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With the objective of developing new methods to acquire diagnostic information, the reconstruction of the broadband absorption coefficient spectra (μ a [λ]) of healthy and chromophobe renal cell carcinoma kidney tissues was performed. By performing a weighted sum of the absorption spectra of proteins, DNA, oxygenated, and deoxygenated hemoglobin, lipids, water, melanin, and lipofuscin, it was possible to obtain a good match of the experimental μ a (λ) of both kidney conditions. The weights used in those reconstructions were estimated using the least squares method, and assuming a total water content of 77% in both kidney tissues, it was possible to calculate the concentrations of the other tissue components. It has been shown that with the development of cancer, the concentrations of proteins, DNA, oxygenated hemoglobin, lipids, and lipofuscin increase, and the concentration of melanin decreases. Future studies based on minimally invasive spectral measurements will allow cancer diagnosis using the proposed approach., (© 2024 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

A fast calculation method was used to obtain the spectral optical properties of human normal and pathological (chromophobe renal cell carcinoma) kidney tissues. Using total transmittance, total reflectance and collimated transmittance spectra acquired from ex vivo kidney samples, the spectral optical properties of both tissues, namely the absorption, the scattering and the reduced scattering coefficients, as well as the scattering anisotropy, dispersion and light penetration depth, were calculated between 200 and 1000 nm. Analysis of the mean absorption coefficient spectra of the kidney tissues showed that both contain melanin and lipofuscin, and that 83 % of the melanin in the normal kidney converts into lipofuscin in the pathological kidney., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Epigenetic mechanisms such as aberrant DNA methylation (DNAme) are known to drive esophageal squamous cell carcinoma (ESCC), yet they remain poorly understood. Here, we studied tumor-specific DNAme in ESCC cases from nine high-incidence countries of Africa, Asia, and South America. Infinium MethylationEPIC array was performed on 108 tumors and 51 normal tissues adjacent to the tumors (NAT) in the discovery phase, and targeted pyrosequencing was performed on 132 tumors and 36 NAT in the replication phase. Top genes for replication were prioritized by weighting methylation results using RNA-sequencing data from The Cancer Genome Atlas and GTEx and validated by qPCR. Methylome analysis comparing tumor and NAT identified 6,796 differentially methylated positions (DMP) and 866 differential methylated regions (DMR), with a 30% methylation (Δβ) difference. The majority of identified DMPs and DMRs were hypermethylated in tumors, particularly in promoters and gene-body regions of genes involved in transcription activation. The top three prioritized genes for replication, PAX9, SIM2 , and THSD4 , had similar methylation differences in the discovery and replication sets. These genes were exclusively expressed in normal esophageal tissues in GTEx and downregulated in tumors. The specificity and sensitivity of these DNAme events in discriminating tumors from NAT were assessed. Our study identified novel, robust, and crucial tumor-specific DNAme events in ESCC tumors across several high-incidence populations of the world. Methylome changes identified in this study may serve as potential targets for biomarker discovery and warrant further functional characterization. SIGNIFICANCE: This largest genome-wide DNA methylation study on ESCC from high-incidence populations of the world identifies functionally relevant and robust DNAme events that could serve as potential tumor-specific markers. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2612/F1.large.jpg., (©2021 American Association for Cancer Research.)

Extracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients. Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH. Release of miR-424 in small EVs was enhanced in cell lines (LNCaP abl ), transgenic mice (Pb-Cre4;Pten flox/flox ;Rosa26 ERG/ERG ) and patient-derived xenograft (PDX) models of aggressive disease. EVs containing miR-424 promoted stem-like traits and tumor-initiating properties in normal prostate epithelial cells while enhanced tumorigenesis in transformed prostate epithelial cells. Intravenous administration of miR-424 positive EVs to mice, mimicking blood circulation, promoted miR-424 transfer and tumor growth in xenograft models. Circulating miR-424 positive EVs from patients with aggressive primary and metastatic tumors induced stem-like features when supplemented to prostate epithelial cells. This study establishes that EVs-mediated transfer of miR-424 across heterogeneous cell populations is an important mechanism of tumor self-sustenance, disease recurrence and progression. These findings might indicate novel approaches for the management and therapy of prostate cancer.

