Forensic Geochemistry Reveals International Ship Dumping as a Source of New Oil Spill in Brazil's Coastline (Bahia) in Late 2023.

In the present study, we applied forensic geochemistry to investigate the origin and fate of spilled oils like tarballs stranded at the beaches of Bahia, in northeastern Brazil, in September 2023, based on their fingerprints. Saturated and aromatic compounds were assessed by gas chromatography, and the oceanic surface circulation patterns were deciphered to determine the geographic origin of the spill. Contamination by petroleum represents an enormous threat to the unique, species-rich ecosystems of the study area. The geochemical fingerprint of the oil spilled in 2023 did not correlate with those of previous events, including the one in 2019, the one in early 2022 in Ceará, and an extensive spill across the Brazilian Northeast in late 2022. However, the fingerprint did correlate with crude oils produced by Middle Eastern countries, most likely Kuwait. The oil of the 2023 spill had a carbonate marine origin from early mature source rocks. These findings, together with the moderate weathering of the 2023 tarballs and the ocean circulation patterns at the time of the event, indicate that the oil was discharged close to the shore of Brazil, to the east or southeast of Salvador, by a tanker on an international route in the South Atlantic.

Use of hormones and risk of venous thromboembolism.

•The risk of venous thromboembolism (VTE) is not increased in women using long-acting reversible contraceptive methods (LARCs) with progestogens. •Oral contraceptives with levonorgestrel or norgestimate confer half the risk of VTE compared to oral contraceptives containing desogestrel, gestodene or drospirenone. •Progestogen-only pills do not confer an increased risk of VTE. •Women using transdermal contraceptive patches and combined oral contraceptives (COCs) are at an approximately eight times greater risk of VTE than non-users of hormonal contraceptives (HCs), corresponding to 9.7 events per 10,000 women/years. •Vaginal rings increase the risk of VTE by 6.5 times compared to not using HC, corresponding to 7.8 events per 10,000 women/years. •Several studies have demonstrated an increased risk of VTE in transgender individuals receiving hormone therapy (HT). •Hormone therapy during menopause increases the risk of VTE by approximately two times, and this risk is increased by obesity, thrombophilia, age over 60 years, surgery and immobilization. •The route of estrogen administration, the dosage and type of progestogen associated with estrogen may affect the risk of VTE in the climacteric. •Combined estrogen-progesterone therapy increases the risk of VTE compared to estrogen monotherapy. •Postmenopausal HT increases the risk of thrombosis at atypical sites.

Burden of liver disease in Brazil, 1996-2022: a retrospective descriptive study of the epidemiology and impact on public healthcare.

Background: Liver disease is a major cause of mortality and morbidity worldwide and its epidemiology depends on the genetic background, exposure to risk factors, access to healthcare and other sociodemographic characteristics. Brazil is a large country with diverse multicultural and ethnic heritages and important socioeconomic inequalities. The burden of liver disease in Brazil, its regions and population is unknown. Methods: We retrieved data from the Unified Health System regarding liver diseases and analyzed the mortality and morbidity from 1996 to 2022 by gender, race/ethnicity, age, region and overall. We calculated the age-specific risk of deaths by liver disease, age-standardization of the data, mean hospitalization and liver transplant-associated costs. Findings: Malignant neoplasm of the liver and intrahepatic bile ducts, alcohol-associated liver disease, fibrosis, and cirrhosis of the liver, other diseases of the liver, hepatic failure, chronic viral hepatitis were identified as the major causes of death and morbidity in Brazil in the period analyzed. The epidemiology of these diseases was diverse, with variations according to geographic regions, gender and race/ethnicity. The major economic burden of liver disease is related to liver transplants, a common outcome of the progression of these diseases. Interpretation: Liver disease in Brazil is a serious issue for the public health system due to the high number of deaths and increasing mortality rate. Our study contributes as a necessary prerequisite for the development of tailored public health policies aimed at mitigating the increasing burden of liver diseases in specific populations and regions. Funding: CNPq, INCT, CAPES, FAPEMIG.

Oxidative stress induction by essential oil from Piper alatipetiolatum (Piperaceae) triggers lethality in the larvae of Culex quinquefasciatus (Diptera: Culicidae).

