Botryoid embryonal rhabdomyosarcoma of the cervix: A case report.

INTRODUCTION AND IMPORTANCE: Rhabdomyosarcoma (RMS) is a malignant tumor that arises from embryonal skeletal muscle cells. It's responsible for 3 % of cancer cases among children aged from 0 to 14 and 1 % among adolescents and young adults aged from 15 to 19. Embryonal RMS (ERMS) is the most prevalent subtype of rhabdomyosarcoma in the female genital tract. Botryoid sarcomas are a polypoid variant of ERMS. Our objective is to describe the clinical, pathological features and the treatment of a patient diagnosed with RMS botryoid of the cervix. CASE PRESENTATION: We report a case of a 19-year-old female patient diagnosed with botryoid RMS of the cervix. The histopathological evaluation of the cervix showed a polypoid tumor lined by squamous epithelium exhibiting a large hypocellular edematous area. It was classified as group II and stage 1, according to the IRSG multicenter studies. Cervical polypectomy was performed as an oncological surgical treatment and adjuvant chemotherapy consisting of Vincristine 1.5 mg/m2/day and Actinomycin D 0.045 mg/kg/day (VA) for 45 weeks. After 6 months of follow up, she had no evidence of recurrence. CLINICAL DISCUSSION: Cervical ERMS is a rare tumor, especially in adolescence. It's usually presents as a cervical polyp or multiple polyps. Multimodal approaches have remarkably improved the prognosis and decreased the need for radical surgery with its associated morbidity. CONCLUSION: There are a variety of treatment strategies for a rare disease such as cervical botryoid RMS. This case was approached through fertility-conserving surgery, followed by adjuvant chemotherapy and oncological clinical follow up.

Exploring electronic, structural and dynamics parameters of phenylbenzothiazole complexes with Mn2+, Cu2+ and Zn2+ for designing new magnetic resonance imaging (MRI) probes: congruence between computation and spectroscopic data.

Cancer is one of the leading causes of human death worldwide, being one of the most serious problems faced by mankind. For the diagnosis, Magnetic Resonance Imaging (MRI), through effective contrast agents (Cas), has greatly helped in the diagnosis at the initial stages. However, it is necessary to include new compounds more effective and selective for cancer diagnosis. The complexes with Mn2+, Cu2+ and Zn2+ have received great attention due to their applications as CAs for MRI. Those materials can shorten the T2 and T2* transverse relaxation times. Thus, the representative structures for hyperfine coupling constants (HFCCs) were selected from docking results by frequency of occupancy calculations. From the Multivariate Analysis to obtain the PCA graphs in the choice of a representative conformations. it is possible to notice that the variable energy does not present a high correlation with the other variables, and structural factors, such as the spatial positions of the metal atoms, seem to be important in the reactivity of the complexes. Structural factors, such as the spatial positions of the metal atoms, seem to be important in the reactivity of the complexes. Theoretical findings suggest that the compounds are capable of increasing the Aiso values of the water molecules, but the complex [Zn(H2O)(NNO)] shows a greater influence, being more sensitive to the Electron paramagnetic resonance parameters than the complexes [CuCl(H2O)NNO] and [MnCl2(H2O)(NNO)] with the explicit solvent and the enzyme. MRI contrast agents have generated various problems due to their high toxicity. In this perspective, this compound may be a promising alternative for transporting the CAs into diseased tissue.Communicated by Ramaswamy H. Sarma.

Prognostic role of hydronephrosis in the treatment of patients with locally advanced cervical cancer: a retrospective cohort.

