Publications by authors named "Paula Soares"

244 Publications

Molecular Pathology of Non-familial Follicular Epithelial-Derived Thyroid Cancer in Adults: From RAS/BRAF-like Tumor Designations to Molecular Risk Stratification.

Endocr Pathol 2021 Mar 2. Epub 2021 Mar 2.

i3S - Instituto de Investigação E Inovação Em Saúde, Universidade Do Porto, 4200-135, Porto, Portugal.

This review addresses the impact of molecular alterations on the diagnosis and prognosis of differentiated thyroid carcinoma (DTC), including papillary, follicular, and well-differentiated carcinoma NOS, as well as oncocytic neoplasms. The molecular characterization of DTC is based upon the well-established dichotomy of BRAF-like and RAS-like designations, together with a remaining third group, less homogeneous, composed of non-BRAF-/non-RAS-like tumors. The role of BRAF V600E mutation in risk stratification is discussed in the clinico-pathological context, namely, staging and invasive features of classic papillary thyroid carcinoma (PTC) and histopathological variants carrying an excellent prognosis (microPTC) or a guarded prognosis, including the aggressive variants tall cell and hobnail cell PTCs. In follicular patterned tumors, namely, follicular thyroid carcinoma (FTC), with or without oncocytic features, the most prevalent molecular alteration are RAS mutations that do not carry prognostic significance. The only genetic alteration that has been proven to play a role in risk stratification of PTC and FTC is TERT promoter (TERTp) mutation.
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http://dx.doi.org/10.1007/s12022-021-09666-1DOI Listing
March 2021

Neuroprotector Effect of Daily 8-Minutes of High-Intensity Interval Training in Rat Aβ1-42 Alzheimer Disease Model.

Curr Alzheimer Res 2021 Feb 18. Epub 2021 Feb 18.

Laboratório de Morfologia Experimental Comparada, Faculdade de Medicina Veterinária, Universidade Estadual do Ceará, Fortaleza, CE. Brazil.

Background: Alzheimer's disease (AD) is the most common and irreversible neurodegenerative disorder, and amyloid peptide plays a central role in its pathogenesis. Physical training contributes as a beneficial adaptation to AD. However, these effects may be underestimated because much of the literature used fixed training prescription variables (intensity and volume) throughout the protocol. Moreover, researchers poorly understand whether chronic high-intensity interval training (HIIT) exerts similar effects on the brain tissue of individuals with AD.

Objective: This study evaluated the effect of 8 minutes of HIIT with incremental overload in an AD model.

Methods: Forty male Wistar rats were divided into four groups: an untrained Sham group, Sham trained group, Aβ1-42 (Alzheimer's) untrained group, and Aβ1-42 (Alzheimer's) trained group (n=10 rats per group). Animals underwent stereotactic surgery and received a hippocampal injection of Aβ1-42 or a saline solution. Seven days after surgery, two weeks of treadmill adaptation followed by a maximal running test (MRT) was performed. Then, animals were subjected to eight weeks of HIIT. Rats were sacrificed 24 h after the behavioral tests (open field and Morris water maze), hippocampal tissue was extracted to analyze the redox balance and BDNF/TrkB pathway, and neuritic plaques (NP) were detected by evaluating silver impregnation.

Results: The AD trained group presented a physical capacity amelioration every two weeks and locomotor, learning, and memory improvements (p<0.05). These effects were accompanied by increased CAT and SOD levels, followed by decreased lipid peroxidation (p<0.05). Furthermore, increased activation of the BDNF/TrkB (p<0.05) pathway and decreased NP was observed.

Conclusions: Based on these results, MRT was essential for an excellent chronic training protocol prescription and overload adjustment. Therefore, 8 minutes of HIIT daily for 8 weeks may reduce behavioral deficits by promoting a positive redox balance and increased activity of the BDNF/TrkB pathway that may contribute to NP attenuation.
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http://dx.doi.org/10.2174/1567205018666210218161856DOI Listing
February 2021

Nanostructured LiFeO by a Biogenic Method for Applications from Electronics to Medicine.

Nanomaterials (Basel) 2021 Jan 14;11(1). Epub 2021 Jan 14.

I3N and Physics Department, University of Aveiro, 3810-193 Aveiro, Portugal.

The physical properties of the cubic and ferrimagnetic spinel ferrite LiFeO has made it an attractive material for electronic and medical applications. In this work, LiFeO nanosized crystallites were synthesized by a novel and eco-friendly sol-gel process, by using powder coconut water as a mediated reaction medium. The dried powders were heat-treated (HT) at temperatures between 400 and 1000 °C, and their structure, morphology, electrical and magnetic characteristics, cytotoxicity, and magnetic hyperthermia assays were performed. The heat treatment of the LiFeO powder tunes the crystallite sizes between 50 nm and 200 nm. When increasing the temperature of the HT, secondary phases start to form. The dielectric analysis revealed, at 300 K and 10 kHz, an increase of ε' (≈10 up to ≈14) with a tanδ almost constant (≈0.3) with the increase of the HT temperature. The cytotoxicity results reveal, for concentrations below 2.5 mg/mL, that all samples have a non-cytotoxicity property. The sample heat-treated at 1000 °C, which revealed hysteresis and magnetic saturation of 73 emu g at 300 K, showed a heating profile adequate for magnetic hyperthermia applications, showing the potential for biomedical applications.
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http://dx.doi.org/10.3390/nano11010193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828716PMC
January 2021

A New Long-Term Composite Drug Delivery System Based on Thermo-Responsive Hydrogel and Nanoclay.