Culex quinquefasciatus is the main vector of lymphatic filariasis in Brazil, which present resistance to commercial insecticides. Nowadays, essential oils (EOs) exhibiting larvicidal activity, such as those derived from Piper alatipetiolatum, provide a promising alternative for vector control, including Culex species. This study aimed to investigate the larvicidal activity and the oxidative stress indicators of the EO from P. alatipetiolatum in Cx. quinquefasciatus larvae. The EO was extracted from P. alatipetiolatum leaves using the hydrodistillation method, resulting in a yield of 7.2 ± 0.1%, analysed by gas chromatography coupled with spectrometry and gas chromatography coupled with flame ionization detector (GC-MS and GC-FID), and evaluated against Cx. quinquefasciatus larvae. Reactive Oxygen and Nitrogen Species (RONS), Catalase (CAT), glutathione-S-transferase (GST), acetylcholinesterase (AChE), and Thiol levels were used as oxidative stress indicators. Analysis by CG-MS and CG-FID revealed that the main compound in the EO was the oxygenated sesquiterpene ishwarone, constituting 78.6% of the composition. Furthermore, the EO exhibited larvicidal activity, ranging from 26 to 100%, with an LC50 of 4.53 µg/mL and LC90 of 15.37 µg/mL. This activity was accompanied by a significant increase in RONS production, alterations in CAT, GST, AChE activity, and thiol levels compared to the control groups (p < 0.05). To the best of our knowledge, this is the first report describing the larvicidal activity and oxidative stress induced by the EO from P. alatipetiolatum against Cx. quinquefasciatus larvae. Therefore, we propose that this EO shows promise as larvicidal agent for the effective control of Cx. quinquefasciatus larvae.

Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6.

BACKGROUND: The maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. The mechanisms that interconnect both processes at the transcriptional level remain underexplored. Nr2f6, a nuclear receptor, regulates metabolism and cell differentiation in peripheral tissues. However, its role in the skeletal muscle is still elusive. Here, we aimed to investigate the effects of Nr2f6 modulation on muscle biology in vivo and in vitro. METHODS: Global RNA-seq was performed in Nr2f6 knockdown C2C12 myocytes (N = 4-5). Molecular and metabolic assays and proliferation experiments were performed using stable Nr2f6 knockdown and Nr2f6 overexpression C2C12 cell lines (N = 3-6). Nr2f6 content was evaluated in lipid overload models in vitro and in vivo (N = 3-6). In vivo experiments included Nr2f6 overexpression in mouse tibialis anterior muscle, followed by gene array transcriptomics and molecular assays (N = 4), ex vivo contractility experiments (N = 5), and histological analysis (N = 7). The conservation of Nr2f6 depletion effects was confirmed in primary skeletal muscle cells of humans and mice. RESULTS: Nr2f6 knockdown upregulated genes associated with muscle differentiation, metabolism, and contraction, while cell cycle-related genes were downregulated. In human skeletal muscle cells, Nr2f6 knockdown significantly increased the expression of myosin heavy chain genes (two-fold to three-fold) and siRNA-mediated depletion of Nr2f6 increased maximal C2C12 myocyte's lipid oxidative capacity by 75% and protected against lipid-induced cell death. Nr2f6 content decreased by 40% in lipid-overloaded myotubes and by 50% in the skeletal muscle of mice fed a high-fat diet. Nr2f6 overexpression in mice resulted in an atrophic and hypoplastic state, characterized by a significant reduction in muscle mass (15%) and myofibre content (18%), followed by an impairment (50%) in force production. These functional phenotypes were accompanied by the establishment of an inflammation-like molecular signature and a decrease in the expression of genes involved in muscle contractility and oxidative metabolism, which was associated with the repression of the uncoupling protein 3 (20%) and PGC-1α (30%) promoters activity following Nr2f6 overexpression in vitro. Additionally, Nr2f6 regulated core components of the cell division machinery, effectively decoupling muscle cell proliferation from differentiation. CONCLUSIONS: Our findings reveal a novel role for Nr2f6 as a molecular transducer that plays a crucial role in maintaining the balance between skeletal muscle contractile function and oxidative capacity. These results have significant implications for the development of potential therapeutic strategies for metabolic diseases and myopathies.

Development of a green and low-cost method to determine mercury content in sediments affected by oil spill on the Brazilian coast.

Tons of crude oil were found on the Brazilian coast in 2019, and studies assessing its chemical composition are still scarce. This study aimed to develop a new and simple technique of cold vapor generation using infrared irradiation coupled with atomic absorption spectrometry to determine mercury content in sediments contaminated by crude oil. Experimental conditions were evaluated, including formic acid concentration, reactor temperature, and carrier gas flow rate. The accuracy of the method was validated by comparison with mercury contents in a certified reference material (PACS-2). The detection limit was found to be 0.44 µg kg-1. The developed method was applied to determine the total mercury content in marine sediment samples collected from beaches in Ceará State. Mercury concentrations ranged from 0.41 to 0.95 mg kg-1. The proposed method is efficient, simple, low-cost, and adequate for its purpose.

Essential oil from Piper tuberculatum Jacq. (Piperaceae) and its majority compound ß-caryophyllene: mechanism of larvicidal action against Aedes aegypti (Diptera: Culicidae) and selective toxicity.

