Stress-induced phosphoprotein 1: how does this co-chaperone influence the metastasis steps?

In several cancer types, metastasis is associated with poor prognosis, survival, and quality of life, representing a life risk more significant than the primary tumor itself. Metastasis is a multi-step process that spreads tumor cells from primary sites to surrounding or distant organs, originating secondary tumors. The interconnected steps that drive metastasis depend of several capabilities that enable cells to detach from the primary tumor, acquire motility and migrate through the basal membrane; invade and spread through the vascular system, and finally settle and originate a new tumor. Recently, stress-induced phosphoprotein 1 (STIP1) has emerged as a protein capable of driving tumor cells through these metastasis steps by mediating several biological processes and signaling pathways. This protein is mainly known for its function as a co-chaperone, acting as a scaffold for the interaction of its client heat-shock proteins Hsp70/90 chaperones; however, it is also known that STIP1 can act independently of chaperones to activate downstream phosphorylation pathways. The over-expression of STIP1 has been reported across various cancer types, identifying it as a potential biomarker for predicting patient prognosis and monitoring the progression of metastasis. Here, we present a discussion on how this co-chaperone mediates the initial steps of metastasis (cell adhesion loss, epithelial-to-mesenchymal transition, and angiogenesis), highlighting the biological mechanisms in which STIP1 plays a vital role, also presenting an overview of the current knowledge regarding its clinical relevance.

Organohalogen compounds in a hotspot for chemical pollution: Assessment in free-ranging Atlantic spotted dolphins (Stenella frontalis).

The assessment of chemical pollution in free-ranging living mammals is viable using remote biopsies and portrays a comprehensive scenario of environmental health. The Southwestern Atlantic Ocean holds incredible biodiversity, but it is under the constant and invisible threat of persistent organic pollutants (POPs) of anthropogenic origin, such as pesticides, brominated flame retardants, and industrial-use compounds (e.g., PCBs). Thus, this study aimed to assess the bioaccumulation of POPs (PCBs, DDTs, HCB, mirex and PBDEs) and natural organobromine compounds (MeO-BDEs) using gas-chromatography coupled to mass spectrometry in biopsy samples of Atlantic spotted dolphins (Stenella frontalis, n = 20) that inhabit and forage both inside and in adjacent areas to degraded (Guanabara Bay) and conserved (Ilha Grande Bay) coastal bays in the Southeastern Brazil. Among the studied compounds, PCBs were predominant in the contamination profile with median concentration of 97.0 µg.g-1 lipid weight (lw), followed by the sum of the p,p' isomers of DDT, DDD, and DDE of 11.0 µg.g-1 lw, the brominated flame retardants PBDEs of 1.6 µg.g-1 lw, and the other organochlorine pesticides mirex of 0.78 µg.g-1 lw, and HCB of 0.049 µg.g-1 lw. The MeO-BDEs were detected with a median concentration of 22.8 µg.g-1 lw. 85 % of the Atlantic spotted dolphins analyzed in this study presented PCB concentration that exceeded even the less conservative threshold limits for adverse health effects (41 µg.g-1 lw). This study shows that despite the conservation status of preserved bays, cetacean species foraging in these locations are still under increased threat. Hence chemical pollution demands local and global efforts to be mitigated.

Targeting EphA2: a promising strategy to overcome chemoresistance and drug resistance in cancer.

Erythropoietin-producing hepatocellular A2 (EphA2) is a vital member of the Eph tyrosine kinase receptor family and has been associated with developmental processes. However, it is often overexpressed in tumors and correlates with cancer progression and worse prognosis due to the activation of its noncanonical signaling pathway. Throughout cancer treatment, the emergence of drug-resistant tumor cells is relatively common. Since the early 2000s, researchers have focused on understanding the role of EphA2 in promoting drug resistance in different types of cancer, as well as finding efficient and secure EphA2 inhibitors. In this review, the current knowledge regarding induced resistance by EphA2 in cancer treatment is summarized, and the types of cancer that lead to the most cancer-related deaths are highlighted. Some EphA2 inhibitors were also investigated. Regardless of whether the cancer treatment has reached a drug-resistance stage in EphA2-overexpressing tumors, once EphA2 is involved in cancer progression and aggressiveness, targeting EphA2 is a promising therapeutic strategy, especially in combination with other target-drugs for synergistic effect. For that reason, monoclonal antibodies against EphA2 and inhibitors of this receptor should be investigated for efficacy and drug toxicity.