Tumor growth is accompanied with dramatic changes in the cellular glycome, such as the aberrant expression of complex branched N-glycans. However, the role of this protumoral N-glycan in immune evasion and whether its removal contributes to enhancement of immune recognition and to unleashing an antitumor immune response remain elusive. We demonstrated that branched N-glycans are used by colorectal cancer cells to escape immune recognition, instructing the creation of immunosuppressive networks through inhibition of IFNγ. The removal of this "glycan-mask" exposed immunogenic mannose glycans that potentiated immune recognition by DC-SIGN-expressing immune cells, resulting in an effective antitumor immune response. We revealed a glycoimmune checkpoint in colorectal cancer, highlighting the therapeutic efficacy of its deglycosylation to potentiate immune recognition and, thus, improving cancer immunotherapy., (©2020 American Association for Cancer Research.)

Previous studies on monocarboxylate transporters expression in prostate cancer (PCa) have shown that monocarboxylate transporter 2 (MCT2) was clearly overexpressed in prostate malignant glands, pointing it out as a putative biomarker for PCa. However, its localization and possible role in PCa cells remained unclear. In this study, we demonstrate that MCT2 localizes mainly at peroxisomes in PCa cells and is able to take advantage of the peroxisomal transport machinery by interacting with Pex19. We have also shown an increase in MCT2 expression from non-malignant to malignant cells that was directly correlated with its peroxisomal localization. Upon analysis of the expression of several peroxisomal β-oxidation proteins in PIN lesions and PCa cells from a large variety of human prostate samples, we suggest that MCT2 presence at peroxisomes is related to an increase in β -oxidation levels which may be crucial for malignant transformation. Our results present novel evidence that may not only contribute to the study of PCa development mechanisms but also pinpoint novel targets for cancer therapy., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Epigenetic mechanisms, including histone deacetylation, are commonly deregulated in cancer. Histone deacetylases (HDACs) play an important role in tumorigenesis and their value as therapeutic targets has been under intense investigation in recent years. In addition to classical HDACs (HDAC classes I, II, and IV), sirtuins (class III HDACs) are currently in the spotlight of cancer research showing promise as cancer biomarkers and therapeutic targets. Translating research knowledge into the clinical setting is, however, a challenging and demanding task. This review describes the association between HDAC deregulation and cancer promotion and highlights recent advances in the use of HDAC inhibitors in the management of neoplastic diseases, with emphasis on urological tumors. Sirtuins' bivalent role in tumor development and therapeutic agents targeting these molecules will be also addressed.

Purpose: Successful therapy of patients with prostate cancer is highly dependent on reliable diagnostic and prognostic biomarkers. Brachyury is considered a negative prognostic factor in colon and lung cancer; however, there are no reports on Brachyury's expression in prostate cancer., Experimental Design: In this study, we aimed to assess the impact of Brachyury expression in prostate tumorigenesis using a large series of human prostate samples comprising benign tissue, prostate intraepithelial neoplasia (PIN) lesions, localized tumor, and metastatic tissues. The results obtained were compared with what can be inferred from the Oncomine database. In addition, multiple in vitro models of prostate cancer were used to dissect the biologic role of Brachyury in prostate cancer progression., Results: We found that Brachyury is significantly overexpressed in prostate cancer and metastatic tumors when compared with normal tissues, both at protein and at mRNA levels. Brachyury expression in the cytoplasm correlates with highly aggressive tumors, whereas the presence of Brachyury in the nucleus is correlated with tumor invasion. We found that Brachyury-positive cells present higher viability, proliferation, migration, and invasion rates than Brachyury-negative cells. Microarray analysis further showed that genes co-expressed with Brachyury are clustered in oncogenic-related pathways, namely cell motility, cell-cycle regulation, and cell metabolism., Conclusions: Collectively, the present study suggests that Brachyury plays an important role in prostate cancer aggressiveness and points, for the first time, to Brachyury as a significant predictor of poor prostate cancer prognosis. Our work paves the way for future studies assessing Brachyury as a possible prostate cancer therapeutic target., (©2014 American Association for Cancer Research.)

