NORAD-Regulated Signaling Pathways in Breast Cancer Progression.

Long non-coding RNA activated by DNA damage (NORAD) has recently been associated with pathologic mechanisms underlying cancer progression. Due to NORAD's extended range of interacting partners, there has been contradictory data on its oncogenic or tumor suppressor roles in BC. This review will summarize the function of NORAD in different BC subtypes and how NORAD impacts crucial signaling pathways in this pathology. Through the preferential binding to pumilio (PUM) proteins PUM1 and PUM2, NORAD has been shown to be involved in the control of cell cycle, angiogenesis, mitosis, DNA replication and transcription and protein translation. More recently, NORAD has been associated with PUM-independent roles, accomplished by interacting with other ncRNAs, mRNAs and proteins. The intricate network of NORAD-mediated signaling pathways may provide insights into the potential design of novel unexplored strategies to overcome chemotherapy resistance in BC treatment.

Prevalence of DICER1 variants in large multinodular goiter: thyroid function, clinical and imaging characteristics.

Objective: Mutations in DICER1 are found in differentiated thyroid carcinoma (DTC) and in multinodular goiter (MNG) at a younger age with other tumors, which characterizes DICER1 syndrome. DICER1 is one driver to DTC; however, it is also found in benign nodules. We speculated that patients with mutations in DICER1 may present long-lasting MNG. Our aim was to investigate the frequency of DICER1 variants in patients with MNG. Subjects and methods: Patients who submitted to total thyroidectomy due to large MNG with symptoms were evaluated. DICER1 hotspots were sequenced from thyroid nodule samples. To confirm somatic mutation, DNA from peripheral blood was also analyzed. Results: Among 715 patients, 154 were evaluated with 56.2 ± 12.3 years old (28-79) and the thyroid volume was 115.7 ± 108 mL (16.2-730). We found 11% with six DICER1 variations in a homo or heterozygous state. Only rs12018992 was a somatic DICER1 variant. All remaining variants were synonymous and likely benign, according to the ClinVar database. The rs12018992 was previously described in an adolescent with DTC, measuring 13 mm. There were no significant differences according to gender, familial history of goiter, age, thyroid volume, TSH and TI-RADS classification between DICER1 carriers. Free T4 were lower in patients with DICER1 polymorphisms (13.77 ± 1.8 vs. 15.44 ± 2.4 pmol/L, p = 0.008), regardless of TSH levels. Conclusion: We conclude that germline DICER1 variants can be found in 11% of large goiters but no second-hit somatic mutation was found. DICER1 is one driver to thyroid lesion and a second-hit event seems unnecessary in the MNG development.

Prevalence of DICER1 variants in large multinodular goiter: thyroid function, clinical and imaging characteristics

ABSTRACT Objective: Mutations in DICER1 are found in differentiated thyroid carcinoma (DTC) and in multinodular goiter (MNG) at a younger age with other tumors, which characterizes DICER1 syndrome. DICER1 is one driver to DTC; however, it is also found in benign nodules. We speculated that patients with mutations in DICER1 may present long-lasting MNG. Our aim was to investigate the frequency of DICER1 variants in patients with MNG. Subjects and methods: Patients who submitted to total thyroidectomy due to large MNG with symptoms were evaluated. DICER1 hotspots were sequenced from thyroid nodule samples. To confirm somatic mutation, DNA from peripheral blood was also analyzed. Results: Among 715 patients, 154 were evaluated with 56.2 ± 12.3 years old (28-79) and the thyroid volume was 115.7 ± 108 mL (16.2-730). We found 11% with six DICER1 variations in a homo or heterozygous state. Only rs12018992 was a somatic DICER1 variant. All remaining variants were synonymous and likely benign, according to the ClinVar database. The rs12018992 was previously described in an adolescent with DTC, measuring 13 mm. There were no significant differences according to gender, familial history of goiter, age, thyroid volume, TSH and TI-RADS classification between DICER1 carriers. Free T4 were lower in patients with DICER1 polymorphisms (13.77 ± 1.8 vs. 15.44 ± 2.4 pmol/L, p = 0.008), regardless of TSH levels. Conclusions: We conclude that germline DICER1 variants can be found in 11% of large goiters but no second-hit somatic mutation was found. DICER1 is one driver to thyroid lesion and a second-hit event seems unnecessary in the MNG development.

Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study.

BACKGROUND: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. METHODS: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. CONCLUSION: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. CLINICALTRIALS.GOV REGISTRY: NCT05558098.

Expression of NORAD correlates with breast cancer aggressiveness and protects breast cancer cells from chemotherapy.

The recently discovered human lncRNA NORAD is induced after DNA damage in a p53-dependent manner. It plays a critical role in the maintenance of genomic stability through interaction with Pumilio proteins, limiting the repression of their target mRNAs. Therefore, NORAD inactivation causes chromosomal instability and aneuploidy, which contributes to the accumulation of genetic abnormalities and tumorigenesis. NORAD has been detected in several types of cancer, including breast cancer, which is the most frequently diagnosed and the second-leading cause of cancer death in women. In the present study, we confirmed upregulated NORAD expression levels in a set of human epithelial breast cancer cell lines (MDA-MB-231, MDA-MB-436, and MDA-MB-468), which belong to the most aggressive subtypes (triple-negative breast cancer). These results are in line with previous data showing that high NORAD expression levels in basal-like tumors were associated with poor prognosis. Here, we demonstrate that NORAD downregulation sensitizes triple-negative breast cancer cells to chemotherapy, through a potential accumulation of genomic aberrations and an impaired capacity to signal DNA damage. These results show that NORAD may represent an unexploited neoadjuvant therapeutic target for chemotherapy-unresponsive breast cancer.

Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study / Dapagliflozina em pacientes com doença crítica: justificativa e desenho do estudo DEFENDER

ABSTRACT Background: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. Methods: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. Conclusion: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. ClinicalTrials.gov registry: NCT05558098

RESUMO Antecedentes: A doença crítica é um importante ônus permanente da assistência médica em todo o mundo e está associada a altas taxas de mortalidade. Os inibidores do cotransportador de sódio-glicose do tipo 2 têm demonstrado consistentemente benefícios nos desfechos cardiovasculares e renais. Os efeitos dos inibidores do cotransportador de sódio-glicose do tipo 2 em doenças agudas ainda não foram devidamente investigados. Métodos: O DEFENDER é um estudo de iniciativa do investigador, multicêntrico, randomizado, aberto, desenhado para avaliar a eficácia e a segurança da dapagliflozina em 500 participantes adultos com disfunção orgânica aguda hospitalizados na unidade de terapia intensiva. Os participantes aptos serão randomizados 1:1 para receber 10mg de dapagliflozina e o tratamento padrão por até 14 dias ou apenas o tratamento padrão. O desfecho primário é um composto hierárquico de mortalidade hospitalar, início de terapia renal substitutiva e tempo de internação na unidade de terapia intensiva, até 28 dias. O monitoramento da segurança será rigoroso durante todo o estudo. Conclusão: O DEFENDER é o primeiro estudo desenvolvido para investigar o uso de um inibidor do cotransportador de sódio-glicose do tipo 2 em pacientes de unidade de terapia intensiva geral com disfunção orgânica aguda. O estudo fornecerá informações relevantes sobre o uso de medicamentos dessa classe promissora em pacientes críticos. Registro ClincalTrials.gov: NCT05558098

Unveiling the hidden threat of microplastics to coral reefs in remote South Atlantic islands.

The widespread presence of marine microplastics (< 5 mm) is a significant concern, as it may harm marine biodiversity and ocean ecosystems. Corals' capacity to ingest microplastics has emerged as a significant threat to reef ecosystems, owing to the detrimental physiological and ecological effects it can trigger. The extent of the impact of microplastics on Brazilian corals remains unclear and this study aimed to investigate its distribution and characteristics in four coral species: Favia gravida, Mussismilia hispida, Montastrea cavernosa, and Siderastrea stellata, found in the Trindade and Martim Vaz Islands - the most isolated archipelago of Brazil, located about 1200 km (680 miles) east of the coast. This study aims to reveal the extent of microplastic distribution in the coral reef environment, assess the amount of microplastics in different coral species, and compare each species' capacity to adhere and accumulate microplastics. A high concentration of ingested and adhered microplastics was detected in all coral species evaluated in the present study. No significant differences were observed in the sampling points which indicates that although the sampling points are located at different distances from the coast, the microplastic pollution is equally distributed in the region. Polyethylene (PE), polyvinyl chloride (PVC), polypropylene (PP), poly(methyl methacrylate) (PMMA), Rayon, and Nylon particles were detected, with a predominance of PE (45.5 %). No significant differences in microplastic concentration were detected among the various species and locations studied. Our research presents findings that demonstrate the extensive occurrence of microplastic contamination in coral colonies located on remote islands.