Natural and anthropogenic organic brominated compounds in the southwestern Atlantic ocean: Bioaccumulation in coastal and oceanic dolphin species.

Marine pollution is considered a current driver of change in the oceans and despite the urgency to develop more studies, there is limited information in the southern hemisphere. This study aimed to analyze the levels and profiles of natural (MeO-PBDEs) and anthropogenic (BFRs: PBDEs, HBB, PBEB) organic brominated compounds in adipose tissue of two species of dolphins with different distribution and trophic requirements from the Southwestern Atlantic Ocean; the short-beaked common dolphin (Delphinus delphis) and the Fraser's dolphin (Lagenodelphis hosei). In addition, we aim to investigate maternal transfer and biological pattern relationship (sex, age, sexual maturity) in short-beaked common dolphin bioaccumulation. The levels of both groups of contaminants were in the same order of magnitude as those reported for other marine mammals on both a regional and global scale. BFRs profiles were dominated by BDE 28 and BDE 47 in short-beaked common dolphin and Fraser's dolphin, respectively, whereas 2-MeO-BDE 68 was the most abundant natural compound in both species. Evidence of maternal transfer, temporary increase in BDE 154 levels and no influence of sex, age, or sexual maturity on brominated compound concentration was observed in short-beaked common dolphin. This study fills a gap in the knowledge of the Southwestern Atlantic Ocean providing new information on emerging organic pollutants bioavailability for dolphins and, therefore, for the different trophic webs. In addition, it serves as a baseline for further contamination assessments.

Biomarker potential of the LEF1/TCF family members in breast cancer: Bioinformatic investigation on expression and clinical significance.

The LEF1/TCF transcription factor family is related to the development of diverse tissue types, including the mammary tissue, and dysregulation of its expression and function has been described to favor breast tumorigenesis. However, the clinical and biological relevance of this gene family in breast cancer is still poorly understood. Here, we used bioinformatics approaches aiming to reduce this gap. We investigated its expression patterns in molecular and immune breast cancer subtypes; its correlation with immune cell infiltration, and its prognostic values in predicting outcomes. Also, through regulons construction, we determined the genes whose expression is influenced by these transcription factors, and the pathways in which they are involved. We found that LEF1 and TCF3 are over-expressed in breast tumors regarding non-tumor samples, while TCF4 and TCF7 are down-expressed, with the gene's methylation status being associated with its expression dysregulation. All four transcription factors presented significance at the diagnostic and prognostic levels. LEF1, TCF4, and TCF7 presented a significant correlation with immune cell infiltration, being associated with the immune subtypes of less favorable outcomes. Altogether, this research contributes to a more accurate understanding of the expression and clinical and biomarker significance of the LEF1/TCF transcription factors in breast cancer.

Fish chorus variation in a tropical estuarine environmenta).

Fish choruses are still understudied in the Southwestern Atlantic Ocean. Temporal and spatial variation of fish choruses at two sites inside Guanabara Bay were investigated between 2021 and 2022; one sampling site was in a Marine Protected Area (MPA), and the other was in a rocky environment closer to vessel trafficking areas. Acoustic recordings were performed on 17 sampling occasions of 24 h, coupled to a temperature data logger. Long-term spectral averages were employed to determine choruses' start, end, and peak times, and third-octave levels were used to characterize spectral characteristics. Fish sounds were also analyzed and investigated with a principal components analysis. Choruses in the MPA lasted, on average, 4.5 h and had a peak frequency of 547.2 ± 226.6 kHz with a peak level of 104.6 ± 8.7 dB re 1 µPa. In contrast, the rocky site choruses lasted 5.5 h on average and had a peak frequency of 371.7 ± 131.0 Hz with a peak level of 113.4 ± 4.0 dB re 1 µPa. Chorus peak frequency was positively correlated to temperature (r = 0.4). Different types of fish sounds were identified, with some acoustics parameters varying between sites. Results indicate more than one chorusing species that may react to different factors.

Brominated flame retardants and natural organobrominated compounds in a vulnerable delphinid species along the Brazilian coast.