Nanomaterials (Basel) 2020 Dec 24;11(1). Epub 2020 Dec 24.

CENIMAT/I3N, Departamento de Ciência dos Materiais, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.

Several problems and limitations faced in the treatment of many diseases can be overcome by using controlled drug delivery systems (DDS), where the active compound is transported to the target site, minimizing undesirable side effects. In situ-forming hydrogels that can be injected as viscous liquids and jellify under physiological conditions and biocompatible clay nanoparticles have been used in DDS development. In this work, polymer-clay composites based on Pluronics (F127 and F68) and nanoclays were developed, aiming at a biocompatible and injectable system for long-term controlled delivery of methylene blue (MB) as a model drug. MB release from the systems produced was carried out at 37 °C in a pH 7.4 medium. The Pluronic formulation selected (F127/F68 18/2 wt.%) displayed a sol/gel transition at approx. 30 °C, needing a 2.5 N force to be injected at 25 °C. The addition of 2 wt.% of Na116 clay decreased the sol/gel transition to 28 °C and significantly enhanced its viscoelastic modulus. The most suitable DDS for long-term application was the Na116-MB hybrid from which, after 15 days, only 3% of the encapsulated MB was released. The system developed in this work proved to be injectable, with a long-term drug delivery profile up to 45 days.
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http://dx.doi.org/10.3390/nano11010025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824189PMC
December 2020

MOHS micrographic surgery for head and neck nonmelanoma skin cancer: An approach for ENT surgeons.

Dermatol Ther 2021 Jan 21;34(1):e14661. Epub 2020 Dec 21.

FMUP-Faculty of Medicine, University of Porto, Porto, Portugal.

Surgery is the main approach for skin cancer, with Mohs micrographic surgery (MMS) allowing the highest cure rates, best esthetics and superior functional outcomes. Ear, nose, and throat (ENT) surgeons are often challenged with patients presenting skin cancer, needing appropriate expertise to its adequate management. This paper highlights the most important aspects of MMS, enabling ENT surgeons to become familiar with its fundamental aspects. A review of the literature was performed, concomitantly presenting the author's outcomes as an ENT surgeon. A total of 51 MMSs were performed in 41 patients, and 78.4% of the tumors were cutaneous basal cell carcinomas (cBCCs), 19.6% were cutaneous squamous cell carcinomas (cSCCs), and one case was a microcystic adnexal carcinoma. Most tumors were located in high-risk areas (88.2%), and 84.3% of them were ≥10 mm in diameter. Most tumors (90.2%) required no more than two MMS excision steps to be completely removed. All cases were managed by reconstruction either using flaps or grafts. Recurrence occurred in only 2% of the cases. This study addressed the main issues of MMS, which may be important in ENT surgeons' daily practice.
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http://dx.doi.org/10.1111/dth.14661DOI Listing
January 2021

Review of the current information on erectile dysfunction in hypertensive males with 40 years of age or older.

Porto Biomed J 2020 Nov-Dec;5(6):e107. Epub 2020 Dec 3.

Faculdade de Medicina da Universidade do Porto (FMUP).

Hypertension (HT) is a prevalent disease, which origin frequently remains undetermined. Antihypertensive treatment (AHT) has been linked with erectile dysfunction (ED), mainly in middle-aged and older males. On the other side, some drugs used in AHT seem to be themselves associated with ED as a secondary effect. This led to the search of coadjuvant therapies for hypertensive patients with ED, considering that both illnesses cause high physical, psychological and economic burden. While the association between AHT and ED has been approached several times, the direct association between blood pressure and ED remains unclear. This review aims to summarize the current knowledge on the relationship between HT, AHT and ED specifically in males with age ≥40 years.
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http://dx.doi.org/10.1097/j.pbj.0000000000000107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721211PMC
December 2020

S616-p-DRP1 associates with locally invasive behavior of follicular cell-derived thyroid carcinoma.

Endocrine 2020 Nov 20. Epub 2020 Nov 20.

Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.

Purpose: Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients' clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC).

Methods: Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals.

Results: DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028).

Conclusions: S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients' risk assessment.
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http://dx.doi.org/10.1007/s12020-020-02546-4DOI Listing
November 2020

Clinicopathological Features as Prognostic Predictors of Poor Outcome in Papillary Thyroid Carcinoma.

Cancers (Basel) 2020 Oct 29;12(11). Epub 2020 Oct 29.

IPATIMUP-Instituto de Patologia e Imunologia Molecular, Universidade do Porto, 4200-135 Porto, Portugal.

Papillary thyroid cancer (PTC) has an indolent nature and usually excellent prognosis. Some PTC clinicopathological features may contribute to the development of aggressive metastatic disease. In this work, we want to evaluate PTC clinicopathological features that are presurgical prognostic predictors of patients' outcomes and find which indicators are more adequate for tailoring surgical procedures and follow-up. We studied a series of 241 PTC patients submitted to surgery. All patients' files and histological tumor samples were reviewed. The 8th edition AJCC/UICC (American Joint Committee on Cancer/Union for International Cancer) Controlstaging system and the 2015 American Thyroid Association risk stratification system were used. Total thyroidectomy was performed in 228 patients, lymphadenectomy in 28 patients. Gross extrathyroidal extension (ETE) was present in 10 patients and 31 tumor resection margins were incomplete. Cervical lymph node metastases (LNMs) were present in 34 patients and distant metastases at diagnosis in four patients. In multivariate analysis, male gender (OR = 15.4, = 0.015), venous invasion (OR = 16.7, = 0.022), and lateral compartment LNM (OR = 26.7, = 0.004) were predictors of mortality; psammoma bodies (PBs) (OR = 4.5, = 0.008), lymph vessel invasion (OR = 6.9, < 0.001), and gross ETE (OR = 16.1, = 0.001) were predictors of structural disease status; male gender (OR = 2.9, = 0.011), lymph vessel invasion (OR = 2.8, = 0.006), and incomplete resection margins (OR = 4.6, < 0.001) were predictors of recurrent/persistent disease. Our study supports that the factors helping to tailor patient's surgery are male gender, presence of PBs, gross ETE, and lateral compartment LNM. Together with pathological factors, lymph vessel invasion, venous invasion, necrosis, and incomplete surgical resection, should be taken into consideration regarding treatment and follow-up of patients.
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http://dx.doi.org/10.3390/cancers12113186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693726PMC
October 2020

Molecular Aspects of Thyroid Calcification.

