RESUMO

INTRODUCTION: Lung cancer in never-smoker (LCINS) patients accounts for 20% of lung cancer cases, and its biology remains poorly understood, particularly in genetically admixed populations. We elucidated the molecular profile of driver genes in Brazilian LCINS. METHODS: The mutational and gene fusion status of 119 lung adenocarcinomas from self-reported never-smoker patients, was assessed using targeted sequencing (NGS), nCounter, and immunohistochemistry. A panel of 46 ancestry-informative markers determined patients' genetic ancestry. RESULTS: The most frequently mutated gene was EGFR (49.6%), followed by TP53 (39.5%), ALK (12.6%), ERBB2 (7.6%), KRAS (5.9%), PIK3CA (1.7%), and less than 1% alterations in RET, NTRK1, MET∆ex14, PDGFRA, and BRAF. Except for TP53 and PIK3CA, all other alterations were mutually exclusive. Genetic ancestry analysis revealed a predominance of European (71.1%), and a higher African ancestry was associated with TP53 mutations. CONCLUSION: Brazilian LCINS exhibited a similar molecular profile to other populations, except the increased ALK and TP53 alterations. Importantly, 73% of these patients have actionable alterations that are suitable for targeted treatments.

RESUMO

Cutaneous squamous cell carcinoma (cSCC) is a common type of skin cancer that can result in significant morbidity, although it is usually well-managed and rarely metastasizes. However, the lack of commercially available cSCC cell lines hinders our understanding of this disease. This study aims to establish and characterize a new metastatic cSCC cell line derived from a Brazilian patient. A tumor biopsy was taken from a metastatic cSCC patient, immortalized, and named HCB-541 after several passages. The cytokeratin expression profile, karyotypic alterations, mutational analysis, mRNA and protein differential expression, tumorigenic capacity in xenograft models, and drug sensitivity were analyzed. The HCB-541 cell line showed a doubling time between 20 and 30 h and high tumorigenic capacity in the xenograft mouse model. The HCB-541 cell line showed hypodiploid and hypotetraploidy populations. We found pathogenic mutations in TP53 p.(Arg248Leu), HRAS (Gln61His) and TERT promoter (C228T) and high-level microsatellite instability (MSI-H) in both tumor and cell line. We observed 37 cancer-related genes differentially expressed when compared with HACAT control cells. The HCB-541 cells exhibited high phosphorylated levels of EGFR, AXL, Tie, FGFR, and ROR2, and high sensitivity to cisplatin, carboplatin, and EGFR inhibitors. Our study successfully established HCB-541, a new cSCC cell line that could be useful as a valuable biological model for understanding the biology and therapy of metastatic skin cancer.

Assuntos

RESUMO

Illiosentis Van Cleave et Lincicome, 1939 initially included two species: Illiosentis furcatus Van Cleave et Lincicome, 1939 found in the West Atlantic from Cape Cod in Massachusetts, USA to northern Argentina and Illiosentis cetratus Van Cleave, 1945 with restricted distribution in the Pacific coast of southern California. We are reporting I. furcatus from Peru for the first time and describe a population of I. cetratus from the California corbina, Menticirrhus undulatus (Girard), from southern California. The proboscis hook formula was 14 longitudinal rows for I. furcatus of 18-23 hooks each compared to 16 rows of 19-24 hooks each reported by Van Cleave (1945). We complete the inadequate description of I. cetratus with new information on sexual differentiation in the length of the trunk, dorsal vs. ventral hooks, hook roots, trunk spines, two types of anterior recurved rooted hooks vs. posterior rootless straight hooks, measurements of dorsal and ventral hooks and spines, shape of hook roots, terminal position of the female gonopore, and of position of the cephalic ganglion at the anterior margin of the trunk. We also include new details of the reproductive system in both sexes including Saefftigen's pouch and cement gland ducts. We present new SEM and light microscope images. The Energy Dispersive X-ray analysis (EDXA) shows a high level of sulfur in anterior, middle and posterior hooks in various hook sites, as well as spectra of hook tips with a higher relative concentration of sulfur compared to other hook sites. For the placement of I. cetratus, phylogenetic analysis of sequences of three molecular markers, 18S, 28S rRNA and mitochondrial cox 1 genes, was performed with other related available sequences. The resulting analysis illustrated that I. cetratus was nested within a separate clade along with species of two genera, Dentitruncus truttae Sinzar, 1955 and Neotegorhynchus cyprini Lisitsyna, Xi, Orosová, Barcák et Oros, 2022 represented our species of Illiosentis separate from species of Tegorhynchus Van Cleave, 1921 (as also according to the morphology) with which the Illiosentis species were previously synonymised.

