83 research outputs found
Assessment of full field digital mammography (FFDM) detected microcalcification is not hindered by low spatial resolution
Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism
Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed âBMFâ, has a statin-like properties, which
blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-
CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics
of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere
formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/
beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration
(OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal
fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding
HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion
diagnostic for BMF-directed personalized therapy
Hydrolaseâlike catalysis and structural resolution of natural products by a metalâorganic framework
The exact chemical structure of nonâcrystallising natural products is still one of the main challenges in Natural Sciences. Despite tremendous advances in total synthesis, the absolute structural determination of a myriad of natural products with very sensitive chemical functionalities remains undone. Here, we show that a metalâorganic framework (MOF) with alcoholâcontaining arms and adsorbed water, enables selective hydrolysis of glycosyl bonds, supramolecular order with the soâformed chiral fragments and absolute determination of the organic structure by singleâcrystal Xâray crystallography in a single operation. This combined strategy based on a biomimetic, cheap, robust and multigram available solid catalyst opens the door to determine the absolute configuration of ketal compounds regardless degradation sensitiveness, and also to design extremelyâmild metalâfree solidâcatalysed processes without formal acid protons.This work was supported by the Ministero dellâIstruzione, dellâUniversitĂ e della Ricerca
(Italy) and the MINECO (Spain) (Projects CTQ2016-75671-P, CTQ 2017-86735-P,
RTC-2017-6331-5, Severo Ochoa program SEV-2016-0683 and Excellence Unit âMaria
de Maeztuâ MDM-2015-0538). R.B. thanks the MIUR (Project PON R&I FSE-FESR
2014â2020) for grant. L.B wishes to thank Italian MIUR for grant n. AIM1899391â1 in
the framework of the project âAzione I.2, MobilitĂ dei Ricercatori, PON R&I 2014â2020â.
Thanks are also extended to the â2019 Post-doctoral Junior Leader-Retaining Fellowship,
la Caixa Foundation (ID100010434 and fellowship code LCF/BQ/PR19/11700011â (J. F.-
S.). S. S.-N. thanks ITQ for the concession of a contract. D.A. acknowledges the financial
support of the Fondazione CARIPLO/âEconomia Circolare: ricerca per un futuro sostenibileâ
2019, Project code: 2019â2090, MOCA. E.P. acknowledges the financial support
of the European Research Council under the European Unionâs Horizon 2020 research
and innovation program/ERC Grant Agreement No. 814804, MOF-reactors
Degradation of Penicillinic Antibiotics and ÎČ-Lactamase Enzymatic Catalysis in a Biomimetic Zn-Based MetalâOrganic Framework
ÎČ-Lactam antibiotics are one of the most commonly prescribed drugs to treat bacterial infections. However, their use has been somehow limited given the emergence of bacteria with resistance mechanisms, such as ÎČ-lactamases, which inactivate them by degrading their four-membered ÎČ-lactam rings. So, a total knowledge of the mechanisms governing the catalytic activity of ÎČ-lactamases is required. Here, we report a novel Zn-based metalâorganic framework (MOF, 1), possessing functional channels capable to accommodate and interact with antibiotics, which catalyze the selective hydrolysis of the penicillinic antibiotics amoxicillin and ceftriaxone. In particular, MOF 1 degrades, very efficiently, the four-membered ÎČ-lactam ring of amoxicillin, acting as a ÎČ-lactamase mimic, and expands the very limited number of MOFs capable to mimic catalytic enzymatic processes. Combined single-crystal X-ray diffraction (SCXRD) studies and density functional (DFT) calculations offer unique snapshots on the host-guest interactions established between amoxicillin and the functional channels of 1. This allows to propose a degradation mechanism based on the activation of a water molecule, promoted by a Zn-bridging hydroxyl group, concertedly to the nucleophilic attack to the carbonyl moiety and the cleaving of CâN bond of the lactam ring.This work was supported by the MICINN (Spain) (Projects PID2019-104778GB-I00, PID2020-115100GB-I00, and Excellence Units âSevero Ochoaâ CEX2021-001230-S and âMaria de Maeztuâ CEX2019-000919-M) and the Ministero dell'Istruzione, dell'UniversitĂ e della Ricerca (Italy). The work has also been funded by Generalitat Valenciana, Prometeo Grupos de InvestigaciĂłn de Excelencia (PROMETEU/2021/054). D.A. also acknowledges the financial support of the European Union - NextGenerationEU under the National Recovery and Resilience Plan (NRRP) of Ministero dell'UniversitĂ e della Ricerca (MUR) (Project code PE0000021, âNetwork 4 Energy Sustainable Transition - NEST). Thanks are also extended to the 2019 Post-doctoral Junior Leader-Retaining Fellowship, la Caixa Foundation (ID100010434 and fellowship code LCF/BQ/PR19/11700011), the âGeneralitat Valencianaâ (SEJI/2020/034) and the âRamĂłn y Cajalâ program (J.F.