Int J Mol Sci 2020 Oct 19;21(20). Epub 2020 Oct 19.

Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, Porto 4200-319, Portugal.

In thyroid cancer, calcification is mainly present in classical papillary thyroid carcinoma (PTC) and in medullary thyroid carcinoma (MTC), despite being described in benign lesions and in other subtypes of thyroid carcinomas. Thyroid calcifications are classified according to their diameter and location. At ultrasonography, microcalcifications appear as hyperechoic spots ≤ 1 mm in diameter and can be named as stromal calcification, bone formation, or psammoma bodies (PBs), whereas calcifications > 1 mm are macrocalcifications. The mechanism of their formation is still poorly understood. Microcalcifications are generally accepted as a reliable indicator of malignancy as they mostly represent PBs. In order to progress in terms of the understanding of the mechanisms behind calcification occurring in thyroid tumors in general, and in PTC in particular, we decided to use histopathology as the basis of the possible cellular and molecular mechanisms of calcification formation in thyroid cancer. We explored the involvement of molecules such as runt-related transcription factor-2 (Runx-2), osteonectin/secreted protein acidic and rich in cysteine (SPARC), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteopontin (OPN) in the formation of calcification. The present review offers a novel insight into the mechanisms underlying the development of calcification in thyroid cancer.
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http://dx.doi.org/10.3390/ijms21207718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589718PMC
October 2020

Early and late behavioral consequences of ethanol withdrawal: focus on brain indoleamine 2,3 dioxygenase activity.

Alcohol 2021 02 5;90:1-9. Epub 2020 Oct 5.

Laboratory of Psychopharmacology, Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal, RN, Brazil. Electronic address:

Anxiety and depression are symptoms associated with ethanol withdrawal that lead individuals to relapse. In the kynurenine pathway, the enzyme indoleamine 2,3 dioxygenase (IDO) is responsible for the conversion of tryptophan to kynurenine, and dysregulation of this pathway has been associated with psychiatric disorders, such as anxiety and depression. The present study evaluated the early and late behavioral and biochemical effects of ethanol withdrawal in rats. Male Wistar rats were submitted to increasing concentrations of ethanol in drinking water during 21 days. In experiment 1, both control and withdrawal groups were submitted to a battery of behavioral tests 3, 5, 10, 19, and 21 days following ethanol removal. In experiment 2, animals were euthanized 3 days (short-term) or 21 days (long-term) after withdrawal, and the brains were dissected altogether, following kynurenine concentration analysis in prefrontal cortex, hippocampus, and striatum. Short-term ethanol withdrawal decreased the exploration of the open arms in the elevated plus-maze. In the forced swimming test, long-term ethanol-withdrawn rats displayed higher immobility time than control animals. Ethanol withdrawal altered neither locomotion nor motor coordination of rats. In experiment 2, kynurenine concentrations were increased in the prefrontal cortex after a long-term period of withdrawal. In conclusion, short-term ethanol withdrawal produced anxiety-like behaviors, while long-term withdrawal favored depressive-like behaviors. Long-term ethanol withdrawal elevated kynurenine levels, specifically in the prefrontal cortex, suggesting that the depressive-like responses observed after long-term withdrawal might be related to the increased IDO activity.
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http://dx.doi.org/10.1016/j.alcohol.2020.09.006DOI Listing
February 2021

Clinical Validation of a Urine Test (Uromonitor-V2) for the Surveillance of Non-Muscle-Invasive Bladder Cancer Patients.

Diagnostics (Basel) 2020 Sep 24;10(10). Epub 2020 Sep 24.

i3S-Instituto de Investigação e Inovação em Saúde, R. Alfredo Allen 208, 4200-135 Porto; Portugal.

The costly and burdensome nature of the current follow-up methods in non-muscle-invasive bladder cancer (NMIBC) drives the development of new methods that may alternate with regular cystoscopy and urine cytology. The Uromonitor-V2 is a new urine-based assay in the detection of hotspot mutations in three genes (, , and ) for evaluation of disease recurrence. The aim of this study was to investigate the Uromonitor-V2's performance in detecting NMIBC recurrence and compare it with urine cytology. From February 2018 to September 2019 patients were enrolled. All subjects underwent a standard-of-care (SOC) cystoscopy, either as part of their follow-up for NMIBC or for a nonmalignant urological pathology. Urine cytology was performed in NMIBC patients. Out of the 105 patients enrolled, 97 were eligible for the study. Twenty patients presented nonmalignant lesions, 29 had a history of NMIBC with disease recurrence, and 49 had a history of NMIBC without recurrence. In NMIBC, the Uromonitor-V2 displayed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 93.1%, 85.4%, 79.4%, and 95.3%, respectively. Urine cytology was available for 52 patients, and the sensitivity, specificity, PPV, and NPV were 26.3%, 90.9%, 62.5%, and 68.2%, respectively. With its high NPV of 95.3%, the Uromonitor-V2 revealed promising properties for the follow-up of patients with NMIBC.
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http://dx.doi.org/10.3390/diagnostics10100745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599569PMC
September 2020

Follicular Lesions with Papillary Nuclear Characteristics: Differences in Chromatin Detected by Computerized Image Analysis.

