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The transformation of a benign phyllodes tumor (PT) into a malignant PT and/or carcinoma is extremely uncommon. We present a case of a 66-year-old female with a huge mass on the left breast which was successfully removed by surgical resection. The pathological diagnosis was infiltrating lobular carcinoma with pure rhabdoid features and the malignant transformation of a benign phyllodes tumor. The first time this rare case was reported, it is demonstrated a special phenomenon through the synchronous transformation of PT grades and the carcinomatous transformation of PT.
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Human tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two important targets in cancer immunotherapy. Extensive research has led to a large number of potent IDO inhibitors; in addition, 52 structures of IDO in complex with inhibitors with a wide array of chemical scaffolds have been documented. In contrast, progress in the development of TDO inhibitors has been limited. Only four structures of TDO in complex with competitive inhibitors that compete with the substrate L-tryptophan for binding to the active site have been reported to date. Here we systematically evaluated the structures of TDO in complex with competitive inhibitors with three types of pharmacophores, imidazo-isoindole, indole-tetrazole, and indole-benzotriazole. The comparative assessment of the protein-inhibitor interactions sheds new light into the structure-based design of enzyme-selective inhibitors.
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Inibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenase , Triptofano Oxigenase , Humanos , Triptofano Oxigenase/antagonistas & inibidores , Triptofano Oxigenase/metabolismo , Triptofano Oxigenase/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/química , Relação Estrutura-Atividade , Indóis/química , Indóis/farmacologia , Indóis/metabolismo , Modelos Moleculares , Tetrazóis/química , Tetrazóis/farmacologia , Tetrazóis/metabolismo , Triptofano/química , Triptofano/metabolismo , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/metabolismo , Ligação ProteicaRESUMO
Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis-decalin. In this paper, we demonstrate that the cis-decalin section of signermycin B can be accessed by an anionic oxy-Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels-Alder reaction of a masked ortho-benzoquinone, generated by oxidation of an α-methoxyphenol in presence of cis-2-hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy-Cope rearrangement to a cis-decalinone. While we could show, that introduction of the 4-ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4-epi-isomer was formed.
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The pathobiology of tau is of great importance for understanding the mechanisms of neurodegeneration in aging and age-associated disorders such as Alzheimer disease (AD) and frontotemporal dementias. It is critical to identify neuronal populations and brain regions that are vulnerable or resistant to tau pathological changes. Pick disease (PiD) is a three-repeat (3R) tauopathy that belongs to the group of frontotemporal lobar degenerations. The neuropathologic changes of PiD are characterized by globular tau-positive neuronal intracytoplasmic inclusions, called Pick bodies, in the granule cells of the dentate gyrus and frontal and temporal neocortices, and ballooned neurons, named Pick neurons, in the neocortex. In the present study, we examined 13 autopsy-confirmed cases of PiD. Using immunohistochemistry for phospho-tau (AT8) and 3R tau isoform, all PiD cases demonstrated extensive lesions involving the hippocampus and neocortex. However, the lateral geniculate body (LGB) is spared of significant tau lesions in contrast to the neighboring hippocampus and other thalamic nuclei. Only 1 PiD case (7.7%) had tau-positive neurons, and 4 cases had tau-positive neurites (31%) in the LGB. By contrast, the LGB does consistently harbor tau lesions in other tauopathies including progressive supranuclear palsy, corticobasal degeneration, and AD.
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Doença de Alzheimer , Neocórtex , Doença de Pick , Tauopatias , Humanos , Doença de Pick/patologia , Proteínas tau/metabolismo , Corpos Geniculados/metabolismo , Corpos Geniculados/patologia , Tauopatias/patologia , Neocórtex/patologiaRESUMO
Breast tumours are embedded in a collagen I-rich extracellular matrix (ECM) network, where nutrients are scarce due to limited blood flow and elevated tumour growth. Metabolic adaptation is required for cancer cells to endure these conditions. Here, we demonstrated that the presence of ECM supported the growth of invasive breast cancer cells, but not non-transformed mammary epithelial cells, under amino acid starvation, through a mechanism that required macropinocytosis-dependent ECM uptake. Importantly, we showed that this behaviour was acquired during carcinoma progression. ECM internalisation, followed by lysosomal degradation, contributed to the up-regulation of the intracellular levels of several amino acids, most notably tyrosine and phenylalanine. This resulted in elevated tyrosine catabolism on ECM under starvation, leading to increased fumarate levels, potentially feeding into the tricarboxylic acid (TCA) cycle. Interestingly, this pathway was required for ECM-dependent cell growth and invasive cell migration under amino acid starvation, as the knockdown of p-hydroxyphenylpyruvate hydroxylase-like protein (HPDL), the third enzyme of the pathway, opposed cell growth and motility on ECM in both 2D and 3D systems, without affecting cell proliferation on plastic. Finally, high HPDL expression correlated with poor prognosis in breast cancer patients. Collectively, our results highlight that the ECM in the tumour microenvironment (TME) represents an alternative source of nutrients to support cancer cell growth by regulating phenylalanine and tyrosine metabolism.