-S.). E.P. acknowledges the financial support of the European Research Council under the European Union's Horizon 2020 research and innovation programme / ERC Grant Agreement No 814804, MOF-reactors. S.S.-N. thanks a fellowship from MINECO (project number CTQ 2017â86735-P). This study forms part of the Advanced Materials programme (MFA/2022/048) and was supported by MCIN with funding from European Union NextGenerationEU (PRTR-C17.I1) and by Generalitat Valenciana. Financial support from Dipartimento di Chimica e Tecnologie Chimiche (CTC), UniversitĂ della Calabria, is also gratefully acknowledged for computational investigation
The added value of quantitative multi-voxel MR spectroscopy in breast magnetic resonance imaging
To determine whether quantitative multivoxel MRS improves the accuracy of MRI in the assessment of breast lesions. Twenty-five consecutive patients with 26 breast lesions a parts per thousand yen1 cm assessed as BI-RADS 3 or 4 with mammography underwent quantitative multivoxel MRS and contrast-enhanced MRI. The choline (Cho) concentration was calculated using the unsuppressed water signal as a concentration reference. ROC analysis established the diagnostic accuracy of MRI and MRS in the assessment of breast lesions. Respective Cho concentrations in 26 breast lesions re-classified by MRI as BI-RADS 2 (n = 5), 3 (n = 8), 4 (n = 5) and 5 (n = 8) were 1.16 +/- 0.43 (mean +/- SD), 1.43 +/- 0.47, 2.98 +/- 2.15 and 4.94 +/- 3.10 mM. Two BI-RADS 3 lesions and all BI-RADS 4 and 5 lesions were malignant on histopathology and had Cho concentrations between 1.7 and 11.8 mM (4.03 +/- 2.72 SD), which were significantly higher (P = 0.01) than that in the 11 benign lesions (0.4-1.5 mM; 1.19 +/- 0.33 SD). Furthermore, Cho concentrations in the benign and malignant breast lesions in BI-RADS 3 category differed (P = 0.01). The accuracy of combined multivoxel MRS/breast MRI BI-RADS re-classification (AUC = 1.00) exceeded that of MRI alone (AUC = 0.96 +/- 0.03). These preliminary data indicate that multivoxel MRS improves the accuracy of MRI when using a Cho concentration cut-off a parts per thousand currency sign1.5 mM for benign lesions. Key Points aEuro cent Quantitative multivoxel MR spectroscopy can improve the accuracy of contrast-enhanced breast MRI. aEuro cent Multivoxel-MRS can differentiate breast lesions by using the highest Cho-concentration. aEuro cent Multivoxel-MRS can exclude patients with benign breast lesions from further invasive diagnostic procedures
Glioblastoma-derived Leptin Induces Tube Formation and Growth of Endothelial Cells: Comparison with VEGF Effects
Selection of diagnostic features on breast MRI to differentiate between malignant and benign lesions using computer-aided diagnosis: differences in lesions presenting as mass and non-mass-like enhancement
Purpose: To investigate methods developed for the characterisation of the morphology and enhancement kinetic features of both mass and non-mass lesions, and to determine their diagnostic performance to differentiate between malignant and benign lesions that present as mass versus non-mass types. Methods: Quantitative analysis of morphological features and enhancement kinetic parameters of breast lesions were used to differentiate among four groups of lesions: 88 malignant (43 mass, 45 non-mass) and 28 benign (19 mass, 9 non-mass). The enhancement kinetics was measured and analysed to obtain transfer constant (Ktrans) and rate constant (kep). For each mass eight shape/margin parameters and 10 enhancement texture features were obtained. For the lesions presenting as nonmass-like enhancement, only the texture parameters were obtained. An artificial neural network (ANN) was used to build the diagnostic model. Results: For lesions presenting as mass, the four selected morphological features could reach an area under the ROC curve (AUC) of 0.87 in differentiating between malignant and benign lesions. The kinetic parameter (kep) analysed from the hot spot of the tumour reached a comparable AUC of 0.88. The combined morphological and kinetic features improved the AUC to 0.93, with a sensitivity of 0.97 and a specificity of 0.80. For lesions presenting as non-mass-like enhancement, four texture features were selected by the ANN and achieved an AUC of 0.76. The kinetic parameter kepfrom the hot spot only achieved an AUC of 0.59, with a low added diagnostic value. Conclusion: The results suggest that the quantitative diagnostic features can be used for developing automated breast CAD (computer-aided diagnosis) for mass lesions to achieve a high diagnostic performance, but more advanced algorithms are needed for diagnosis of lesions presenting as non-mass-like enhancement. © The Author(s) 2009