Arch Endocrinol Metab 2020 Aug 28. Epub 2020 Aug 28.

Departamento de Medicina Interna, Faculdade de Medicina de Botucatu, Universidade Estadual de São Paulo, Botucatu, SP, Brasil.

Objective: Follicular lesions of the thyroid with papillary carcinoma nuclear characteristics are classified as infiltrative follicular variant of papillary thyroid carcinoma-FVPTC (IFVPTC), encapsulated/well demarcated FVPTC with tumour capsular invasion (IEFVPTC), and the newly described category "non-invasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) formerly known as non-invasive encapsulated FVPTC. This study evaluated whether computerized image analysis can detect nuclear differences between these three tumour subtypes.

Materials And Methods: Slides with histological material from 15 cases of NIFTP and 33 cases of FVPTC subtypes (22 IEFVPTC, and 11 IFVPTC) were analyzed using the Image J image processing program. Tumour cells were compared for both nuclear morphometry and chromatin textural characteristics.

Results: Nuclei from NIFTP and IFVPTC tumours differed in terms of chromatin textural features (grey intensity): mean (92.37 ± 21.01 vs 72.99 ± 14.73, p = 0.02), median (84.93 ± 21.17 vs 65.18 ± 17.08, p = 0.02), standard deviation (47.77 ± 9.55 vs 39.39 ± 7.18; p = 0.02), and coefficient of variation of standard deviation (19.96 ± 4.01 vs 24.75 ± 3.31; p = 0.003). No differences were found in relation to IEFVPTC.

Conclusion: Computerized image analysis revealed differences in nuclear texture between NIFTP and IFVPTC, but not for IEFVPTC.
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http://dx.doi.org/10.20945/2359-3997000000282DOI Listing
August 2020

Sexuality and associated risk factors in pregnant women.

Rev Bras Enferm 2020 31;73 Suppl 4:e20180786. Epub 2020 Jul 31.

Universidade Federal do Ceará, Fortaleza, Ceará, Brazil.

Objectives: to assess the sexual function of pregnant women and the influence of sociodemographic, obstetric, and behavioral factors on sexual dysfunction.

Methods: cross-sectional study conducted with 141 pregnant women attended by the Single Health System and 120 by one private service, totaling 261 participants. A questionnaire containing sociodemographic, obstetric, and behavioral variables was applied, as well as the Female Sexual Function Index instrument, which was used to assess sexual function. Associations between variables and sexual dysfunction were made using the chi-square test, considering a statistically significant result when p < 0.05.

Results: among the participants, 32.1% had sexual dysfunction, and the variables "age", "income" and "type of health service" had an influence on sexual dysfunction. The prevalence of pregnant women was between 21 and 30 years old (p < 0.001), with an income between 1 and 2 minimum wages (p = 0.048) and used the public health system network (p = 0.000).

Conclusions: the factors associated with sexual dysfunction are "young pregnant women", "low income" and "attended in the public health service".
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http://dx.doi.org/10.1590/0034-7167-2018-0786DOI Listing
July 2020

Predictive Biomarkers and Patient Outcome in Platinum-Resistant (PLD-Treated) Ovarian Cancer.

Diagnostics (Basel) 2020 Jul 28;10(8). Epub 2020 Jul 28.

Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.

Identification of predictive biomarkers for ovarian cancer (OC) treatment, particularly in the platinum-resistant/refractory setting, is highly relevant for clinical management. E-cadherin, vimentin, and osteopontin (OPN) are proteins associated with tumor microenvironment (TME) remodelling that play key roles in cancer. This study aimed to evaluate the association between the staining patterns of these proteins with survival outcomes in a series of OC patients, namely in patients with platinum-resistant/refractory disease. Low E-cadherin expression and high vimentin expression in all patient groups (as well as for E-cadherin in the platinum-resistant arm) were significantly associated with longer overall survival (OS). Low cytoplasmic OPN expression (and cytoplasmic and membrane OPN in the platinum-resistant arm) were significantly associated with longer OS. In patients that responded to treatment (pegylated liposomal doxorubicin (PLD) or other), low cytoplasmic OPN expression was also associated with longer progression-free survival (PFS). In the other hand, high nuclear OPN-c expression in patients that respond to treatment was associated with longer OS and longer PFS. Longer PFS was also associated with high expression of both nuclear and cytoplasm OPN-c, in platinum-resistant patients and in those that responded to PLD. Our study indicates that the expression of E-cadherin, vimentin, and OPN may have prognostic implications. Nuclear OPN-c and cytoplasm OPN expression are putative predictive markers in platinum-resistant (PLD treated) ovarian cancer patients.
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http://dx.doi.org/10.3390/diagnostics10080525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459532PMC
July 2020

Comprehensive Assessment of mRNA Expression across a Large Cohort of Benign and Malignant Thyroid Tumours.

Cancers (Basel) 2020 Jul 9;12(7). Epub 2020 Jul 9.

Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal.