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Aminoácidos , Neoplasias da Mama , Humanos , Feminino , Aminoácidos/metabolismo , Neoplasias da Mama/metabolismo , Matriz Extracelular/metabolismo , Tirosina/metabolismo , Fenilalanina , Microambiente TumoralRESUMO
The purpose of this study was to assess the effect of a calcium silicate-based sealers (CeraSeal) and an epoxy resin-based sealer (AH Plus) on cytotoxicity and cell migration of stem cell from the human apical papilla (hSCAPs) by using the Alamar Blue, Annexin V-FICT and wound healing assays. In Alamar Blue assay, hSCAPs exposed to undiluted CeraSeal extract had significantly higher cell viability compared with that observed when cells were treated with AH Plus in all experimental period (p < 0.001). The flow cytometry analysis confirmed the comparison on viable cells and indicated that AH Plus increased apoptosis compared to CeraSeal and the control groups (p < 0.001). Additionally, AH Plus exhibited significantly lower level of cell migration than CeraSeal and the control for up to 48 h observation (p < 0.01). In summary, calcium silicate-based sealer (CeraSeal) is less cytotoxic and more biocompatible than epoxy resin-based sealer (AH Plus).
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Resinas Epóxi , Materiais Restauradores do Canal Radicular , Humanos , Resinas Epóxi/toxicidade , Materiais Restauradores do Canal Radicular/toxicidade , Cavidade Pulpar , Teste de Materiais , Compostos de Cálcio/toxicidade , Silicatos/toxicidade , Células-Tronco , Movimento CelularRESUMO
INTRODUCTION AND IMPORTANCE: Papillary thyroid carcinoma is the most common type of malignancy in endocrine tumor. Women with breast cancer have an increased risk of developing thyroid cancer. Especially, patients with BRCA1 germline variants, which belong to the DNA DSB repair system, there may be a genetic susceptibility to thyroid cancer. CASE PRESENTATION: This study investigated a 47-year-old Vietnamese female patient with BRCA1 mutation, namely NM_007294.3 (BRCA1): c.4998insA (p. Tyr1666Terfs), who developed PTC after one year of breast cancer treatment. CLINICAL DISCUSSION: Factors that are thought to increase the risk of thyroid cancer after breast cancer treatment include treatment methods, hormonal factors, genetic susceptibility, and others. A hypothesis is breast cancer with BRCA1 mutation increases the risk of thyroid cancer. CONCLUSION: Understanding the relationship between breast and thyroid cancer helps clinicians for well management of both diseases and also contributes to the development of new preventive strategies, diagnostics and therapeutics as so as a new research direction.
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Plastic biodegradation by insects has made significant progress, opening up new avenues for the treatment of plastic waste. Wax moth larvae, for example, have attracted the attention of the scientific community because they are known to chew, ingest, and biodegrade natural polymer bee waxes. Despite this, we know very little about how these insects perform on manufactured plastics or how manufactured plastics affect insect metabolism. As a result, we studied the metabolism of greater wax moths (Galleria mellonella) fed on molasses-supplemented polylactic acid plastic (PLA) blocks. An analysis of the central carbon metabolism (CCM) metabolites was performed using liquid chromatography triple quadrupole mass spectrometry (LC-QQQ-MS), while an analysis of untargeted metabolites and lipids was conducted using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS). In total, 169 targeted CCM metabolites, 222 untargeted polar metabolites, and 196 untargeted nonpolar lipids were identified within the insect samples. In contrast, compared to control larvae, PLA-fed larvae displayed significantly different levels of 97 CCM metabolites, 75 polar metabolites, and 57 lipids. Purine and pyrimidine metabolisms were affected by PLA feeding, as well as amino acid metabolism, carbohydrates, cofactors, vitamins, and related metabolisms. Additionally, PLA exposure disrupted insect energy metabolism and oxidative stress, among other metabolic disturbances. The larvae fed PLA have lower levels of several lipids, suggesting a reduction in lipid reserves, and ceramide levels are likely to have changed due to apoptosis and inflammation. The study indicates that G. mellonella larvae could ingest PLA but this process causes some metabolic stress for the host. Future studies of the molecular pathways of this biodegradation process might help to provide strategies for stress reduction that would speed up insect digestion of plastic.