Assuntos

RESUMO

Adenoid cystic carcinoma (ACC) is an aggressive tumor with a high propensity for distant metastasis and perineural invasion. This tumor is more commonly found in regions of the head and neck, mainly the salivary glands. In general, the primary treatment modality for ACC is surgical resection and, in some cases, postoperative radiotherapy. However, no effective systemic treatment is available for patients with advanced disease. Furthermore, this tumor type is characterized by recurrent molecular alterations, especially rearrangements involving the MYB, MYBL1, and NFIB genes. In addition, they also reported copy number alterations (CNAs) that impact genes. One of them is C-KIT, mutations that affect signaling pathways such as NOTCH, PI3KCA, and PTEN, as well as alterations in chromatin remodeling genes. The identification of new molecular targets enables the development of specific therapies. Despite ongoing investigations into immunotherapy, tyrosine kinase inhibitors, and anti-angiogenics, no systemic therapy is approved by the FDA for ACC. In this review, we report the genetic and cytogenetic findings on head and neck ACC, highlighting possible targets for therapeutic interventions.

RESUMO

Gastric cancer (GC) is an important cancer-related death worldwide. Among its histological subtypes, intestinal gastric cancer (IGC) is the most common. A previous work showed that increased expression of the THY1 gene was associated with poor overall survival in IGC. Furthermore, it was shown that IGC tumor cells with high expression of THY1 have a greater capacity for tumorigenesis and metastasis in vitro. This study aimed to identify molecular differences between IGC with high and low expression of THY1. Using a feature selection method, a group of 35 genes were found to be the most informative gene set for THY1high IGC tumors. Through a classification model, these genes differentiate THY1high from THY1low tumors with 100% of accuracy both in the test subset and the independent test set. Additionally, this group of 35 genes correctly clustered 100% of the samples. An extensive validation of this potential molecular signature in multiple cohorts successfully segregated between THY1high and THY1low IGC tumors (>95%), proving to be independent of the gene expression quantification methodology. These genes are involved in central processes to tumor biology, such as the epithelial-mesenchymal transition (EMT) and remodeling of the tumor tissue composition. Moreover, patients with THY1high IGC demonstrated poor survival and a more advanced clinicopathological staging. Our findings revealed a molecular signature for IGC with high THY1 expression. This signature showed EMT and remodeling of the tumor tissue composition potentially related to the biology of IGC. Altogether, our results indicate that THY1high IGC tumors are a particular subset of tumors with a specific molecular and prognosis profile.

Assuntos

RESUMO

The morphology of cystacanths and adults of Profilicollis altmani (Perry, 1942) Van Cleave, 1947 (Polymorphidae) were studied from the Pacific mole crab Emerita analoga (Stimpson) (Crustacea, Hippidae) and Belcher's gull Larus belcheri (Vigors) (Aves, Laridae), respectively, in Peru. Comparative morphometrics with accounts of other populations of P. altmani from elsewhere off the Pacific and Atlantic coasts of North and South America revealed marked intraspecific population variations. We report scanning electron micrographs (SEM) of new features, not before noted or captured in line drawings by earlier observers. We further present microscope images that reveal internal details not previously reported or possible to see with SEM. Energy dispersive X-ray analysis (EDXA) revealed unusual patterns in the chemistry of proboscis hooks especially the high sulfur and diminished phosphorous and calcium in hook tips and low sulfur and high levels of phosphorous and calcium at mid hooks. The size and shape of all hooks of the cystacanths are reported for the first time. Histopathological studies in L. belcheri from Peru are also included. Cystacanths of P. altmani from California were also analyzed for molecular patterns and compared with other sequences reported from other locations. The molecular data and the analysis of our new sequences of cytochrome oxidase I (COI) showed that haplotypes of P. altmani had low genetic variation; the species is not geographically structured, and within its clade no monophyletic group is formed.