The presence of promoter (p) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of in thyroid tumours is still largely unknown. We analysed frozen samples from a series of benign and malignant thyroid tumours, displaying non-aggressive features and low mutational burden in order to evaluate the presence of p mutations and mRNA expression in these settings. In this series, p mutations were found in 2%, only in malignant cases, in larger cancers, and from older patients. mRNA expression was detected in both benign and malignant tumours, with increased frequencies in the malignant tumours with aggressive histotypes, larger tumours, and from older patients. In benign tumours, mRNA expression was found in 17% of the follicular thyroid adenoma (FTA) with increased levels of expression in smaller tumours and associated with the presence of thyroiditis. p mutations and mRNA expression are correlated with worse prognosis features in malignant thyroid tumours, whereas mRNA expression in the benign tumours is associated with the presence of thyroiditis.
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http://dx.doi.org/10.3390/cancers12071846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408963PMC
July 2020

Prognostic Significance of RAS Mutations and P53 Expression in Cutaneous Squamous Cell Carcinomas.

Genes (Basel) 2020 07 6;11(7). Epub 2020 Jul 6.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.

is considered the most commonly-altered gene in cutaneous squamous cell carcinoma (cSCC). Conversely, mutations have been reported in a low percentage of cSCC. The objective of our study was to evaluate the frequency of p53 expression and mutations in cSCC and correlate them with clinicopathological features and patient outcome. We performed immunohistochemistry for p53 and genetic profiling for mutations in a retrospective series of cSCC. The predictive value of p53 expression, mutations, and clinicopathological parameters was assessed using logistic regression models. The overall frequency of mutations was 9.3% (15/162), and 82.1% of the cases (133/162) had p53 overexpression. mutations rate was 3.2% (1/31) of in situ cSCCs and 10.7% (14/131) of invasive cSCCs. mutations were more frequently associated with an infiltrative than an expansive pattern of invasion ( = 0.046). p53 overexpression was a predictor of recurrence in the univariate analysis. Our results indicate that mutations associate with features of local aggressiveness. Larger studies with more recurrent and metastatic cSCCs are necessary to further address the prognostic significance of p53 overexpression in patients' risk stratification.
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http://dx.doi.org/10.3390/genes11070751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397334PMC
July 2020

A 30-Year Long-Term Experience in Appendix Neuroendocrine Neoplasms-Granting a Positive Outcome.

Cancers (Basel) 2020 May 26;12(6). Epub 2020 May 26.

Instituto de Investigação e Inovação em Saúde (i3S), 4200-135 Porto, Portugal.

Neuroendocrine neoplasms (NENs) are the most common tumor of the appendix and have an excellent prognosis. Appendiceal tumors diagnosed between 1989 and 2019 were reviewed, and clinical data were collected from patient files. Part of the series was immuno-profiled for markers related to cell cycle proliferation and/or senescence-type, apoptotic, and metastatic potential. Appendix NENs were detected in 74 patients, with 0.47% of incidence per appendectomy. The median age of the patients was 21.5 years, with two age peaks of incidence at 17.0 and 55.2 years. The median tumors size was 5.8 mm, and most were smaller than 10 mm. Lymphovascular and perineural invasion, as well as necrosis, was associated with larger tumor size. G1 tumors composed 96.0% of the cohort. The presence of moderate/strong p16 and the absent/low Bcl-2 expression was frequently observed and associated with a smaller size. This study represents one of the largest cohorts and with a long follow-up. For tumors smaller than 10 mm appendicectomy was sufficient as a curative procedure, as revealed by the good outcome. This series presented a 100% disease-free survival. The indolent phenotype of appendix NENs is supported by the expression of markers that point towards a strong inhibition of cell replication and growth inhibition.
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http://dx.doi.org/10.3390/cancers12061357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353034PMC
May 2020

Effects of Fundamental Frequency, Vocal Intensity, Sample Duration, and Vowel Context in Cepstral and Spectral Measures of Dysphonic Voices.

J Speech Lang Hear Res 2020 05 29;63(5):1326-1339. Epub 2020 Apr 29.

Department of Phoniatrics and Speech Pathology, Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, Switzerland.

Purpose Smoothed cepstral peak prominence (CPPS) and harmonics-to-noise ratio (HNR) are acoustic measures related to the periodicity, harmonicity, and noise components of an acoustic signal. To date, there is little evidence about the advantages of CPPS over HNR in voice diagnostics. Recent studies indicate that voice fundamental frequency (F0) and intensity (sound pressure level [SPL]), sample duration (DUR), vowel context (speech vs. sustained phonation), and syllable stress (SS) may influence CPPS and HNR results. The scope of this work was to investigate the effects of voice F0 and SPL, DUR, SS, and token on CPPS and HNR in dysphonic voices. Method In this retrospective study, 27 Brazilian Portuguese speakers with voice disorders were investigated. Recordings of sustained vowels (SVs) /a:/ and manually extracted vowels (EVs) /a/ from Consensus Auditory-Perceptual Evaluation of Voice sentences were acoustically analyzed with the Praat program. Results There was a highly significant effect of F0, SPL, and DUR on both CPPS and HNR ( < .001), whereas SS and vowel context significantly affected CPPS only ( < .05). Higher SPL, F0, and lower DUR were related to higher CPPS and HNR. SVs moderately-to-highly correlated with EVs for CPPS, whereas HNR had few and moderate correlations. In addition, CPPS and HNR highly correlated in SVs and seven EVs ( < .05). Conclusion Speaking prosodic variations of F0, SPL, and DUR influenced both CPPS and HNR measures and led to acoustic differences between sustained and excised vowels, especially in CPPS. Vowel context, prosodic factors, and token type should be controlled for in clinical acoustic voice assessment.
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http://dx.doi.org/10.1044/2020_JSLHR-19-00049DOI Listing
May 2020

Evaluation of the role of mitochondria in the non-targeted effects of ionizing radiation using cybrid cellular models.