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Mariposas , Animais , Abelhas , Larva/metabolismo , Mariposas/metabolismo , Poliésteres , Plásticos , Estresse Oxidativo , Ceras/metabolismo , LipídeosRESUMO
OBJECTIVE: To assess accuracy of whole slide imaging (WSI) in the interpretation of permanent and frozen sections in surgical pathology and the identification of tumors in cutaneous en face frozen sections. METHODS: Twenty glass slides containing cutaneous en face frozen sections were selected from twenty cases of keratinocyte carcinomas treated with Mohs micrographic surgery. Ten slides contained tumor and ten did not. A blinded dermatologic surgeon used traditional light microscopy (LM) to assess physical slides for tumor presence and type, while noting the confidence (scale 1-10) and time (min) in making the determination. After a seven-day washout period, the surgeon repeated this process using WSI of the same slides, each de-identified and scanned at 20x using the Aperio AT2 (Leica Biosystems). RESULTS: Percent agreement between LM and WSI was 100%, with Cohen's kappa of 1.0. The average time taken to determine tumor presence was significantly greater using WSI than LM. Similarly, the surgeon was significantly more confident using LM than WSI. CONCLUSION: This proof-of-concept study suggests that diagnostic concordance is excellent between LM and WSI in the evaluation of Mohs frozen sections. However, WSI was cumbersome to use, not ergonomic, and required significantly more time.
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Carcinoma , Patologia Clínica , Humanos , Microscopia/métodos , Interpretação de Imagem Assistida por Computador/métodos , Secções Congeladas , Patologia Clínica/métodosRESUMO
Polyphenol-rich solutions, such as plant extracts and teas, can modify the salivary pellicle and improve the protection against dental erosion. In this study, we further explored how these polyphenol-rich plant extracts solutions behave in the presence of fluoride. We distributed enamel specimens into 9 groups (n = 15): Control_No_F- (Deionized water); Control_F- (500 ppm F-), Grape_Seed_No_F- (Grape seed extract), Grape_Seed_F- (Grape seed extract + 500 ppm F-), Grapefruit_Seed_No_F- (Grapefruit seed extract), Grapefruit_Seed_F- (Grapefruit seed extract + 500 ppm F-), Blueberry_No_F- (Blueberry extract), Blueberry_F- (Blueberry extract + 500 ppm F-), and Sn2+/F-_Rinse (commercial solution containing 800 ppm Sn2+ and 500 ppm F-). The specimens were submitted to 5 cycles (1 cycle per day), and each cycle consisted of: salivary pellicle formation (human saliva, 30 min, 37°C), modification of the pellicle (2 min, 25°C), pellicle formation (60 min, 37°C), and an erosive challenge (1 min, citric acid). Between cycles, the specimens were kept in a humid chamber. Relative surface hardness (rSH), relative surface reflection intensity (rSRI) and calcium released to the acid were analysed, using general linear models, and Kruskal-Wallis with post-hoc Dunn's tests. We observed that the presence of fluoride in synergy with the extract solutions provided better protection than the groups containing extract or fluoride only. For rSH, we observed a significant main effect of extracts (F(4,117) = 9.20; p<0.001) and fluoride (F(1,117) = 511.55; p<0.001), with a significant interaction (F(3,117) = 6.71; p<0.001). Grape_Seed_F- showed the best protection, better than fluoride, and Sn2+/F-_Rinse. Calcium results also showed greater protection for the groups containing fluoride, whereas for rSRI, despite a significant interaction between extract and fluoride (F(3,117) = 226.05; p<0.001), the differences between the groups were not as clearly observed. We conclude that polyphenols from plant extracts, when combined with fluoride, improve the protective effect of salivary pellicles against enamel erosion.