Guiana dolphins, Sotalia guianensis, are vulnerable to extinction along their distribution on the Brazilian coast and assessing chemical pollution is of utmost importance for their conservation. For this study, 51 carcasses of Guiana dolphins were sampled across the Brazilian coast to investigate legacy and emerging brominated flame retardants (BFRs) as well as the naturally-produced MeO-BDEs. PBDEs and MeO-BDEs were detected in all samples analyzed, whereas emerging BFRs were detected in 16 % of the samples, all in Rio de Janeiro state. PBDE concentrations varied between 2.24 and 799 ng.g-1 lipid weight (lw), emerging BFRs between 0.12 and 1.51 ng.g-1 lw and MeO-BDEs between 3.82 and 10,247 ng.g-1 lw. Concentrations of legacy and emerging BFRs and natural compounds varied considerably according to the sampling site and reflected both the local anthropogenic impact of the region and the diversity/mass of biosynthesizers. The PBDE concentrations are lower than what was found for delphinids in the Northern Hemisphere around the same sampling period and most sampling sites presented mean concentrations lower than the limits for endocrine disruption known to date for marine mammals of 460 ng.g-1 lw, except for sampled from Santa Catarina state, in Southern Brazil. Conversely, MeO-BDE concentrations are higher than those of the Northern Hemisphere, particularly close to the Abrolhos Bans and Royal Charlotte formation, that are hotspots for biodiversity. Despite the elevated concentrations reported for this group, there is not much information regarding the effects of such elevated concentrations for these marine mammals. The distinct patterns observed along the Brazilian coast show that organobrominated compounds can be used to identify the ecological segregation of delphinids and that conservation actions should be planned considering the local threats.

Feeding ecology based on stable carbon and nitrogen isotopes: A comparative study on different Guiana dolphin tissues.

Different tissues are used for stable isotope analysis in cetacean investigations. However, variation in the isotopic composition of tissues with different turnover rates has been reported for cetaceans. To better understand stable carbon and nitrogen isotopes (δ13C and δ15N) in skin compared to other tissues, this study assessed the isotopic variation among the liver, muscle, and skin of Guiana dolphins (Sotalia guianensis), as well as the influence of sex on these variations. No differences were found in δ13C among male tissues, but females showed lower values in the liver compared to muscle and skin. Differences in δ15N were observed among all tissues, with different variation patterns for males and females. Four females were distinguished from males and other females by their 13C depletion in all tissues and δ15N variation pattern. We conclude that skin and muscle may be equivalent in δ13C values for Guiana dolphins. The multiple-tissue analysis brings new insights into their feeding ecology and provides background for stable isotope analysis using non-destructive sampling techniques in small cetaceans.

The deep dive of organohalogen compounds: Bioaccumulation in the top predators of mesopelagic trophic webs, pygmy and dwarf sperm whales, from the Southwestern Atlantic ocean.

Kogia sima and Kogia breviceps are apex predators of mesopelagic trophic webs being far from most anthropogenic threats. However, chemical pollutants and naturally synthesized compounds may travel long distances. This study aimed to use kogiid whales as sentinels of mesopelagic trophic webs in the Southwestern Atlantic Ocean. Persistent organic pollutants (POPs), e.g., polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT) and metabolites, mirex, hexachlorobenzene (HCB), polybrominated diphenylethers (PBDEs), pentabromoethylbenzene (PBEB) and hexabromobenzene (HBB), and the naturally produced methoxylated BDE (MeO-BDEs) were determined in the blubber of 16 K. sima and 15 K. breviceps. Among the organochlorine compounds, DDTs were the main group found in K. sima and in K. breviceps (1636.6 and 3983.3 ng g-1 lw, respective medians), followed by PCBs (425.9 and 956.1 ng g-1 lw, respectively), mirex (184.1 and 375.6 ng g-1 lw, respectively), and HCB (132.4 and 340.3 ng g-1 lw, respectively). As for the organobromine, the natural MeO-BDEs were predominant (1676.7 and 501.6 ng g-1 lw, respectively), followed by PBDEs (13.6 and 10.3 ng g-1 lw, respectively) and PBEB (2.2 and 2.9 ng g-1 lw, respectively). In general, POPs concentration was higher in K. breviceps than in K. sima. Conversely, MeO-BDEs concentration was higher in K. sima than in K. breviceps. Differences in concentrations in these sympatric odontocetes were attributed to distinct species, sampling sites, and biological parameters and suggest some level of niche segregation. It is noteworthy the long-range reach and bioaccumulation of these synthetic compounds in an unexplored habitat, that present an increasing economic interest.

Screening of Exosome-Derived Proteins and Their Potential as Biomarkers in Diagnostic and Prognostic for Pancreatic Cancer.