GPER mediates the angiocrine actions induced by IGF1 through the HIF-1α/VEGF pathway in the breast tumor microenvironment
The G protein estrogen receptor GPER/GPR30 mediates estrogen action in breast cancer cells as well as in breast cancer-associated fibroblasts (CAFs), which are key components of microenvironment driving tumor progression. GPER is a transcriptional target of hypoxia inducible factor 1 alpha (HIF-1α) and activates VEGF expression and angiogenesis in hypoxic breast tumor microenvironment. Furthermore, IGF1/IGF1R signaling, which has angiogenic effects, has been shown to activate GPER in breast cancer cells. We analyzed gene expression data from published studies representing almost 5000 breast cancer patients to investigate whether GPER and IGF1 signaling establish an angiocrine gene signature in breast cancer patients. Next, we used GPER-positive but estrogen receptor (ER)-negative primary CAF cells derived from patient breast tumours and SKBR3 breast cancer cells to investigate the role of GPER in the regulation of VEGF expression and angiogenesis triggered by IGF1. We performed gene expression and promoter studies, western blotting and immunofluorescence analysis, gene silencing strategies and endothelial tube formation assays to evaluate the involvement of the HIF-1α/GPER/VEGF signaling in the biological responses to IGF1. We first determined that GPER is co-expressed with IGF1R and with the vessel marker CD34 in human breast tumors (nâ=â4972). Next, we determined that IGF1/IGF1R signaling engages the ERK1/2 and AKT transduction pathways to induce the expression of HIF-1α and its targets GPER and VEGF. We found that a functional cooperation between HIF-1α and GPER is essential for the transcriptional activation of VEGF induced by IGF1. Finally, using conditioned medium from CAFs and SKBR3 cells stimulated with IGF1, we established that HIF-1α and GPER are both required for VEGF-induced human vascular endothelial cell tube formation. These findings shed new light on the essential role played by GPER in IGF1/IGF1R signaling that induces breast tumor angiogenesis. Targeting the multifaceted interactions between cancer cells and tumor microenvironment involving both GPCRs and growth factor receptors has potential in future combination anticancer therapies
Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy
<p>Abstract</p> <p>Background</p> <p>Tumor hypoxia is marked by enhanced expression of hypoxia-inducible factor-α (HIF-1α) and glucose transporter-1 (Glut-1). Hypoxic conditions have also been associated with overexpression of angiogenic factors, such as leptin. The aim of our study was to analyze the relationships between hypoxia markers HIF-1α, Glut-1, leptin, leptin receptor (ObR) and other breast cancer biomarkers in primary and metastatic breast cancer in patients treated or untreated with preoperative chemotherapy.</p> <p>Methods</p> <p>The expression of different biomarkers was examined by immunohistochemistry in 116 primary breast cancers and 65 lymph node metastases. Forty five of these samples were obtained form patients who received preoperative chemotherapy and 71 from untreated patients.</p> <p>Results</p> <p>In primary tumors without preoperative chemotherapy, HIF-1α and Glut-1 were positively correlated (p = 0.02, r = 0.437). HIF-1α in primary and metastatic tumors without preoperative therapy positively correlated with leptin (p < 0.0001, r = 0.532; p = 0.013, r = 0.533, respectively) and ObR (p = 0.002, r = 0.319; p = 0.083, r = 0.387, respectively). Hypoxia markers HIF-1α and Glut-1 were negatively associated with estrogen receptor alpha (ERα) and positively correlated with estrogen receptor beta (ERÎČ). In this group of tumors, a positive correlation between Glut-1 and proliferation marker Ki-67 (p = 0.017, r = 0.433) was noted. The associations between HIF-1α and Glut-1, HIF-1α and leptin, HIF-1α and ERα as well as Glut-1 and ERÎČ were lost following preoperative chemotherapy.</p> <p>Conclusions</p> <p>Intratumoral hypoxia in breast cancer is marked by coordinated expression of such markers as HIF-1α, Glut-1, leptin and ObR. The relationships among these proteins can be altered by preoperative chemotherapy.</p
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