Sci Rep 2020 04 9;10(1):6131. Epub 2020 Apr 9.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.

Radiobiology is moving towards a better understanding of the intercellular signaling that occurs upon radiation and how its effects relate to the dose applied. The mitochondrial role in orchestrating this biological response needs to be further explored. Cybrids (cytoplasmic hybrids) are useful cell models for studying the involvement of mitochondria in cellular processes. In the present study we used cybrid cell lines to investigate the role of mitochondria in the response to radiation exposure. Cybrid cell lines, derived from the osteosarcoma human cell line 143B, harboring, either wild-type mitochondrial DNA (Cy143Bwt), cells with mitochondria with mutated DNA that causes mitochondrial dysfunction (Cy143Bmut), as well as cells without mitochondrial DNA (mtDNA) (143B-Rho0), were irradiated with 0.2 Gy and 2.0 Gy. Evaluation of the non-targeted (or bystander) effects in non-irradiated cells were assessed by using conditioned media from the irradiated cells. DNA double stranded breaks were assessed with the γH2AX assay. Both directly irradiated cells and cells treated with the conditioned media, showed increased DNA damage. The effect of the irradiated cells media was different according to the cell line it derived from: from Cy143Bwt cells irradiated with 0.2 Gy (low dose) and from Cy143Bmut irradiated with 2.0 Gy (high dose) induced highest DNA damage. Notably, media obtained from cells without mtDNA, the143B-Rho0 cell line, produced no effect in DNA damage. These results point to a possible role of mitochondria in the radiation-induced non-targeted effects. Furthermore, it indicates that cybrid models are valuable tools for radiobiological studies.
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http://dx.doi.org/10.1038/s41598-020-63011-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145863PMC
April 2020

Reliable blood cancer cells' telomere length evaluation by qPCR.

Cancer Med 2020 05 6;9(9):3153-3162. Epub 2020 Mar 6.

Bordeaux University, INSERM U1053 Bordeaux Research in Translational Oncology (BaRITOn), Cutaneous Lymphoma Oncogenesis Team, Bordeaux, France.

Background: Telomere shortening is linked to a range of different human diseases, hence reliable measurement methods are needed to uncover such associations. Among the plethora of telomere length measurement methods, qPCR is reported as easy to conduct and a cost-effective approach to study samples with low DNA amounts.

Methods: Cancer cells' telomere length was evaluated by relative and absolute qPCR methods.

Results: Robust and reproducible telomere length measurements were optimized taking into account a careful reference gene selection and by knowing the cancer cells ploidy. qPCR data were compared to "gold standard" measurement from terminal restriction fragment (TRF).

Conclusions: Our study provides guidance and recommendations for accurate telomere length measurement by qPCR in cancer cells, taking advantage of our expertise in telomere homeostasis investigation in primary cutaneous T-cell lymphomas. Furthermore, our data emphasize the requirement of samples with both, high DNA quality and high tumor cells representation.
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http://dx.doi.org/10.1002/cam4.2816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196062PMC
May 2020

Promoter Mutation as a Potential Predictive Biomarker in BCG-Treated Bladder Cancer Patients.

Int J Mol Sci 2020 Jan 31;21(3). Epub 2020 Jan 31.

Instituto de Investigação e Inovação em Saúde (i3S), 4200-135 Porto, Portugal.

Telomerase reverse transcriptase gene promoter () mutations are recognized as one of the most frequent genetic events in bladder cancer (BC). No studies have focused on the relevance of TERTp mutations in the specific group of tumors treated with Bacillus Calmette-Guérin (BCG) intravesical therapy. Methods - 125 non muscle invasive BC treated with BCG therapy (BCG-NMIBC) were screened for mutations, rs2853669 single nucleotide polymorphism, and Fibroblast Growth Factor Receptor 3 () hotspot mutations. Results - mutations were found in 56.0% of BCG-NMIBC and were not associated with tumor stage or grade. mutations were found in 44.9% of the cases and were not associated with tumor stage or grade nor with mutations. The rs2853669 single nucleotide polymorphism was associated with tumors of higher grade. The specific c.1-146G>A mutation was an independent predictor of nonrecurrence after BCG therapy (hazard ratio-0.382; 95% confidence interval-0.150-0.971, = 0.048). Conclusions - mutations are frequent in BCG-NMIBC and -146G>A appears to be an independent predictive marker of response to BCG treatment with an impact in recurrence-free survival.
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http://dx.doi.org/10.3390/ijms21030947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037401PMC
January 2020

Biomarkers for Bladder Cancer Diagnosis and Surveillance: A Comprehensive Review.

Diagnostics (Basel) 2020 Jan 13;10(1). Epub 2020 Jan 13.

i3S-Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Portugal.

Bladder cancer (BC) ranks as the sixth most prevalent cancer in the world, with a steady rise in its incidence and prevalence, and is accompanied by a high morbidity and mortality. BC is a complex disease with several molecular and pathological pathways, thus reflecting different behaviors depending on the clinical staging of the tumor and molecular type. Diagnosis and monitoring of BC is mainly performed by invasive tests, namely periodic cystoscopies; this procedure, although a reliable method, is highly uncomfortable for the patient and it is not exempt of comorbidities. Currently, there is no formal indication for the use of molecular biomarkers in clinical practice, even though there are several tests available. There is an imperative need for a clinical non-invasive testing for early detection, disease monitoring, and treatment response in BC. In this review, we aim to assess and compare different tests based on molecular biomarkers and evaluate their potential role as new molecules for bladder cancer diagnosis, follow-up, and treatment response monitoring.
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http://dx.doi.org/10.3390/diagnostics10010039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169395PMC
January 2020

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study.