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Extrato de Sementes de Uva , Erosão Dentária , Humanos , Fluoretos/farmacologia , Erosão Dentária/prevenção & controle , Fluoreto de Sódio , Cálcio , Polifenóis , Extrato de Sementes de Uva/farmacologia , Esmalte DentárioRESUMO
Post-translational modifications (PTMs) on intact histones play a major role in regulating chromatin dynamics and influence biological processes such as DNA transcription, replication, and repair. The nature and position of each histone PTM is crucial to decipher how this information is translated into biological response. In the present work, the potential of a novel tandem top-"double-down" approachâultraviolet photodissociation followed by mobility and mass-selected electron capture dissociation and mass spectrometry (UVPD-TIMS-q-ECD-ToF MS/MS)âis illustrated for the characterization of HeLa derived intact histone H4 proteoforms. The comparison between q-ECD-ToF MS/MS spectra and traditional Fourier-transform-ion cyclotron resonance-ECD MS/MS spectra of a H4 standard showed a similar sequence coverage (â¼75%) with significant faster data acquisition in the ToF MS/MS platform (â¼3 vs â¼15 min). Multiple mass shifts (e.g., 14 and 42 Da) were observed for the HeLa derived H4 proteoforms for which the top-down UVPD and ECD fragmentation analysis were consistent in detecting the presence of acetylated PTMs at the N-terminus and Lys5, Lys8, Lys12, and Lys16 residues, as well as methylated, dimethylated, and trimethylated PTMs at the Lys20 residue with a high sequence coverage (â¼90%). The presented top-down results are in good agreement with bottom-up TIMS ToF MS/MS experiments and allowed for additional description of PTMs at the N-terminus. The integration of a 213 nm UV laser in the present platform allowed for UVPD events prior to the ion mobility-mass precursor separation for collision-induced dissociation (CID)/ECD-ToF MS. Selected c305+ UVPD fragments, from different H4 proteoforms (e.g., Ac + Me2, 2Ac + Me2 and 3Ac + Me2), exhibited multiple IMS bands for which similar CID/ECD fragmentation patterns per IMS band pointed toward the presence of conformers, adopting the same PTM distribution, with a clear assignment of the PTM localization for each of the c305+ UVPD fragment H4 proteoforms. These results were consistent with the biological "zip" model, where acetylation proceeds in the Lys16 to Lys5 direction. This novel platform further enhances the structural toolbox with alternative fragmentation mechanisms (UVPD, CID, and ECD) in tandem with fast, high-resolution mobility separations and shows great promise for global proteoform analysis.
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Histonas , Espectrometria de Massas em Tandem , Humanos , Histonas/química , Espectrometria de Massas em Tandem/métodos , Elétrons , Processamento de Proteína Pós-Traducional , Análise de FourierRESUMO
Several novel members of the vertebrate globin family were recently discovered with unique structural features that are not found in traditional penta-coordinate globins. Here we combine structural tools to better understand and recognize molecular determinants that contribute to the stability of hexacoordinate globin X (GbX) from Danio rerio (zebrafish). pH-induced unfolding data indicates increased stability of GbX with pHmid of 1.9 ± 0.1 for met GbXWT, 2.4 ± 0.1 for met GbXC65A, and 3.4 ± 0.1 for GbXH90V. These results are in good agreement with GbX unfolding experiments using GuHCl, where a ΔGunf 13.8 ± 2.5 kcal mol-1 and 16.3 ± 2.6 kcal mol-1 are observed for metGbXWT, and metGbXC65A constructs, respectively, and diminished stability is measured for GbXH90V, ΔGunf = 9.5 ± 3.6 kcal mol-1. The metGbXWT and metGbXC65A also exhibit high thermal stability (melting points of 118 °C and 107 °C, respectively). Native ion mobility - mass spectrometry (IM-MS) experiments showed a narrow charge state distribution (9-12+) characteristics of a native, structured protein; a single mobility band was observed for the native states. Collision induced unfolding IM-MS experiments showed a two-state transition, in good agreement with the solution studies. GbXWT retains the heme over a wide range of charge states, suggesting strong interactions between the prosthetic group and the apoprotein. The above results indicate that in addition to the disulfide bond and the heme iron hexa-coordination, other structural determinants enhance stability of this protein.