BACKGROUND: Obstructive uropathy is present in almost 50% of patients with advanced cervical cancer and is associated with worse outcomes. OBJECTIVE: To estimate the prognostic role of hydronephrosis and the impact of ureteral obstruction resolution in patients with locally advanced cervical cancer undergoing treatment. METHODS: A retrospective cohort study was conducted of patients with International Federation of Gynecology and Obstetrics 2018 stage IIIB to IVA treated in a tertiary oncologic referral center in Brazil between January 2009 and June 2018. Three different groups were evaluated: (I) without hydronephrosis, (II) with hydronephrosis and urinary diversion, and (III) with hydronephrosis but no urinary diversion. Kaplan-Meier curves and log-rank tests estimated overall survival and progression-free survival based on the presence of hydronephrosis and urinary diversion. Clinicopathological variables were evaluated using univariate and multivariate Cox proportional hazard regression model for overall survival and progression-free survival. RESULTS: A total of 151 patients were evaluated: group I - 62 (41.1%); II - 44 (29.1%), and III - 45 (29.8%). Stage, histological type or grade, tumor size, parametrial or lymph node involvement were not statistically different between groups. Group I had more favorable overall survival than groups II (p<0.003) and III (p<0.02); however, no difference was noted between groups II and III. Progression-free survival was similar between groups (log-rank test p=0.95). Univariate analysis revealed hydronephrosis (p=0.002) and concurrent chemoradiotherapy (p<0.001) as a prognostic factor for worse overall survival; while tumor size (p=0.023), pelvic lymphadenopathy (p=0.015), and histological type (p=0.03) were associated with worse progression-free survival. On multivariate analysis, hydronephrosis remained as an independently associated factor with worse overall survival (HR=2.06; 95% CI 1.12 to 3.79, p=0.02). CONCLUSION: Patients with locally advanced cervical cancer with hydronephrosis had lower overall survival even after controlling for potential confounding factors, but no difference in progression-free survival. Urinary diversion showed no impact on overall survival or progression-free survival.

Semysinthetic biflavonoid Morelloflavone-7,4',7″,3‴,4‴-penta-O-butanoyl is a more potent inhibitor of Proprotein Convertases Subtilisin/Kexin PC1/3 than Kex2 and Furin.

BACKGROUND: Garcinia brasiliensis is a species native to the Amazon forest. The white mucilaginous pulp is used in folk medicine as a wound healing agent and for peptic ulcer, urinary, and tumor disease treatments. The activity of the proprotein convertases (PCs) Subtilisin/Kex is associated with the development of viral, bacterial and fungal infections, osteoporosis, hyperglycemia, atherosclerosis, cardiovascular, neurodegenerative and neoplastic diseases. METHODS: Morelloflavone (BF1) and semisynthetic biflavonoid (BF2, 3 and 4) from Garcinia brasiliensis were tested as inhibitor of PCs Kex2, PC1/3 and Furin, and determined IC50, Ki, human proinflammatory cytokines secretion in Caco-2 cells, mechanism of inhibition, and performed molecular docking studies. RESULTS: Biflavonoids were more effective in the inhibition of neuroendocrine PC1/3 than mammalian Furin and fungal Kex2. BF1 presented a mixed inhibition mechanism for Kex2 and PC1, and competitive inhibition for Furin. BF4 has no good interaction with Kex2 and Furin since carboxypropyl groups results in steric hindrance to ligand-protein interactions. Carboxypropyl groups of BF4 promote steric hindrance with Kex2 and Furin, but effective in the affinity of PC1/3. BF4 was more efficient at inhibiting PCl/3 (IC50 = 1.13 µM and Ki = 0,59 µM, simple linear competitive mechanism of inhibition) than Kex2, Furin. Also, our results strongly suggested that BF4 also inhibits the endogenous cellular PC1/3 activity in Caco-2 cells, since PC1/3 inhibition by BF4 causes a large increase in IL-8 and IL-1ß secretion in Caco-2 cells. CONCLUSIONS: BF4 is a potent and selective inhibitor of PC1/3. GENERAL SIGNIFICANCE: BF4 is the best candidate for further clinical studies on inhibition of PC1/3.

A tetraprenylated benzophenone 7-epiclusianone induces cell cycle arrest at G1/S transition by modulating critical regulators of cell cycle in breast cancer cell lines.

Breast cancer is a complex disease and encompassing different types of tumor. Although advances in understanding of the molecular bases of breast cancer biology, the therapeutic proposals available still are not effective. In this scenario, the present study aimed to evaluate the mechanisms associated to antitumor activity of 7-Epiclusianone (7-Epi), a tetraprenylated benzophenone, on luminal A (MCF-7) and claudin-low (Hs 578T) breast cancer cell lines. We found that 7-Epi efficiently inhibited cell proliferation and migration of these cells; however MCF-7 was slightly more responsive than Hs 578T. Cell cycle analysis showed accumulation of cells at G0/G1 phase with drastic reduction of S population in treated cultures. This effect was associated to downregulation of CDKN1A (p21) and cyclin E in both cell lines. In addition, 7-Epi reduced cyclin D1 and p-ERK expression levels in MCF-7 cell line. Cytotoxic effect of 7-Epi on breast cancer cell lines was associated to its ability to increase BAX/BCL-2 ratio. In conclusion, our findings showed that 7-Epi is a promising antitumor agent against breast cancer by modulating critical regulators of the cell cycle and apoptosis.