Background: Monocarboxylate transporter 2 (MCT2) is a transmembrane protein involved in the transport of monocarboxylates such as pyruvate and lactate. In a previous study we described overexpression of MCT2 in prostate carcinoma raising the hypothesis of using MCT2 as a possible biomarker in prostate cancer. With the present study we aimed to compare the pattern of expression of MCT2 and alpha-methylacyl-CoA racemase (AMACR), in prostate carcinoma, PIN lesions, non-neoplastic prostate tissue, and normal prostate and compare their sensitivity and specificity. Also, we wanted to evaluate the value of using MCT2 in combination with AMACR and the negative markers 34βE12 or p63 to detect prostate cancer., Methods: A total of 349 cases, including prostate carcinoma, non-neoplastic prostate tissue and PIN lesions, from radical prostatectomies were examined by immunohistochemistry for AMACR, MCT2, p63, and 34βE12, using tissue microarrays (TMAs). Normal prostate from radical cystoprostatectomy was also studied., Results: Our study revealed that MCT2, similarly to AMACR, was consistently expressed in prostate cancer regardless of the Gleason score. In combination with AMACR and p63 or 34βE12, MCT2 helped to improve the diagnosis of prostate carcinoma. Also, overexpression of MCT2 as well as AMACR in PIN lesions may indicate the involvement of these two proteins in prostate cancer initiation., Conclusions: We provided evidence for the presence of MCT2 in prostate cancer, selectively labeling malignant glands. Importantly, assessment of MCT2 together with AMACR, along with the negative markers, highly increases the accuracy in prostate cancer diagnosis., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Monocarboxylate transporters (MCTs) are transmembrane proteins involved in the transport of monocarboxylates across the plasma membrane, which appear to play an important role in solid tumours, however the role of MCTs in prostate cancer is largely unknown. The aim of the present work was to evaluate the clinico-pathological value of monocarboxylate transporters (MCTs) expression, namely MCT1, MCT2 and MCT4, together with CD147 and gp70 as MCT1/4 and MCT2 chaperones, respectively, in prostate carcinoma., Methods: Prostate tissues were obtained from 171 patients, who performed radical prostatectomy and 14 patients who performed cystoprostatectomy. Samples and clinico-pathological data were retrieved and organized into tissue microarray (TMAs) blocks. Protein expression was evaluated by immunohistochemistry in neoplastic (n = 171), adjacent non-neoplastic tissues (n = 135), PIN lesions (n = 40) and normal prostatic tissue (n = 14). Protein expression was correlated with patients' clinicopathologic characteristics., Results: In the present study, a significant increase of MCT2 and MCT4 expression in the cytoplasm of tumour cells and a significant decrease in both MCT1 and CD147 expression in prostate tumour cells was observed when compared to normal tissue. All MCT isoforms and CD147 were expressed in PIN lesions. Importantly, for MCT2 and MCT4 the expression levels in PIN lesions were between normal and tumour tissue, which might indicate a role for these MCTs in the malignant transformation. Associations were found between MCT1, MCT4 and CD147 expressions and poor prognosis markers; importantly MCT4 and CD147 overexpression correlated with higher PSA levels, Gleason score and pT stage, as well as with perineural invasion and biochemical recurrence., Conclusions: Our data provides novel evidence for the involvement of MCTs in prostate cancer. According to our results, we consider that MCT2 should be further explored as tumour marker and both MCT4 and CD147 as markers of poor prognosis in prostate cancer.

A stereological study was carried out on postnatal cerebellar granule cells of rats aged 6 and 10 days, for detecting whether and how much they would differ from those of young adult rats. The following parameters were estimated: number-weighted mean volume of the nucleus and of the soma; mean total surface area of the soma; mean absolute volumes per cell of total cytoplasm, mitochondria, Golgi apparatus, and cytosol; mean surface density of the rough endoplasmic reticulum (RER); mean total surface area of the RER. These values were compared between the two postnatal ages. In addition, those values were also analysed in comparison to the ones depicted in young adult rats (60 days), already published by our team, in order to detect similarities between them. It was noticed that, between 6 and 10 days, the mean surface density of the RER was the only parameter that did not change significantly. The comparison of each of the postnatal ages with 60 days revealed that, with the exception of the absolute volume of Golgi apparatus, significant differences were displayed concerning other organelles and cellular compartments. It was concluded that, although fine structural differences have been disclosed, from the stereological point of view postnatal granule cells at 10 days were practically similar to the young adult ones at 60 days. Some potential physiological implications have been considered.