Guidelines from the Brazilian society of surgical oncology regarding indications and technical aspects of neck dissection in papillary, follicular, and medullary thyroid cancers.

Objective: The purpose of these guidelines is to provide specific recommendations for the surgical treatment of neck metastases in patients with papillary, follicular, and medullary thyroid carcinomas. Materials and methods: Recommendations were developed based on research of scientific articles (preferentially meta-analyses) and guidelines issued by international medical specialty societies. The American College of Physicians' Guideline Grading System was used to determine the levels of evidence and grades of recommendations. The following questions were answered: A) Is elective neck dissection indicated in the treatment of papillary, follicular, and medullary thyroid carcinoma? B) When should central, lateral, and modified radical neck dissection be performed? C) Could molecular tests guide the extent of the neck dissection? Results and conclusion: Recommendation 1: Elective central neck dissection is not indicated in patients with cN0 well-differentiated thyroid carcinoma or in those with noninvasive T1 and T2 tumors but may be considered in T3-T4 tumors or in the presence of metastases in the lateral neck compartments. Recommendation 2: Elective central neck dissection is recommended in medullary thyroid carcinoma. Recommendation 3: Selective neck dissection of levels II-V should be indicated to treat neck metastases in papillary thyroid cancer, an approach that decreases the risk of recurrence and mortality. Recommendation 4: Compartmental neck dissection is indicated in the treatment of lymph node recurrence after elective or therapeutic neck dissection; "berry node picking" is not recommended. Recommendation 5: There are currently no recommendations regarding the use of molecular tests in guiding the extent of neck dissection in thyroid cancer.

Ultrasonography in the Assessment of Tumors of the Cheek: Water Mouth Distension Technique.

PURPOSE: To describe a new B-mode ultrasound examination technique to assess cheek tumors. MATERIALS AND METHODS: 30 cheek oral cavity lesions of different histological types (11 benign and 19 malignant) from 23 patients (11 women and 12 men, 7-82 years old, mean age of 49.5 years) were analyzed. Transcutaneous oral B-mode ultrasound (5-12 MHz transducer) was carried out in two stages. Initially it was performed conventionally with an empty mouth. Next, the patient was asked to keep their oral cavity filled with water (like when using a mouthwash) during imaging for the new test examination technique. The anatomical layers of this region and the characteristics of the tumors were evaluated. Lesions were classified as ill defined, partially defined, or defined. Conventional findings were compared to those of the new technique using the Wilcoxon signed-rank test. Ultrasound results were compared to histological findings analyzed by an independent team. RESULTS: The conventional empty mouth technique was able to confidently define lesion extension in only 6 of the 30 lesions, while the water-filled mouth technique was able to confidently define lesion extension in 29 of the 30 lesions (p<0.00001). CONCLUSION: We present a novel technique that dramatically improves ultrasound staging of cheek oral cavity tumors. In addition to the increase in ultrasound accuracy, this technique does not require any special equipment or extra cost, is very well tolerated by patients, and thus should be considered in the evaluation of every patient undergoing transcutaneous cheek ultrasound for oral cavity lesion characterization.

Guidelines from the Brazilian society of surgical oncology regarding indications and technical aspects of neck dissection in papillary, follicular, and medullary thyroid cancers

ABSTRACT Objective: The purpose of these guidelines is to provide specific recommendations for the surgical treatment of neck metastases in patients with papillary, follicular, and medullary thyroid carcinomas. Materials and methods: Recommendations were developed based on research of scientific articles (preferentially meta-analyses) and guidelines issued by international medical specialty societies. The American College of Physicians' Guideline Grading System was used to determine the levels of evidence and grades of recommendations. The following questions were answered: A) Is elective neck dissection indicated in the treatment of papillary, follicular, and medullary thyroid carcinoma? B) When should central, lateral, and modified radical neck dissection be performed? C) Could molecular tests guide the extent of the neck dissection? Results/conclusion: Recommendation 1: Elective central neck dissection is not indicated in patients with cN0 well-differentiated thyroid carcinoma or in those with noninvasive T1 and T2 tumors but may be considered in T3-T4 tumors or in the presence of metastases in the lateral neck compartments. Recommendation 2: Elective central neck dissection is recommended in medullary thyroid carcinoma. Recommendation 3: Selective neck dissection of levels II-V should be indicated to treat neck metastases in papillary thyroid cancer, an approach that decreases the risk of recurrence and mortality. Recommendation 4: Compartmental neck dissection is indicated in the treatment of lymph node recurrence after elective or therapeutic neck dissection; "berry node picking" is not recommended. Recommendation 5: There are currently no recommendations regarding the use of molecular tests in guiding the extent of neck dissection in thyroid cancer.