Deep learning in gastric tissue diseases: a systematic review.

Background: In recent years, deep learning has gained remarkable attention in medical image analysis due to its capacity to provide results comparable to specialists and, in some cases, surpass them. Despite the emergence of deep learning research on gastric tissues diseases, few intensive reviews are addressing this topic. Method: We performed a systematic review related to applications of deep learning in gastric tissue disease analysis by digital histology, endoscopy and radiology images. Conclusions: This review highlighted the high potential and shortcomings in deep learning research studies applied to gastric cancer, ulcer, gastritis and non-malignant diseases. Our results demonstrate the effectiveness of gastric tissue analysis by deep learning applications. Moreover, we also identified gaps of evaluation metrics, and image collection availability, therefore, impacting experimental reproducibility.

In vivo schistosomicidal activity of 7-epiclusianone and its quantification in the plasma of healthy and Schistosoma mansoni infected mice using UPLC-MS/MS.

BACKGROUND: The tetraprenylated benzophenone 7-epiclusianone (7-epi) is a substance isolated from the fruits of Garcinia brasiliensis and in vitro studies have demonstrated that 7-epi is effective against Schistosoma mansoni adult worms. HYPOTHESIS/PURPOSE: Here we report the in vivo evaluation of 7-epi and its pharmacokinetic in healthy and Schistosoma mansoni infected mice. STUDY DESIGN AND METHODS: In this work, we assayed the schistosomicidal activity of 7-epi at the dose of 100 mg/kg and 300 mg/kg body weight/day in S. mansoni experimentally infected mice. Besides, two groups of animals were treated and a detailed analysis of plasma samples was performed by liquid chromatography coupled to mass spectrometry (LC-MS/MS). RESULTS: The worm burden showed a reduction in the infected mice after treatment with 300 mg/kg for five days (p < .05). And we found an increase of AUC0-∞ (20846 vs. 32438 ng.h/ml) and a decrease of total apparent clearance (0.006 vs. 0.004 l/h/kg) of 7- epi in the infected group compared to the healthy group. Consequently, the half-life increased (1.73 vs. 6.11 h) and Cmax was reduced (5427.5 vs. 3321.0 ng/ml) in the infected group compared to the healthy group. In addition, histopathological investigations were performed analysing liver samples from healthy and infected mice. CONCLUSION: The results showed significant schistosomicidal in vivo activity at 300 mg/kg. In addition, livers from S. mansoni infected mice showed a greater number of egg granulomas and the changes in the pharmacokinetic parameters in this group could be associated with the pathology of the murine experimental schistosomiasis.

Biological and Chemical Aspects of Natural Biflavonoids from Plants: A Brief Review.

BACKGROUND: Biflavonoids belong to a subclass of the plant flavonoids family and are limited to several species in the plant kingdom. In the literature, biflavonoids are extensively reported for their pharmacological properties including anti-inflammatory, antioxidant, inhibitory activity against phospholipase A2 (PLA2) and antiprotozoal activity. METHOD: These activities have been discovered from the small number of biflavonoid structures that have been investigated, although the natural biflavonoids library is likely to be large. In addition, many medicinal properties and traditional use of plants are attributed to the presence of bioflavonoids among their secondary metabolites. Structurally, biflavonoids are polyphenol compounds comprising of two identical or non-identical flavonflavonoid units joined in a symmetrical or unsymmetrical manner through an alkyl or an alkoxy-based linker of varying length. Due to their chemical and biological importance, several bioprospective phytochemical studies and chemical approaches using coupling and molecular rearrangement strategies have been developed to identify and synthesize new bioactive biflavonoids. CONCLUSION: In this brief review, we present some basic structural aspects for classification and nomenclature of bioflavonoids and a compilation of the literature data published in the last 7 years, concerning the discovery of new natural biflavonoids of plant origin and their pharmacological and biological properties.

Anticancer activity of 7-epiclusianone, a benzophenone from Garcinia brasiliensis, in glioblastoma.