Front Genet 2019 18;10:1237. Epub 2019 Dec 18.

i3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal.

Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70-75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. promoter mutations and hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor, capable of detecting trace amounts of promoter (c.1-124C > T and c.1-146C > T) and (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.
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http://dx.doi.org/10.3389/fgene.2019.01237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930177PMC
December 2019

Relevant dose of the environmental contaminant, tributyltin, promotes histomorphological changes in the thyroid gland of male rats.

Mol Cell Endocrinol 2020 02 9;502:110677. Epub 2019 Dec 9.

Laboratório de Endocrinologia Experimental-LEEx, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil; Programa de Pós-graduação em Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Brazil; Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil. Electronic address:

Organotin compounds, such as tributyltin (TBT), are common environmental contaminants and suspected endocrine-disrupting chemicals. Tributyltin is found in antifouling paints, widely used in ships and other vessels. The present study evaluated whether a 15-day treatment with TBT at a dose of 100 ng/kg/day could induce histomorphological changes in the thyroid gland of rats. TBT promoted relevant alterations in the thyroid architecture, being the most relevant histological findings the presence of increased number of small-size follicles in the treated group. In qualitative analyses, colloid vacuolization, papillary budging structures, cystic degeneration and chronic thyroiditis, were observed. Moreover, histomorphometric analysis showed statistically significant changes in the follicular architecture of TBT-treated rats, mainly a decrease in the follicle area (colloid) and an increased epithelial height that resulted in an increased epithelial height/colloid ratio. Augmented collagen deposition was also seen in the thyroids of treated groups. In immunohistochemical (IHC) analyses, the localization of NIS protein was described and a significant increased proliferation index (evaluated by Ki67 positive cells) in the treated group was reported. As an indirect measurement of oxidative stress, mitochondrial protein SDHA was also analyzed by IHC analysis. Although the cytoplasmic expression of SDHA was observed in both groups, the staining intensity score was higher in TBT-treated group. Our results suggest that besides causing histomorphological changes, environmental relevant dose of TBT treatment can also induce oxidative alterations.
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http://dx.doi.org/10.1016/j.mce.2019.110677DOI Listing
February 2020

Cancer incidence after childhood irradiation for tinea capitis in a Portuguese cohort.

Br J Radiol 2020 Jan 11;93(1105):20180677. Epub 2019 Nov 11.

IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45 4200-135, Porto, Portugal.

Objectives: Our aim was to compare cancer incidence in a cohort exposed in childhood (1950-63) to a therapeutic dose of radiation in the North of Portugal and followed-up until the end of 2012, with the incidence rates for the same age and sex in the general population.

Methods: A population-based North Region cancer registry (RORENO) was used to assess which members of the cohort developed cancer. The association between radiation exposure and overall and specific cancer sites was evaluated using standardised incidence ratios (SIR).

Results: Over the full follow-up period, 3357 individuals of the 5356 original tinea capitis (TC) cohort (63%) were retrieved in the RORENO, and 399 new cancer cases were identified, representing an increased risk of 49% when compared with the general population (SIR = 1.49; 95% CI: 1.35-1.64). The risk was slightly higher in males than in females (SIR = 1.65; 95% CI: 1.43-1.89 SIR = 1.35; CI = 1.17-1.55). The risk was slightly higher in the individuals exposed to a higher radiation dose (SIR = 1.78; 95% CI: 1.22-2.51 for ≥630 R SIR = 1.46; 95% CI: 1.31-1.62 for 325-475 R). In females, there was an excess cancer risk in all cancers with the higher radiation dose (SIR = 2.00; 95% CI: 1.21-3.13 for ≥630 R SIR = 1.30; 95% CI: 1.11-1.51 for 325-475 R) which was not observed in males, and for combined dose categories significantly raised SIRs for thyroid and head and neck cancer, suggesting a possible higher radiosensitivity of females. An increased risk was also observed for some cancers located far from the irradiated area.

Conclusions: The results suggest an association between radiation exposure and later increased cancer risk for cancers located near the radiation exposed area, mainly thyroid, and head and neck cancers. Further studies are necessary to disentangle possible non-radiation causes for distant cancers increased risk.

Advances In Knowledge: This paper shows a possible association between childhood X-ray epilation and increased risk of cancer which was not previously investigated in the Portuguese TC cohort.
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http://dx.doi.org/10.1259/bjr.20180677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948089PMC
January 2020

Variants of Papillary Thyroid Carcinoma: An Algorithmic Cytomorphology-Based Approach to Cytology Specimens.

Acta Cytol 2020 21;64(4):288-298. Epub 2019 Oct 21.

Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.

Background: Thyroid cancer accounts for 1% of cancer cases in developed countries, in which papillary thyroid carcinoma (PTC) is the most common type. There are multiple variants of PTC described to date, some of them with aggressive behavior and poor clinical outcome. These variants are well described and accepted in recent guidelines of many international societies, and the prognostic and management implications are well laid out. Due to their established clinical importance and to guide appropriate surgical management, it is now imperative in clinical practice, including cytopathology, to differentiate aggressive variants from nonaggressive ones. This review aims to describe the variants of PTC and to provide a practical algorithmic approach to facilitate the cytological diagnosis of these variants.