TITLE: Évaluation comparative de la morphologie de Profilicollis altmani (Acanthocephala, Polymorphidae) de crustacés et d'oiseaux de rivage au Pérou, en particulier l'analyse élémentaire des crochet (EDXA), l'imagerie SEM, l'histopathologie et le profil moléculaire. ABSTRACT: La morphologie des cystacanthes et des adultes de Profilicollis altmani (Perry, 1942) Van Cleave, 1947 (Polymorphidae) a été étudiée, respectivement, à partir du crustacé Emerita analoga (Stimpson) (Crustacea, Hippidae) et du Goéland Siméon Larus belcheri (Vigors) (Aves, Laridae), au Pérou. La morphométrie comparative avec des données d'autres populations de P. altmani d'autres localités au large des côtes du Pacifique et de l'Atlantique de l'Amérique du Nord et du Sud a révélé des variations intraspécifiques marquées des populations. Nous rapportons des nouvelles observations de microscopie électronique à balayage, non notées auparavant ou non capturées dans des dessins au trait par des observateurs antérieurs. Nous présentons en outre des images au microscope qui révèlent des détails internes qui n'ont pas été signalés auparavant ni possibles à voir avec MET. L'analyse aux rayons X à dispersion d'énergie (EDXA) a révélé des modèles inhabituels dans la chimie des crochets de la trompe, en particulier la teneur élevée en soufre et une diminution du phosphore et du calcium dans les pointes des crochets et des niveaux faibles en soufre et en phosphore et en calcium au milieu des crochets. La taille et la forme de tous les crochets des cystacanthes sont décrites pour la première fois. Des études histopathologiques sur L. belcheri du Pérou sont également incluses. Les cystacanthes de P. altmani de Californie ont également été analysés pour les modèles moléculaires et comparés à d'autres séquences rapportées d'autres endroits. Les données moléculaires et l'analyse de nos nouvelles séquences de cytochrome oxydase I (COI) ont montré que les haplotypes de P. altmani avaient une faible variation génétique. L'espèce n'est pas structurée géographiquement, et au sein de son clade aucun groupe monophylétique n'est formé.

Assuntos

RESUMO

In view of growing concerns, in a One Health context, regarding the transport and dissemination of pathogenic microorganisms among seabirds and other vertebrate animals, including humans, the aim of this study was to identify Salmonella spp. in stranded and non-stranded resident and migratory wild seabirds from the Brazilian coast. Antimicrobial susceptibility and molecular profiles, quinolone resistance genes and antigenic characterization of the isolates were also carried out. Fresh faeces and cloacal swabs were obtained totaling 122 seabirds sampled throughout different Brazilian coast regions. At the laboratory, sample culturing, Salmonella spp. isolation and biochemical identification were performed, followed by antigenic profile identification by serum agglutination, susceptibility profile characterization by the agar disc diffusion technique, detection of quinolone resistance genes (qnrA, qnrB, qnrS) using the multiplex polymerase chain reaction technique (multiplex PCR) and, finally, isolates profiles identification by pulsed field gel electrophoresis (PFGE). Salmonella enterica subsp. enterica was identified in 7% of the studied birds, comprising three different serovars: Panama (63 %), Typhimurium (25 %) and Newport (13 %). The most important findings reported herein are the first description of Salmonella panama in seabirds and the totality of isolates being resistant (or intermediate) to at least one tested antimicrobial, with emphasis on quinolone resistance. The molecular results suggest that the observed resistance cannot be explained by the presence of plasmid-mediated quinolone resistance genes. The PFGE suggests that the Panama and Newport profiles detected herein are not yet widespread in Brazil, unlike Typhimurium, which is already well distributed throughout the country. Considering this finding, we suggest that seabirds are an important link in the epidemiological chain of this serovar. The monitoring of these bacteria in seabirds, as well as of their susceptibility profiles to antimicrobials, must be continuous, strengthening the role of these animals as environmental health indicators and sentinels.