BACKGROUND: Glioblastoma is the most common tumor of the central nervous system and one of the hardest tumors to treat. Consequently, the search for novel therapeutic options is imperative. 7-epiclusianone, a tetraprenylated benzophenone isolated from the epicarp of the native plant Garcinia brasiliensis, exhibits a range of biological activities but its prospect anticancer activity is underexplored. Thus, the aim of the present study was to evaluate the influence of 7-epiclusianone on proliferation, clonogenic capacity, cell cycle progression and induction of apoptosis in two glioblastoma cell lines (U251MG and U138MG). METHODS: Cell viability was measured by the MTS assay; for the clonogenic assay, colonies were stained with Giemsa and counted by direct visual inspection; For cell cycle analysis, cells were stained with propidium iodide and analyzed by cytometry; Cyclin A expression was determined by immunoblotting; Apoptotic cell death was determined by annexin V fluorescein isothiocyanate labeling and Caspase-3 activity in living cells. RESULTS: Viability of both cell lines was drastically inhibited; moreover, the colony formation capacity was significantly reduced, demonstrating long-term effects even after removal of the drug. 7-epiclusianone treatment at low concentrations also altered cell cycle progression, decreased the S and G2/M populations and at higher concentrations increased the number of cells at sub-G1, in concordance with the increase of apoptotic cells. CONCLUSION: The present study demonstrates for the first time the anticancer potential of 7-epiclusianone against glioblastoma cells, thus meriting its further investigation as a potential therapeutic agent.

Benzophenone derivatives as cysteine protease inhibitors and biological activity against Leishmania(L.) amazonensis amastigotes.

The leishmanicidal potential of benzophenones has been described, some of them highlighting their potential as cysteine protease inhibitors. Therefore, this work described leishmanicidal activity of nine benzophenone derivatives (1a-c;2a-c;3a-c) against intramacrophage amastigote forms of Leishmania(L.)amazonensis (IC50) and the cytotoxic effect on murine peritoneal macrophages (CC50). The derivative 1c exhibited a selectivity index SI (CC50/IC50) of 6.7, besides cytotoxicity lower than Amphotericin B (p< 0.05). Moreover it showed inhibitory activity against papain (42.8±0.3, p<0.05), and when tested on trypanosomatids cysteine proteases 1c also proved to be a potent inhibitor of rCPB2.8, rCPB3.0 and cruzain, showing non-competitive inhibition mechanism by enzymatic assays in vitro.So, benzophenone 1c is interesting drug candidate prototype, with a multi-target directed mode of action, inhibiting rCPB2.8, rCPB3.0 and cruzain.

In vitro and in vivo photoprotective/photochemopreventive potential of Garcinia brasiliensis epicarp extract.

The damaging effects of sunlight to the skin has triggered studies that involve the synthesis and extraction of organic compounds from natural sources that can absorb UV radiation, and studies on polyphenolic compounds with antioxidant and anti-inflammatory properties that can be used as photochemopreventive agents for reducing skin damage. We investigated the in vitro and in vivo photoprotective/photochemopreventive potential of Garcinia brasiliensis epicarp extract (GbEE). We evaluated the cell viability of L929 fibroblasts after UVB exposure using a quartz plate containing the extract solution or the GbEE formulation. The in vivo photoprotective effect of the GbEE formulation was evaluated by measuring the UVB damage-induced decrease in endogenous reduced glutathione (GSH), the increase in myeloperoxidase (MPO) activity and secretion of cytokines IL-1ß and TNF-α. The in vitro methodology using fibroblasts showed that the photoprotective properties of the GbEE solutions and 10% GbEE formulation were similar to the commercial sunscreen (SPF-15). In vivo results demonstrated of the GbEE formulation in decreasing UVB induced-damage such as GSH depletion, an increased in MPO activity and secretion of cytokines IL-1ß and TNF-α. The results showed that the extract has great potential for use as a sunscreen in topical formulations in addition to UV filters.

Inhibition of cysteine proteases by a natural biflavone: behavioral evaluation of fukugetin as papain and cruzain inhibitor.

Cruzain is the major cysteine protease of Trypanosoma cruzi, the infectious agent responsible for Chagas disease, and cruzain inhibitors display considerable antitrypanosomal activity. In the present work we elucidated crystallographic data of fukugetin, a biflavone isolated from Garcinia brasiliensis, and investigated the role of this molecule as cysteine protease inhibitor. The kinetic analyses demonstrated that fukugetin inhibited cruzain and papain by a slow reversible type inhibition with K(I) of 1.1 and 13.4 µM, respectively. However, cruzain inhibition was about 12 times faster than papain inhibition. Lineweaver-Burk plots demonstrated partial competitive inhibition for cruzain and hyperbolic mixed-type inhibition for papain. Furthermore, the docking results showed that the biflavone binds to ring C' in the S2 pocket and to ring C in the S3 pocket through hydrophobic interactions and hydrogen bonds. Finally, fukugetin also presented inhibitory activity on proteases of the T. cruzi extract, with IC50 of 7 µM.