In the oncological area, pancreatic cancer is one of the most lethal diseases, with 5-year survival rising just 10% in high-development countries. This disease is genetically characterized by KRAS as a driven mutation followed by SMAD4, CDKN2, and TP53-associated mutations. In clinical aspects, pancreatic cancer presents unspecific clinical symptoms with the absence of screening and early plasmatic biomarker, being that CA19-9 is the unique plasmatic biomarker having specificity and sensitivity limitations. We analyzed the plasmatic exosome proteomic profile of 23 patients with pancreatic cancer and 10 healthy controls by using Nanoscale liquid chromatography coupled to tandem mass spectrometry (NanoLC-MS/MS). The pancreatic cancer patients were subdivided into IPMN and PDAC. Our findings show 33, 34, and 7 differentially expressed proteins when comparing the IPMN vs. control, PDAC-No treatment vs. control, and PDAC-No treatment vs. IPMN groups, highlighting proteins of the complement system and coagulation, such as C3, APOB, and SERPINA. Additionally, PDAC with no treatment showed 11 differentially expressed proteins when compared to Folfirinox neoadjuvant therapy or Gemcitabine adjuvant therapy. So here, we found plasmatic exosome-derived differentially expressed proteins among cancer patients (IPMN, PDAC) when comparing with healthy controls, which could represent alternative biomarkers for diagnostic and prognostic evaluation, supporting further scientific and clinical studies on pancreatic cancer.

Understanding trophic transference role in mercury biomagnification and bioaccumulation in the Atlantic spotted dolphin (Stenella frontalis).

Mercury is a metal of toxicological importance that occurs naturally. However, its concentration can be affected by anthropogenic activities and has the potential to bioaccumulate and biomagnify in food webs. Thus, knowing how its concentration varies along the trophic levels allows us to understand its potential risks to the biota. The present study aimed to investigate mercury transfer through the Stenella frontalis food web in Ilha Grande Bay (IGB), Rio de Janeiro state, Brazil. Samples of muscle and liver of S. frontalis were obtained from carcasses (n = 8) found stranded in the IGB, and its potential prey species were collected in fishing landings in the same Bay (n = 145). Total mercury (THg) concentrations were determined by atomic absorption spectrometry, and the δ15N was determined by an isotope ratio mass spectrometer. To investigate how trophic transfer affects mercury contamination in biota, six linear models were applied between THg logarithmic concentrations and δ15N or trophic position (TP). The trophic magnification factor (TMF) was calculated from each model to estimate the trophic transfer. Mean THg concentration in S. frontalis was higher in the liver than in muscle, but no correlation was found with age and δ15N values. Instead, the hepatic and muscular THg concentrations positively correlated with the trophic position. In the summer, THg concentration, TP, and δ15N values in prey species varied significantly, as well as in the winter, except for THg concentration. All trophic transfer models were significant in both seasons, and the TMF >1. The present study showed that trophic transfer is an essential factor in mercury biomagnification in both seasons but is not the unique driver. Both δ15N and TP could explain mercury trophic transfer, but TP better integrates metabolic diversity and seasonality.

Fatal toxoplasmosis in a captive squirrel monkey (Saimiri boliviensis) in Portugal.

New World monkeys are especially vulnerable to develop severe clinical manifestations and succumb to acute toxoplasmosis. This study aimed to describe the histopathological findings and genotypic characterization of the Toxoplasma gondii strain involved in a lethal case occurring in a zoo-housed black-capped squirrel monkey (Saimiri boliviensis) in Portugal. Cyst-like structures suggestive of Sarcocystidae parasites and acute injuries in liver and brain were observed by light microscopy examination. By immunohistochemistry, calprotectin, T. gondii antigen and Iba1 antigen had a positive signaling in lung, liver and brain tissues. Toxoplasma gondii B1, ITS1 and 529 repetitive element fragments amplifications together with the genotyping of 13 microsatellite markers confirmed a systemic T. gondii infection linked to a non-clonal type II strain. This description is consistent to the majority T. gondii strains circulating in Europe.

High-throughput proteomics of breast cancer subtypes: Biological characterization and multiple candidate biomarker panels to patients' stratification.