Evaluation of activation and proliferation of hepatic stellate cells (HSCs) must be grounded on solid quantitative data under normal conditions. The HSC index (HSCI), number of HSCs per 1000 hepatocytes (HEP), is often used in hepatology but has been never determined using stereology. Systematically sampled sections were immunostained against glial fibrillary acidic protein and carcinoembryonic antigen, allowing unequivocal distinction of HSC and mononuclear/binuclear HEP. With the optical disector the HSCI was estimated as 109 (coefficient of error = 0.04). This work provides a sound technical basis for experiments in which the estimation of HSCI and/or simultaneous quantification of HSC and HEP are relevant.

Two cases of multiple lymphomatous polyposis (MLP) are presented, involving different segments of the gastrointestinal tract. Both cases display the characteristic clinical and pathologic features of MLP. In addition, we were able to document, for the first time, the endoscopic ultrasonographic findings in this disease. This new ancillary diagnostic technique was found to be very helpful in the evaluation of the structural changes of the wall of the gastrointestinal tract and in the detection of affected lymph nodes.

Cortical cerebellar basket cells are stable postmitotic cells; hence, they are liable to endure age-related changes. Since the cerebellum is a vital organ for the postural control, equilibrium and motor coordination, we aimed to determine the quantitative morphological changes in those interneurons with the ageing process, using unbiased techniques. Material from the cerebellar cortex (Crus I and Crus II) was collected from female rats aged 2, 6, 9, 12, 15, 18, 21 and 24 mo (5 animals per each age group), fixed by intracardiac perfusion, and processed for transmission electron microscopy, using conventional techniques. Serial semithin sections were obtained (5 blocks from each rat), enabling the determination of the number-weighted mean nuclear volume (by the nucleator method). On ultrathin sections, 25 cell profiles from each animal were photographed. The volume density of the nucleus, ground substance, mitochondria, Golgi apparatus (Golgi) and dense bodies (DB), and the mean surface density of the rough endoplasmic reticulum (RER) were determined, by point counting, using a morphometric grid. The mean total volumes of the soma and organelles and the mean total surface area of the RER [SN (RER)] were then calculated. The results were analysed with 1-way ANOVA; posthoc pairwise comparisons of group means were performed using the Newman-Keuls test. The relation between age and each of the parameters was studied by regression analysis. Significant age-related changes were observed for the mean volumes of the soma, ground substance, Golgi, DB, and SN (RER). Positive linear trends were found for the mean volumes of the ground substance, Golgi, and DB; a negative linear trend was found for the SN (RER). These results indicate that rat cerebellar basket cells endure important age-related changes. The significant decrease in the SN (RER) may be responsible for a reduction in the rate of protein synthesis. Additionally, it may be implicated in a cascade of events leading to cell damage due to the excitotoxic activity of glutamate, which could interfere in the functioning of the complex cerebellar neuronal network.

A stereological study was performed on cerebellar granule cells from rats 2 to 24 months of age (eight different ages, five animals per age group) to quantify age-related alterations in the rough endoplasmic reticulum (RER). The mean surface density and the mean total surface area of the nucleus, as well as the mean absolute volume of euchromatin per cell, were also estimated to examine whether or not these had quantitative relationships with the RER. The mean surface density and the mean total surface area of RER per cell changed significantly, attaining maximum values at 24 months of 1733 microm(2)/1000 microm(3) (0.06) and 64 microm(2) (0.03), respectively, (coefficients of variation in parentheses). The corresponding values at 2 months were 706 microm(2)/1000 microm(3) (0.20) and 26 microm(2) (0.24). The mean absolute volume of the euchromatin changed significantly, with a minimum value of 57 microm(3) (0.05) occurring at 21 months. We postulate that the increase in RER may be part of a mechanism that compensates for an age-related decrease in euchromatin. An increase in the RER network may improve intracellular transport of proteins, production of which is apparently diminished with aging. The increase may also compensate for the reported decrease in calcium buffer capacity of smooth endoplasmic reticulum.