Summary: Subtyping PTC variants on fine needle aspiration cytology (FNAC) is challenging even for the most experienced cytopathologist. To facilitate a correct subtyping on FNAC, we propose a stepwise approach that is mainly designed for conventional smear methodology. This approach requires first to stratify the lesions into oncocytic and nononcocytic features before analyzing further details in cell morphology and pattern. Key Messages: (1) Subtyping in PTC is possible on cytopathology. (2) The main aim of the cytopathologist is to differentiate aggressive from nonaggressive variants. (3) The subtyping of PTC can help in the surgical management of the patients.
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http://dx.doi.org/10.1159/000503576DOI Listing
July 2020

Interaction of Genetic Variations in and Modulates the Risk of Hashimoto's Thyroiditis.

Thyroid 2019 09;29(9):1302-1315

Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and/or cellular defense to stress. The transcription factor Nrf2, encoded by , is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in on the risk of developing HT. In a case-control candidate gene association study, functional SNPs in the promoter (rs35652124, rs6706649, and rs6721961) were examined either as independent risk factors or in combination with a previously characterized HT risk allele (rs28665122) in the gene , encoding selenoprotein S (SelS). A total of 997 individuals from the north of Portugal (Porto) were enrolled, comprising 481 HT patients and 516 unrelated healthy controls. and SNPs were genotyped using TaqMan assays and Sanger sequencing, respectively. Odds ratios (ORs) were calculated using logistic regression, with adjustment for sex and age. Expression of SelS was analyzed by immunohistochemistry in thyroid tissue from HT patients and control subjects. Molecular interactions between the Nrf2 and SelS pathways were investigated in thyroid tissues from mice and in rat PCCL3 thyroid follicular cells. When all three SNPs were considered together, the presence of one or more minor alleles was associated with a near-significant increased risk (OR = 1.43,  = 0.072). Among subjects harboring only major alleles, there was no increased HT risk associated with heterozygosity or homozygosity for the minor allele. Conversely, in subjects heterozygous or homozygous for the risk allele, the presence of an minor allele significantly increased HT risk by 2.8-fold ( = 0.003). Immunohistochemistry showed reduced expression of SelS in thyroid follicular cells of HT patients. In Nrf2 knockout mice, there was reduced expression of SelS in thyroid follicular cells; conversely, in PCCL3 cells, reducing SelS expression caused reduced activity of Nrf2 signaling. The promoter genotype interacts with the promoter genotype to modulate the risk of HT in a Portuguese population. This interaction may be due to a bidirectional positive feedback between the Nrf2 and SelS pathways.
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http://dx.doi.org/10.1089/thy.2018.0480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760180PMC
September 2019

Characterization and antitumor activity of the extracellular carbohydrate polymer from the cyanobacterium Synechocystis ΔsigF mutant.

Int J Biol Macromol 2019 Sep 21;136:1219-1227. Epub 2019 Jun 21.

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IBMC - Instituto de Biologia Celular e Molecular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; FCUP - Faculdade de Ciências, Departamento de Biologia, Universidade do Porto, Rua do Campo Alegre, Edifício FC4, 4169-007 Porto, Portugal. Electronic address:

Cyanobacterial extracellular carbohydrate polymers are particularly attractive for biotechnological applications. Previously, we determined the monosaccharidic composition of the polymer of a Synechocystis ΔsigF overproducing mutant. Here, we further characterized this polymer, demonstrated that it is possible to recover it in high yields, and successfully use it for biomedical research. This amorphous polymer is formed by a mesh of fibrils/lamellar structures with high porosity, is constituted by high molecular mass fractions, is highly sulfated and displays low viscosity, even in highly concentrated aqueous solutions. FTIR analysis confirmed the presence of several functional groups. We demonstrated that the ΔsigF polymer has strong biological activity, decreasing the viability of melanoma, thyroid and ovary carcinoma cells by inducing high levels of apoptosis, through p53 and caspase-3 activation. Therefore, the ΔsigF Synechocystis mutant is a promising platform for the sustainable production of biological active carbohydrate polymer(s) with the desired characteristics for biomedical applications.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.06.152DOI Listing
September 2019

Differential Expression of HMGA1 and HMGA2 in pituitary neuroendocrine tumors.

Mol Cell Endocrinol 2019 06 15;490:80-87. Epub 2019 Apr 15.

Laboratory of Experimental Endocrinology - LEEx, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Brazil; Graduate Program in Endocrinology, Faculty of Medicine, Federal University of Rio de Janeiro, Brazil; Graduate Program in Pharmacology and Medicinal Chemistry, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Brazil. Electronic address:

Defining biomarkers for invasive pituitary neuroendocrine tumors (PitNETs) is highly desirable. The high mobility group A (HMGA) proteins are among the most widely expressed cancer-associated proteins. Indeed, their overexpression is a frequent feature of human malignancies, including PitNETs. We show that nonfunctioning PitNETs (NF-PitNETs) express significantly higher levels of HMGA1 than somatotropinomas (GHs) and corticotropinomas (ACTHs). Furthermore, HMGA2 expression was detected only in NF-PitNETs and was significantly higher in larger tumors than in smaller tumors. HMGA expression analysis generally focuses on nuclear staining. Here, cytoplasmic HMGA staining was also found. PitNETs displayed strong nuclear HMGA1 and strong cytoplasmic HMGA2 immunoreactivity. Interestingly, the HMGA1 and HMGA2 nuclear expression levels were significantly higher in invasive adenomas than in noninvasive adenomas. The highest levels of nuclear HMGA2 were found in GHs. In conclusion, we show that overexpression of nuclear HMGA proteins could be a potential biomarker of invasive PitNETs, particularly HMGA2 for GHs. HMGA2 might be a reliable biomarker for NF-PitNETs.
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http://dx.doi.org/10.1016/j.mce.2019.04.010DOI Listing
June 2019