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Globinas , Peixe-Zebra , Animais , Apoproteínas , Dissulfetos , Globinas/química , Heme/química , Ferro , Dobramento de ProteínaRESUMO
Probiotics such as Lactobacillus spp. play an important role in human health as they embark beneficial effect on the human gastrointestinal microflora composition and immune system. Dysbiosis in the gastrointestinal microbial composition has been identified as a major contributor to chronic inflammatory conditions, such as inflammatory bowel disease (IBD). Higher prevalence of IBD is often recorded in most of the developed Western countries, but recent data has shown an increase in previously regarded as lower risk regions, such as Japan, Malaysia, Singapore, and India. Although the IBD etiology remains a subject of speculation, the disease is likely to have developed because of interaction between extrinsic environmental elements; the host's immune system, and the gut microbial composition. Compared to conventional treatments, probiotics and probiotic-based interventions including the introduction of specific prebiotics, symbiotic and postbiotic products had been demonstrated as more promising therapeutic measures. The present review discusses the association between gut dysbiosis, the pathogenesis of IBD, and risk factors leading to gut dysbiosis. In addition, it discusses recent studies focused on the alteration of the gastrointestinal microbiome as an effective therapy for IBD. The impact of the COVID-19 pandemic and other viral infections on IBD are also discussed in this review. Clinical and animal-based studies have shown that probiotic-based therapies can restore the gastrointestinal microbiota balance and reduce gut inflammations. Therefore, this review also assesses the status quo of these microbial-based therapies for the treatment of IBD. A better understanding of the mechanisms of their actions on modulating altered gut microbiota is required to enhance the effectiveness of the IBD therapeutics.
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Abiogenic metals Pb and Hg are highly toxic since chronic and/or acute exposure often leads to severe neuropathologies. Mn2+ is an essential metal ion but in excess can impair neuronal function. In this study, we address in vitro the interactions between neuronal calcium sensor 1 (NCS1) and divalent cations. Results showed that non-physiological ions (Pb2+ and Mn2+) bind to EF-hands in NCS1 with nanomolar affinity and lower equilibrium dissociation constant than the physiological Ca2+ ion. (Kd, Pb2+ = 7.0 ± 1.0 nM; Kd, Mn2+ = 34.0 ± 6.0 nM; K). Native ultra-high resolution mass spectrometry (FT-ICR MS) and trapped ion mobility spectrometry-mass spectrometry (nESI-TIMS-MS) studies provided the NCS1-metal complex compositions-up to four Ca2+ or Mn2+ ions and three Pb2+ ions (Mâ Pb1-3Ca1-3, Mâ Mn1-4Ca1-2, and Mâ Ca1-4) were observed in complex-and similarity across the mobility profiles suggests that the overall native structure is preserved regardless of the number and type of cations. However, the non-physiological metal ions (Pb2+, Mn2+, and Hg2+) binding to NCS1 leads to more efficient quenching of Trp emission and a decrease in W30 and W103 solvent exposure compared to the apo and Ca2+ bound form, although the secondary structural rearrangement and exposure of hydrophobic sites are analogous to those for Ca2+ bound protein. Only Pb2+ and Hg2+ binding to EF-hands leads to the NCS1 dimerization whereas Mn2+ bound NCS1 remains in the monomeric form, suggesting that other factors in addition to metal ion coordination, are required for protein dimerization.
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Cálcio , Chumbo , Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Manganês/metabolismo , Proteínas Sensoras de Cálcio Neuronal , NeuropeptídeosRESUMO
Background: The androgen receptor (AR) has recently emerged as a useful marker for the more favorable prognosis and better outcomes among women with estrogen receptor (ER) + ve breast cancer (BC) and the further refinement of BC subtype. Furthermore, AR expression in ER - ve tumors has a particular prognostic significance. Additionally, the ratio of nuclear AR to ER may critically have an influence on tumor biology and respond to endocrine therapy. Purpose: To define the AR expression and AR:ER ratio, and explored their correlation with the clinicopathological features, prognosis, and survival outcomes in the various subclasses of invasive BC. Methods: The current study was conducted on 522 BC patients who had surgical operations, without neoadjuvant chemotherapy by applying a retrospective cohort analysis. The clinicopathological characteristics were recorded. Immunohistochemical staining was performed on AR, ER, PR, HER2, and Ki67. Expression of AR was paired into different immunophenotypes for analysis with clinicopathological features and survival. All BC patients' survival was analyzed using Kaplan-Meier and log-rank models. Results: The presence of AR was detected in 65.3%. Positive AR, the ratio of AR:ER<2, luminal androgen receptor (LAR) + and AR + HER2 + immunophenotypes were significantly associated with better prognostic features. AR:ER<2 was observed in the prolonged overall survival (OS) and disease-free survival (DFS) (87.9 and 86.2%, respectively) compared to AR:ER≥2 (25.0% in both) (P < .001). In contrast, in HR + ve BCs, the AR expression was not significantly correlated with survival. The multivariate model revealed that the ratio of nuclear AR to ER remained as an independent prognostic variable. Conclusion: The AR expression had a distinct OS and DFS. The AR:ER ratio is an independent indicator for predicting the OS and DFS of BC patients in both univariate and multivariate analyses.
