemically stable, most of the drug is excreted unchanged after administration, and is generally only partially removed in the sewage treatment plants (STPs). Thus, the efficiency of biological processes in the remediation of norfloxacin was investigated by the present work, verifying the removal mechanisms involved. Its objective was to verify the drug's biodegradability and toxicity. In order to perform biodegradability tests, sludges were collected in Arrudas STP (Sabara, Minas Gerais) from the treatment processes with activated sludge, upflow anaerobic sludge blanket (UASB) reactors and anaerobic biodigester. Bench-scale reactors were assembled with acclimatized and non-acclimatized sludge. Samples had their biodegradability monitored by determination of total organic carbon and norfloxacin molar absorptivity by UV/Vis spectrophotometry. The toxicity was determined by tests with Aliivibrio fischeri. Among the used biomass, UASB reactors was the most efficient in removing norfloxacin (23%), followed by anaerobic biodigester (18%), and activated sludge (13%). Regarding ecotoxicity, the anaerobic degradation promoted the elimination of antibiotic toxicity, while with aerobic degradation, the effluents generated remained toxic.

A toxicity assessment of 30 pharmaceuticals using Aliivibrio fischeri: a comparison of the acute effects of different formulations.

Considerable quantities of different classes of drugs are consumed annually worldwide. These drugs, once disposed, often remain stable, even after conventional or advanced treatments. Although there have been a number of studies on the potential harm caused by drugs when released into the environment, few studies have investigated the toxicity of pharmaceutical excipients. In the present study, the acute toxicity of 30 drugs was tested to Aliivibrio fischeri. Ten different active ingredients were investigated, each in three distinct formulations: generic, similar and reference (brand drug). The aim of the study was to evaluate the harmful potential of drugs frequently sold in drugstores and to assess the contribution of excipients towards the observed acute toxicity. Within the 10 drugs evaluated, only one, dexchlorpheniramine maleate, was not toxic in any formulation. The toxicities of the three formulations were often different, even though the active ingredient has been the same. For some drugs, such as diazepam, glibenclamide, metformin, nimesulide, hydrochlorothiazide and simvastatin, only one or two of the three formulations tested were toxic to A. fischeri. These results highlight the toxicological potential of drug excipients, but not exclusively the toxicity of the active ingredients.

Degradation of antibiotics norfloxacin by Fenton, UV and UV/H2O2.

This study aimed to evaluate the degradation of the antibiotic norfloxacin, using direct photolysis (UV), photolysis with hydrogen peroxide (UV/H2O2) and Fenton's oxidation processes. Initially, it was evaluated the behavior of the antibiotic norfloxacin on direct photolysis, in order to see if the process could be a pertinent way to eliminate the drug in water treatment stations. The results showed that the use of direct photolysis was not effective in the degradation of the antibiotic, reaching a degradation rate of 85% and a mineralization rate of 2% in 7 h of reaction; leading to the formation of intermediates products. To optimize the UV treatment, it was used the combined UV/H2O2 process. Several concentrations of hydrogen peroxide (0.7, 1.4, 2.1, 2.8, 3.5 and 4.2 mmol/L) at pH 7 were tested. The concentration of 2.1 mmol/L reached a degradation rate of 100% in 100 min of reaction. Based on this result, the speed of the reaction at pH 2, 3, 5, and 10 was evaluated for that same concentration of H2O2. The shortest reaction time (60 min) was verified at pH 2 and 3. For the treatment using Fenton oxidation, a degradation rate of 60% of the compound and a mineralization rate of 55% was obtained in 60 min. The study revealed that the Fenton oxidation and UV/H2O2 can be used for norfloxacin removal, reaching respectively degradation rates of 100% and 60%, and mineralization rates of 55% and 32%.