BACKGROUND AND AIMS: The actual classification of breast tumors in subtypes represents an attempt to stratify patients into clinically cohesive groups, nevertheless, clinicians still lack reproducible and reliable protein biomarkers for breast cancer subtype discrimination. In this study, we aimed to access the differentially expressed proteins between these tumors and its biological implications, contributing to the subtype's biological and clinical characterization, and with protein panels for subtype discrimination. METHODS: In our study, we applied high-throughput mass spectrometry, bioinformatic, and machine learning approaches to investigate the proteome of different breast cancer subtypes. RESULTS: We identified that each subtype depends on different protein expression patterns to sustain its malignancy, and also alterations in pathways and processes that can be associated with each subtype and its biological and clinical behaviors. Regarding subtype biomarkers, our panels achieved performances with at least 75% of sensibility and 92% of specificity. In the validation cohort, the panels obtained acceptable to outstanding performances (AUC = 0.740 to 1.00). CONCLUSIONS: In general, our results expand the accuracy of breast cancer subtypes' proteomic landscape and improve the understanding of its biological heterogeneity. In addition, we identified potential protein biomarkers for the stratification of breast cancer patients, improving the repertoire of reliable protein biomarkers. SIGNIFICANCE: Breast cancer is the most diagnosed cancer type worldwide and the most lethal cancer in women. As a heterogeneous disease, breast cancer tumors can be classified into four major subtypes, each presenting particular molecular alterations, clinical behaviors, and treatment responses. Thus, a pivotal step in patient management and clinical decisions is accurately classifying breast tumor subtypes. Currently, this classification is made by the immunohistochemical detection of four classical markers (estrogen receptor, progesterone receptor, HER2 receptor, and the Ki-67 index); however, it is known that these markers alone do not fully discriminate the breast tumor subtypes. Also, the poor understanding of the molecular alterations of each subtype leads to a challenging decision-making process regarding treatment choice and prognostic determination. This study, through high-throughput label-free mass-spectrometry data acquisition and downstream bioinformatic analysis, advances in the proteomic discrimination of breast tumors and achieves an in-depth characterization of the subtype's proteomes. Here, we indicate how the variations in the subtype's proteome can influence the tumor's biological and clinical differences, highlighting the variation in the expression pattern of oncoproteins and tumor suppressor proteins between subtypes. Also, through our machine-learning approach, we propose multi-protein panels with the potential to discriminate the breast cancer subtypes. Our panels achieved high classification performance in our cohort and in the independent validation cohort, demonstrating their potential to improve the current tumor discrimination system as complements to the classical immunohistochemical classification.

Major regulators of the multi-step metastatic process are potential therapeutic targets for breast cancer management.

Metastasis is a multi-step process that leads to the dissemination of tumor cells to new sites and, consequently, to multi-organ neoplasia. Although most lethal breast cancer cases are related to metastasis occurrence, little is known about the dysregulation of each step, and clinicians still lack reliable therapeutic targets for metastasis impairment. To fill these gaps, we constructed and analyzed gene regulatory networks for each metastasis step (cell adhesion loss, epithelial-to-mesenchymal transition, and angiogenesis). Through topological analysis, we identified E2F1, EGR1, EZH2, JUN, TP63, and miR-200c-3p as general hub-regulators, FLI1 for cell-adhesion loss specifically, and TRIM28, TCF3, and miR-429 for angiogenesis. Applying the FANMOD algorithm, we identified 60 coherent feed-forward loops regulating metastasis-related genes associated with distant metastasis-free survival prediction. miR-139-5p, miR-200c-3p, miR-454-3p, and miR-1301-3p, among others, were the FFL's mediators. The expression of the regulators and mediators was observed to impact overall survival and to go along with metastasis occurrence. Lastly, we selected 12 key regulators and observed that they are potential therapeutic targets for canonical and candidate antineoplastics and immunomodulatory drugs, like trastuzumab, goserelin, and calcitriol. Our results highlight the relevance of miRNAs in mediating feed-forward loops and regulating the expression of metastasis-related genes. Altogether, our results contribute to understanding the multi-step metastasis complexity and identifying novel therapeutic targets and drugs for breast cancer management.

Mercury toxicology in Epinephelidae fishes: A multiple tissue approach in two groupers species from southwestern Atlantic (SE-Brazil).