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Neoplasias da Mama , Receptores de Estrogênio , Androgênios , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Receptores Androgênicos/genética , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Estudos Retrospectivos , VietnãRESUMO
Insects used to treat organic waste streams and produce valuable protein products are increasingly exposed to plastic contaminated source material assimilating plastic carbon into organic biomass, which is pervasive and hazardous to organisms. Our understanding of this increased insect-plastic interaction remains limited and needs urgent scientific attention if plastic biodegradation and production rates of quality protein are to be improved. Herein, we investigated the biochemical impact of various plastics using three insect models. Black Soldier Fly (BSF), Mealworm (MW), and Wax Moth (WM) larva were each exposed to a plastic substrate (PET, PE, PS, Expanded PE, PP, and PLA) as the primary carbon source for five days to explore any positive metabolic benefits in terms of insect performance and plastic degradation potential. Central carbon metabolism (CCM) metabolites were analyzed via a targeted tMRM liquid chromatography triple quadrupole mass spectrometry (LC-QqQ-MS) method. Unique expressed pathways were observed for each insect model. When reared on PET, BSF larvae were found to have an elevated pyrimidine metabolism, while the purine metabolism pathway was strongly expressed on other plastics. BSF also exhibited a downregulated Vitamin B6 metabolism across all plastics, indicating a likely gut-symbiont breakdown. The MW and WM model insects were metabolically more active on PLA and expanded foam plastics. Further, WM exhibited an elevation in Vitamin B6 metabolism. This data suggests a positive insect-specific interaction towards certain plastic types that warrants further investigation. It is anticipated that through deeper insight into the metabolic impact and benefits afforded from certain plastics, an insect biotransformation pipeline can be established that links fit-for-purpose insect models to individual plastic types that address our growing plastic waste issue.
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Dípteros , Mariposas , Tenebrio , Animais , Carbono/metabolismo , Dípteros/metabolismo , Insetos , Larva/metabolismo , Plásticos/metabolismo , Poliésteres/metabolismo , Vitamina B 6/metabolismoRESUMO
Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions-in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses.
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Fibromatosis-like metaplastic carcinoma is a special variant of spindle cell carcinoma, a type of metaplastic carcinomas. It has a favorable prognosis, unlike other metaplastic carcinomas, with a particular clinical behavior characterized by frequent local recurrence, the meager potential for axillary lymph nodes, and distant metastases. We presented the case of a 51-year-old female with a large mass on the left breast, which was successfully removed by surgical resection. The pathological diagnosis was fibromatosis-like metaplastic carcinoma with the help of morphology and immunohistochemistry adjustment.
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Extracellular histone H4 is an attractive drug target owing to its roles in organ failure in sepsis and other diseases. To identify inhibitors using in silico methods, information on histone H4 structural dynamics and three-dimensional (3D) structural coordinates is required. Here, DNA-free histone H4 type 1 (H4.1) was characterized by utilizing tandem nonlinear and linear ion mobility spectrometry (FAIMS-TIMS) coupled to mass spectrometry (MS) complemented with molecular dynamics (MD) simulations. The gas-phase structures of H4.1 are dependent on the starting solution conditions, evidenced by differences in charge state distributions, mobility distributions, and collision-induced unfolding (CIU) pathways. The experimental results show that H4.1 adopts diverse conformational types from compact (C) to partially folded (P) and subsequently elongated (E) structures. Molecular dynamics simulations provided candidate structures for the histone H4.1 monomer in solution and for the gas-phase structures observed using FAIMS-IMS-TOF MS as a function of the charge state and mobility distribution. A combination of the FAIMS-TIMS experimental results with theoretical dipole calculations reveals the important role of charge distribution in the dipole alignment of H4.1 elongated structures at high electric fields. A comparison of the secondary and primary structures of DNA-free H2A.1 and H4.1 is made based on the experimental IMS-MS and MD findings.