In order to determine the value of flow cytometric (FCM) immunophenotyping of fine-needle aspirates (FNA) in the diagnosis and classification of lymphoproliferative diseases, 61 tissue samples were studied and compared with the cytologic/histological results. In vivo and ex vivo FNA biopsy yielded the material for FCM, which comprised an extensive number of lymphoid cell markers. In all but three cases sufficient cells were collected. Overall, malignancy was diagnosed in 33 cases from a total of 47 (70.2%), and in the remaining cases malignancy was not detected. Eleven cases were correctly diagnosed as reactive processes (11/11). There were no false positive cases of malignancy, as diagnosed by FCM-FNA. The best accuracy was achieved in the low-grade B-cell lymphomas and lymphoblastic lymphoma/leukemia. We conclude that in a significant number of cases, FCM-FNA permits the separation between lymphoid malignancies and reactive processes without false positive results. It was found to be particularly useful in the differential diagnosis of mantle-cell and small-lymphocytic lymphoma and in the identification of lymphoblastic lymphoma/leukemia., (Copyright 1999 Wiley-Liss, Inc.)

Because cerebellar granule cells are fixed post-mitotic cells, it is expected that they undergo age-related changes like other neurons. To examine this possibility, a stereological study on granule cells of rat neocerebellar cortex was performed for an age spectrum of 2 to 24 months using eight different age groups. The nucleator method, together with point and intersection counting, was used to obtain primary data; arithmetical calculations determined the secondary data. In the soma, the absolute surface area did not change significantly; the volume did, however, exhibit a significant negative linear trend with age. Excluding dense bodies, the absolute volumes of the cytoplasmic components did not vary significantly. The absolute volume of dense bodies displayed a significant positive linear trend with age. Significant positive correlations were detected between the somatic volume and the absolute volume of either mitochondria or ground substance. It was concluded that granule cells showed a fair degree of morphological stability through 18 months. However, the observed changes warn that accompanying physiological alterations may occur, with putative effects on motor coordination.

A morphometric study on age changes of rat cerebellar cortex (Crus I and Crus II) was carried out. The nuclear volume of the granule cells was estimated by means of two unbiased stereological methods: the nucleator, which enabled the estimation of the number-weighted mean volume (VN), and the point-sampled intercepts method, allowing the determination of the volume-weighted mean volume (VV). These parameters enabled the estimation of the coefficient of variation of nuclear volume in the number-weighted distribution [CV(VN)]. All parameters were determined in eight age groups (2, 6, 9, 12, 15, 18, 21, and 24 months--five animals per age) and the mean values of each age group were compared using one-way ANOVA with post hoc comparisons, and regression analysis. It was demonstrated for the first time, using unbiased techniques, that the nucleus of granule cells of the cerebellar cortex showed a significant decrease in its mean volumes (VV) with age, especially from 21 months onwards. Although CV(VN) was not correlated with age, it was also demonstrated that these cells bear a considerable nuclear size pleomorphy that was maintained throughout the age spectrum.

The aquatic ecosystems quality can be evaluated through the analysis of physico-chemical and biological parameters. However, the biological parameters differ from the physico-chemical ones, having the advantage of providing information on the water quality concerning longer periods of time--specially if one considers sessil organisms--thus reflecting, in a better way, the general ecological conditions of the water body. It is necessary, though, that the taxonomic information be translated into simple numerical values (indices), in order to simplify its interpretation as well as providing subsidies for the elaboration of water quality criteria. Several numerical biological indices can be applied, some of them to specific communities, and others to the hole biological community of an aquatic environment. Three kinds of indices are more generally applied to evaluate the pollutant impacts on aquatic communities: biotic, diversity and community comparison indices. The biotic indices will measure the variation in terms of tolerance and relative sensitivity of the occurring organisms to a certain pollution condition; the diversity indices evaluate the effect of pollution in terms of the community structure; the community comparison indices (also named similarity or dissimilarity indices) establish the effects of pollutants on the community composition. It is important, for the numerical indices users, to know the limitations of each method, so that the interpretation of the values obtained may be made in the light of such limitations.