Epinephelidae fishes are important to reef ecosystems, as well as for commercial fishing and cultural heritage. Additionally, most of these species are at some risk of extinction, as Epinephelus marginatus and Hyporthodus nigritus. This study aimed to determine total mercury (THg) concentrations and burden on eight tissues of E. marginatus and H. nigritus. A Cold Vapor/Atomic Absorption Spectrometer was used for the THg determination. THg concentrations and burden varied significantly between tissues in both species. The highest concentrations were determined in the liver, and the greatest burden was in muscle. The gonad concentrations were higher than the toxicological threshold. General trends of increase in THg concentrations and burden along growth were observed. Mercury is a threat for both species evaluated, raising this concern for other Epinephelidae species.

An additional threat to populations predicted to collapse: Organobromine compounds of natural and anthropogenic sources in rough-toothed dolphins from the Southwestern Atlantic Ocean.

Organic contaminants with toxic effects, like the conventional brominated flame retardants (BFRs) and BFRs of emergent concern, and their synergistic effects with other micropollutants, can be an additional threat to delphinids. Rough-toothed dolphins (Steno bredanensis) populations strongly associated with coastal environments already face a potential risk of decline due to high exposure to organochlorine pollutants. Moreover, natural organobromine compounds are important indicators of the environment's health. Polybrominated diphenyl ethers (PBDEs), pentabromoethylbenzene (PBEB), hexabromobenzene (HBB) and the methoxylated PBDEs (MeO-BDEs) were determined in the blubber of rough-toothed dolphins from three ecological populations from the Southwestern Atlantic Ocean (Southeastern, Southern and Outer Continental Shelf/Southern populations, SE, S, and OCS/S, respectively). The profile was dominated by the naturally produced MeO-BDEs (mainly 2'-MeO-BDE 68 and 6-MeO-BDE 47), followed by the anthropogenic BFRs PBDEs (mainly BDE 47). Median ΣMeO-BDE concentrations varied between 705.4 and 3346.0 ng g-1 lw among populations and ΣPBDE from 89.4 until 538.0 ng g-1 lw. Concentrations of anthropogenic organobromine compounds (ΣPBDE, BDE 99 and BDE 100) were higher in SE population than in OCS/S, indicating a coast - ocean gradient of contamination. Negative correlations were found between the concentration of the natural compounds and age, suggesting their metabolization and/or biodilution and maternal transference. Conversely, positive correlations were found between the concentrations of BDE 153 and BDE 154 and age, indicating low biotransformation capability of these heavy congeners. The levels of PBDEs found are concerning, particularly for SE population, because they are similar to concentrations known for the onset of endocrine disruption in other marine mammals and may be an additional threat to a population in a hotspot for chemical pollution.

2023 Guidelines on the Diagnosis and Treatment of Insomnia in Adults - Brazilian Sleep Association.

Chronic insomnia disorder (simplified in this document as insomnia) is an increasingly common clinical condition in society and a frequent complaint at the offices of different areas of health practice (particularly Medicine and Psychology). This scenario has been accompanied by a significant evolution in treatment, as well as challenges in approaching patients in an appropriately way. This clinical guideline, coordinated by the Brazilian Sleep Association and the Brazilian Association of Sleep Medicine and counting on the active participation of various specialists in the area, encompasses an update on the diagnosis and treatment of insomnia in adults. To this end, it followed a structured methodology. Topics of interest related to diagnosis were written based on theoretical framework, evidence in the literature, and professional experience. As for the topics related to the treatment of insomnia, a series of questions were developed based on the PICO acronym (P - Patient, problem, or population; I - Intervention; C - Comparison, control, or comparator; O - Outcome). The work groups defined the eligible options within each of these parameters. Regarding pharmacological interventions, only the ones currently available in Brazil or possibly becoming available in the upcoming years were considered eligible. Systematic reviews were conducted to help prepare the texts and define the level of evidence for each intervention. The final result is an objective and practical document providing recommendations with the best scientific support available to professionals involved in the management of insomnia.

Comprehensive analysis of the large and small ribosomal proteins in breast cancer: Insights on proteomic and transcriptomic expression patterns, regulation, mutational landscape, and prognostic significance.