New record and a new species of Lissosabinea Christoffersen, 1988 (Decapoda: Caridea: Crangonidae) from Brazil.

Lissosabinea tridentata (Pequegnat, 1970) known hitherto from the Gulf of Mexico off Florida (24N) and only western Atlantic representative of the genus, is reported here for the first time from much further south, Brazil off the coast of Esprito Santo, Vitria-Trindade Seamount Chain, Montague Bank (20S), between 310 and 391 m. A second western Atlantic species, Lissosabinea christofferseni sp. nov., is described here as new from material collected in the Abrolhos Bank, at depth between 340360 m. One exuviae and one damaged specimen, reported in 1988 from off the coast of Chu, Brazil (34S) (at that time mistakenly referred to as Uruguay) and attributed to Lissosabinea cf. tridentata are herein referred to the new species. It has been clarified that Lissosabinea christofferseni sp. nov. and L. tridentata have a transverse row of teeth adjacent to the posterior margin of the sixth pleonal sternite; in crangonids, such a feature is so far known only in Placopsicrangron formosa Komai Chan, 2009.

Brachyuran crabs (Crustacea, Decapoda) from the remote oceanic Archipelago Trindade and Martin Vaz, South Atlantic Ocean.

Forty species of shore and shallow water brachyuran crabs are reported from the remote oceanic Archipelago Trindade and Martin Vaz (TMV), 11 of which were previously known from Trindade Island, 28 are recorded from the Archipelago for the first time, and one is a new species, Epialtus parvulus sp. nov. This brings the total known shore and shallow water decapod fauna of TMV to 99 species. The opportunity is taken here to elaborate on the taxonomy of the species reported from TMV. One new genus, Mecataleptodius, is recognized for two species, Cancer parvulus Fabricius, 1793, its type species, and Cataleptodius olsoni Manning Chace, 1990, endemic to Ascension Island. The following seven nominal species are synonymized: Acanthonyx dissimulatus Coelho in Coelho Torres, 1993; A. scutiformis (Dana, 1851a); Dromia gouveai Melo Campos Junior, 1999; Epialtus portoricensis Rathbun, 1923; Ranilia guinotae Melo Campos Junior, 1994; R. saldanhai H. Rodrigues da Costa, 1970; and Omalacantha garthi (Lemos de Castro, 1953). TMV is a subset of the western Atlantic crab fauna (23 species or 57.5%), also including 8 (20%) amphi-Atlantic species, 3 (7.5%) amphi-American, 3 (7.5%) endemic, 2 (5%) cosmopolitan, 1 (2.5%) known from both sides of the Atlantic and the Indo-West Pacific. The crab fauna of TMV, Ascension (AS) and Saint Helena (SH) are compared with one another as well as with that of the oceanic islands Fernando de Noronha (FN) and the Rocas Atoll (RA) by means of nonmetric multidimensional scaling (NMDS) applied to a dissimilarity matrix generated by Jaccards coefficient. TMV-FN-RA and AS-SH clustered into two distinct groups according to the composition of their crab fauna. The NMDS analysis ranked the species that cause segregation of the crab faunal assemblages among TMV, AS, and SH, while revealing a gradient in species composition between the two groups of islands (TMV-FN-RA and AS-SH) formed by the amphi-Atlantic species. Island isolation, age and size alone do not explain the existing differences in species richness among TMV, AS and SH. The taxonomic composition of the shallow water fauna in these islands is likely to have been determined by several variables that were interwoven differently along their evolutionary history.

Characteristics and prevalence of orofacial pain as an initial symptom of oral and oropharyngeal cancer and its impact on the patient's functionality and quality of life.