The genus Caesalpinia L. (Caesalpiniaceae): phytochemical and pharmacological characteristics.

The genus Caesalpinia (Caesalpiniaceae) has more than 500 species, many of which have not yet been investigated for potential pharmacological activity. Several classes of chemical compounds, such as flavonoids, diterpenes, and steroids, have been isolated from various species of the genus Caesalpinia. It has been reported in the literature that these species exhibit a wide range of pharmacological properties, including antiulcer, anticancer, antidiabetic, anti-inflammatory, antimicrobial, and antirheumatic activities that have proven to be efficacious in ethnomedicinal practices. In this review we present chemical and pharmacological data from recent phytochemical studies on various plants of the genus Caesalpinia.

Isolation and evaluation of the antioxidant activity of phenolic constituents of the Garcinia brasiliensis epicarp.

A new glycosylated biflavonone, morelloflavone-4'″-O-ß-d-glycosyl, and the known compounds 1,3,6,7-tetrahydroxyxanthone, morelloflavone (fukugetin) and morelloflavone-7″-O-ß-d-glycosyl (fukugeside) were isolated from the epicarp of Garcinia brasiliensis collected in Brazil. The structures of these compounds were established using 1H and 13C NMR, COSY, gHMQC and gHMBC spectroscopy. The compounds exhibited antioxidant activity. The greatest potency was displayed by morelloflavone (2), with IC50=49.5mM against DPPH and absorbance of 0.583 at 400µg/mL for the reduction of Fe3+. The weakest potency was displayed by 1,3,6,7-tetrahydroxyxanthone (1), with IC50=148mM against DPPH and absorbance of 0.194 at 400µg/mL for the reduction of Fe3+.

Organic and conventional Coffea arabica L.: a comparative study of the chemical composition and physiological, biochemical and toxicological effects in Wistar rats.

Differentiation between organic and conventional coffee has increased due to the growing demand and high consumption of healthy foods that contain compounds with antioxidant potential, which have been associated with the reduction of chronic diseases. We used organic and conventional coffee in powder 4% (w/w) and infusions 5%, 10% and 20% (w/v) incorporated in a commercial diet to test in vivo. The levels of chlorogenic acid, caffeine and trigonelline were determined by high performance liquid chromatography. The body weight, weight gain, food consumption, aberrant foci crypt, mucin depleted foci, stress biomarkers protein carbonyl and malondialdehyde, biochemical parameters and behavior of the rats were compared between the experimental and control groups within a framework of colon carcinogenesis. The organic coffee showed higher levels of chlorogenic acid, caffeine and trigonelline than conventional, however, this difference did not significantly affect behavior. The infusions had an antioxidant effect, reducing the levels of malondialdehyde; however, the biochemical parameters of the serum were not altered, and there was neither induction nor prevention of preneoplasic lesions.

Antiproliferative effect of benzophenones and their influence on cathepsin activity.

The antiproliferative activity of two prenylated benzophenones isolated from Rheedia brasiliensis, the triprenylated garciniaphenone and the tetraprenylated benzophenone 7-epiclusianone, was investigated against human cancer cell lines. The antiproliferative activity on melanoma (UACC-62), breast (MCF-7), drug-resistant breast (NCI-ADR), lung/non-small cells (NCI460), ovarian (OVCAR 03), prostate (PC03), kidney (786-0), lung (NCI-460) and tongue (CRL-1624 and CRL-1623) cancer cells was determined using spectrophotometric quantification of the cellular protein content. The effect of these benzophenones on the activity of cathepsins B and G was also investigated. Garciniaphenone displayed cytostatic activity in all cell lines, whereas 7-epiclusianone showed a dose-dependent cytotoxic effect. The IC(50) values for cell proliferation revealed that 7-epiclusianone is more active than garciniaphenone against most of the cell lines. Furthermore, the antiproliferative effects demonstrated by garciniaphenone and 7-epiclusianone were related to their cathepsin inhibiting properties. In conclusion, 7-epiclusianone is a promising naturally occurring agent which displays multiple inhibitory effects which may be working in concert to inhibit cancer cell proliferation in vitro. The putative pathway by which 7-epiclusianone affects cancer cell development may involve cathepsin inhibition.