Several evidence has demonstrated the involvement of the ribosomal proteins (RPs) in many malignancies, however, the function and clinical relevance of the RPs in breast cancer remains unclear. The present study aims to contribute to the understanding of the role of the RPs in breast tumorigenesis and its clinical implications in the field of biomarker discovery and outcome prediction. We investigated the proteomic and transcriptomic expression of the RPs in non-tumor and tumor tissues of different breast cancer subtypes, and integrated bioinformatics approaches and online databases to comprehensively evaluate the potential functions, regulatory networks, mutational landscape, and prognostic values of the ribosomal proteins in breast cancer. Our results show that 33 RPs have deregulated expression in breast cancer and its subtypes and that 26 RPs have potential as prognostic markers in a subtype-dependent way, with mutations in RP genes being frequent in breast tumors and related to overall survival and relapse-free status. Our RP gene regulatory network indicates the transcription factors MYC, ETS1, and SPI1, and the miRNAs has-let-7c-5p, has-mir-20b-5p, and has-mir-4668-3p as regulators of the RPs expression in breast cancer. The RPs were associated with several clinicopathological parameters of breast cancer and predicted to be involved in ribosomal-independent mechanisms such as regulation of the SLITS-ROBO pathway. This study comprehensively investigated the ribosomal proteins in breast cancer, suggesting that the RPs have clinical potential as biomarkers of diagnostic and prognostic, also providing an in-depth view of the RPs significance in breast cancer.

The Role of Pyrazolopyridine Derivatives on Different Steps of Herpes Simplex Virus Type-1 In Vitro Replicative Cycle.

Herpes simplex virus type-1 (HSV-1) infection causes several disorders, and acyclovir is used as a reference compound. However, resistant strains are commonly observed. Herein, we investigate the effects of N-heterocyclic compounds (pyrazolopyridine derivatives), named ARA-04, ARA-05, and AM-57, on HSV-1 in vitro replication. We show that the 50% effective concentration (EC50) values of the compounds ARA-04, ARA-05, and AM-57 were 1.00 ± 0.10, 1.00 ± 0.05, and 0.70 ± 0.10 µM, respectively. These compounds presented high 50% cytotoxic concentration (CC50) values, which resulted in a selective index (SI) of 1000, 1000, and 857.1 for ARA-04, ARA-05, and AM-57, respectively. To gain insight into which step of the HSV-1 replication cycle these molecules would impair, we performed adsorption and penetration inhibition assays and time-of-addition experiments. Our results indicated that ARA-04 and ARA-05 affected viral adsorption, while AM-57 interfered with the virus replication during its α- and γ-phases and decreased ICP27 content during initial and late events of HSV-1 replication. In addition, we also observed that AM-57 caused a strong decrease in viral gD content, which was reinforced by in silico calculations that suggested AM-57 interacts preferentially with the viral complex between a general transcription factor and virion protein (TFIIBc-VP16). In contrast, ARA-04 and ARA-05 interact preferentially in the proteins responsible for the viral adsorption process (nectin-1 and glycoprotein). Thus, our results suggest that the 1H-pyrazolo[3,4-b]pyridine derivatives inhibit the HSV-1 replicative cycle with a novel mechanism of action, and its scaffold can be used as a template for the synthesis of promising new molecules with antiviral effects, including to reinforce the presented data herein for a limited number of molecules.

Franciscana dolphins, Pontoporia blainvillei, as environmental sentinels of the world's largest mining disaster: Temporal trends for organohalogen compounds and their consequences for an endangered population.

On November 5th, 2015, the Fundão dam collapsed in Minas Gerais, southeastern Brazil, releasing millions of cubic meters of mud containing mining residue into the Doce River. Two weeks later, the mud arrived to the marine environment, triggering changes in franciscana dolphin habitat, Pontoporia blainvillei, from Franciscana Management Area Ia. This is an isolated population of the most endangered cetacean species in the South Atlantic Ocean. Organohalogen compounds (OHCs) may pose a threat to this endangered population because of their endocrine disrupting properties. Hence, this study sought to determine if there were differences in the bioaccumulation profile of OHC (PCBs, DDTs, Mirex, HCB, HCHs, PBDEs, PBEB, HBBZ and MeO-BDEs) in franciscana dolphins before and after dam collapse and to build a temporal trend. Blubber of 33 stranded individuals was collected in Espírito Santo state for organohalogen assessment between 2003 and 2019. Differences were found between franciscana dolphins collected prior to and after the disaster. Additionally, significant temporal trends for organochlorine pesticides and natural and anthropogenic organobromine were detected. The increase in pesticide concentrations after 2015 is suggestive of their reavailability in the environment. The decline in organobromine over time could be due to their debromination in the marine environment and alterations in the composition of their natural producers. PCBs remained stable during the period of the study. Our findings show an increase in endocrine disruptor concentrations, which is of great concern for this endangered population.