Assuntos

RESUMO

BACKGROUND: The role of the molecular tumour board (MTB) is to recommend personalised therapy for patients with cancer beyond standard-of-care treatment. A comprehensive molecular analysis of the tumour in a molecular pathology laboratory is important for all targeted therapies approaches. Here we report the 1-year experience of the Instituto Alexander Fleming Molecular Tumour Board. PATIENTS AND METHODS: The MTB of the Instituto Alexander Fleming was launched in December 2019 in a monthly meeting. In each interactive monthly session, five cases were presented and discussed by the members. These cases were referred by the treating oncologists. The MTB recommendations were sent to each physician individually, and to the rest of the meeting participants. This was discussed with the patients/families by the treating oncologist. The final decision to choose therapy was left to the treating physicians. Of the 32 patients presented at MTB, 28 (87.5%) had potentially actionable alterations and only 4 (12.5%) had no actionable mutation. Six (19%) patients received a local regulatory agency approved drug recommendation, nine (28%) patients received an off-label approval treatment recommendation and three (9%) patients did not receive the treatment due to access and reimbursement of the drug. CONCLUSION: In most of the cases evaluated, the MTB was able to provide treatment recommendations based on targetable genetic alterations. Molecular-guided extended personalised patient care is effective for a small but clinically significant proportion of patients in challenging clinical situations. We believe that the implementation of a MTB is feasible in the Latin America (LATAM) region.

RESUMO

Gastric carcinoma (GC) is one of the most aggressive cancers and the second leading cause of cancer death in the world. According to the Lauren classification, this adenocarcinoma is divided into two subtypes, intestinal and diffuse, which differ in their clinical, epidemiological and molecular features. Several studies have attempted to delineate the molecular signature of gastric cancer to develop new and non-invasive screening tests that improve diagnosis and lead to new treatment strategies. However, a consensus signature has not yet been identified for each condition. Thus, this work aimed to analyze the gene expression profile of Brazilian intestinal-type GC tissues using microarrays and compare the results to those of non-tumor tissue samples. Moreover, we compared our intestinal-type gastric carcinoma profile with those obtained from populations worldwide to assess their similarity. The results identified a molecular signature for intestinal-type GC and revealed that 38 genes differentially expressed in Brazilian intestinal-type gastric carcinoma samples can successfully distinguish gastric tumors from non-tumor tissue in the global population. These differentially expressed genes participate in biological processes important to cell homeostasis. Furthermore, Kaplan-Meier analysis suggested that 7 of these genes could individually be able to predict overall survival in intestinal-type gastric cancer patients.

RESUMO

Background: In 2017, there will be 107,000 cases of gynecologic cancer diagnosed in the US with an overall survival of around 70%-most occurring in post-menopausal individuals. In this study, we have examined a younger (≤ 40 years of age) subpopulation of these women with high grade/ high stage gynecologic malignancies, attempting to identify unique genetic abnormalities or combinations thereof through tissue block specimens. This information was then analyzed in light of known target therapies to see if genetic analysis in this setting would yield significant therapeutic advantage. Methods: We retrospectively evaluated patients with high grade/high stage gynecologic cancers (≤ 40 years of age), examined the presence and status of 400 oncogenes and tumors suppressor genes from Formalin-fixed, Paraffin-embedded (FFPE) tissue and functionally classified mutations by SIFT and Polyphen. Results: Twenty women were identified and stratified into positive and negative outcomes. No demographic, clinicopathologic or treatment factors were significant between these groups. Of the 400 genes evaluated, twelve mutations were significant between the groups, six with targeted therapies. Mutations associated with negative outcomes within histologies/locations were evaluated: ERBB3 in epithelial (ovarian), ALK/GPR124/KMT2D in neuroendocrine (ovarian/endometrial), ROS1/EGFR, ROS1/ERBB3/KMT2D/NIRK1 and GPR124 in sarcoma. All negative outcomes were void of mutations in APC/ABL2. A predictive model for negative outcomes in our cohort was developed from these data: AKAP9-/MBD1-/APC-/ABL2- with a mutation load of > 20.5. Conclusions: Unique multi-gene and mutational outcome correlations were identified in our cohort. Resulting complex mutational profiles in distinctly aggressive gynecologic cancers suggested potential for novel therapeutic treatment. Future larger scale studies will be needed to correlate the genotypic and phenotypic features identified here (AU)

Assuntos