OBJECTIVE: To evaluate the prevalence and characteristics of orofacial pain in oral and oropharyngeal cancer (OOC), at diagnosis. MATERIAL AND METHODS: a) Study group (SG; n = 74) patients with cancer were divided into 2 subgroups: oral cancer (OC) and oropharyngeal cancer (OPC); b) control group (CG; n = 74) patients within dental care. STUDY DESIGN: An Orofacial Pain Assessment, verbal descriptive scale, Helkimo dysfunction index, Quality of Life questionnaire, and Karnofsky performance status (KPS) was used for evaluation. RESULTS: The mean age was 58.46 years (79.7% male) in SG, 58.61 years (20.3% male) in CG. The pain within the SG was indicated by the following: prevalence = 91.9% (21.6% in stages 0, I, or II; 70.3% in III or IV); reason for seeking care = 50.1%; main complaint = 55.4%; most important issue in the past 7 days = 74.3%; breakthrough-like pain = 64.9%; main features: chewing or swallowing as triggering factors, wake up patient, variable duration, independent of daytime, multiple descriptors, and earache. The following indexes were worse within the SG: clinical dysfunction, quality of life, and KPS. In addition, the OC subgroup reported toothache-like pain and burning; whereas the OPC subgroup reported heavy swallowing as triggering factor, throat as location, and a bilateral earache. CONCLUSION: At diagnosis, orofacial pain, including breakthrough-like pain, was prevalent in patients with OOC, and the pattern was heterogeneous. Predominantly, the pain was moderate to severe, related to stage of cancer, and already compromising the patients' quality of life and functionality.

Additions to the morphology of the Phyllophoridae and the Sclerodactylidae. I. Type species of Phyllophorella, Selenkiella, Cladolella and Clarkiella, with the description a new species of Thorsonia (Holothuroidea: Dendrochirotida).

The phyllophorids Phyllophorella robusta, Selenkiella siamense and Cladolella virgo, as well as the sclerodactylid Clarkiella discoveryi, are the type species of their respective genera, all described by Heding Panning (1954) and each known only from a single specimen, were revisited in order to reassess their morphology by means of optical and electron microscopy, and micro-computed tomography. Additionally, a new species of phyllophorid is described, the fourth of the genus Thorsonia.

Risk factors associated with disease-specific mortality in papillary thyroid cancer patients with distant metastases.

PURPOSE: Papillary thyroid carcinoma (PTC) is among the most curable cancer types. Even though uncommon, some patients present distant metastatic disease at diagnosis or during the follow-up and most of them have long-term survival. However, there continues to be controversies regarding what clinicopathological features are associated with mortality in these patients. This paper evaluates the factors related to poor disease-specific survival (DSS) in patients with metastatic PTC. METHODS: A retrospective cohort study included PTC patients with distant metastasis from a tertiary public oncological center. Clinicopathological features, treatment modalities, and outcome were reviewed. RESULTS: Between 1986 and 2014, 108 patients were diagnosed with metastatic PTC. In the multivariate analysis male sex (HR = 2.65; 95%CI: 1.08-6.53; P = 0.033), radioiodine refractory disease (HR = 9.50; 95%CI: 1.23-73.38; P = 0.031) and metastasis at multiple sites (HR = 5.91; 95%CI: 1.80-19.32; P = 0.003) were independent risk factors for death in patients with metastatic PTC. CONCLUSION: Male patients with metastatic PTC, with radioiodine refractory disease and metastasis at multiple sites have a high risk of death.

A new species of Parathyone (Holothuroidea: Dendrochirotida: Cucumariidae) from northeastern Brazil, with a key to species.

A new species of Dendrochirotida sea cucumber, Parathyone itapuaensis, is described and illustrated herein based on specimens collected from rocky intertidal regions of the northeastern coast of Brazil. The new species is characterized by a suite of morphological characters revealed by light stereomicroscope, SEM and microCT studies of the calcareous ring, dermal ossicles, Polian vesicles and madreporite. Parathyone itapuaensis sp. nov. is characterized by having 10 tentacles, two Polian vesicles and single madreporite; length of anterior process (radial plate) larger than length of the base of the radial plate; body wall with buttons with triangular knobs and knobbed multiperforated plates in the anal region; and tentacles with arched rods, knobbed in the margins and shallow cups knobbed in the outer and inner surfaces. A key to the recognition of Parathyone species is given.