Synthetic insecticides have been the primary approach in controlling Aedes aegypti; however, their indiscriminate use has led to the development of resistance and toxicity to non-target animals. In contrast, essential oils (EOs) are alternatives for vector control. This study investigated the mechanism of larvicidal action of the EO and ß-caryophyllene from Piper tuberculatum against A. aegypti larvae, as well as evaluated the toxicity of both on non-target animals. The EO extracted from P. tuberculatum leaves was majority constituted of ß-caryophyllene (54.8%). Both demonstrated larvicidal activity (LC50 of 48.61 and 57.20 ppm, p < 0.05), acetylcholinesterase inhibition (IC50 of 57.78 and 71.97 ppm), and an increase in the production of reactive oxygen and nitrogen species in larvae after exposure to the EO and ß-caryophyllene. Furthermore, EO and ß-caryophyllene demonstrate no toxicity to non-target animals Toxorhynchites haemorrhoidalis, Anisops bouvieri, and Diplonychus indicus (100% of survival rate), while the insecticide α-cypermethrin was highly toxic (100% of death). The results demonstrate that the EO from P. tuberculatum and ß-caryophyllene are important larvicidal agents.

Essential oil and fenchone extracted from Tetradenia riparia (Hochstetter.) Codd (Lamiaceae) induce oxidative stress in Culex quinquefasciatus larvae (Diptera: Culicidae) without causing lethal effects on non-target animals.

We investigated the larvicidal activity of the essential oil (EO) from Tetradenia riparia and its majority compound fenchone for controlling Culex quinquefasciatus larvae, focusing on reactive oxygen and nitrogen species (RONS), catalase (CAT), glutathione S-transferase (GST), acetylcholinesterase (AChE) activities, and total thiol content as oxidative stress indicators. Moreover, the lethal effect of EO and fenchone was evaluated against Anisops bouvieri, Diplonychus indicus, Danio rerio, and Paracheirodon axelrodi. The EO and fenchone (5 to 25 µg/mL) showed larvicidal activity (LC50 from 16.05 to 18.94 µg/mL), followed by an overproduction of RONS, and changes in the activity of CAT, GST, AChE, and total thiol content. The Kaplan-Meier followed by Log-rank (Mantel-Cox) analyses showed a 100% survival rate for A. bouvieri, D. indicus, D. rerio, and P. axelrodi when exposed to EO and fenchone (262.6 and 302.60 µg/mL), while α-cypermethrin (0.25 µg/mL) was extremely toxic to these non-target animals, causing 100% of death. These findings emphasize that the EO from T. riparia and fenchone serve as suitable larvicides for controlling C. quinquefasciatus larvae, without imposing lethal effects on the non-target animals investigated.

Fusion-driven cutaneous and superficial mesenchymal and adnexal tumors-A clinicopathologic and molecular study of 15 cases, including a novel case of ACTB::ZMIZ2-rearranged adnexal carcinoma.

BACKGROUND: While the list of fusion-driven soft tissue neoplasms is expanding rapidly, their importance among cutaneous and superficial mesenchymal and adnexal neoplasms remains poorly understood. This challenge is especially evident in cases with ambiguous histopathology that are difficult to classify based on morphology. AIMS: Our goal was to investigate the benefits of next-generation sequencing in diagnosing complex cutaneous neoplasms. MATERIALS & METHODS: Departmental archives were searched for fusion-driven cutaneous neoplasms. Slides were retrieved and clinical information including follow-up was obtained. RESULTS: Fifteen cases occurred in eight female and seven male patients, with a median age of 26 years (range: 1-83) at diagnosis. Tumors involved the extremities (9), scalp (5), and head and neck (1). Predominant features included myoepithelial (5), nested spindled with clear cytoplasm (2), atypical adnexal/squamoid (2), small round blue cell (2), cellular spindled (3), and fibrohistiocytic morphology (1). Most frequently encountered fusions involved EWSR1 (6) fused to ERG (1), FLI1 (1), CREB1 (2), CREM (1), PBX3 (1), followed by PLAG1 (4) with LIFR (2), TRPS1 (1) and CHCHD7. Additional fusions encountered were YAP1::NUTM1, EML4::ALK, SS18::SSX1 (2), and a novel fusion: ACTB::ZMIZ2. Integration of histologic features and molecular findings led to final diagnoses of primary cutaneous Ewing sarcoma (2), soft tissue myoepithelioma (4), cutaneous syncytial myoepithelioma (1), cutaneous adnexal carcinoma (1), porocarcinoma (1), inflammatory myofibroblastic tumor (1), synovial sarcoma (2), clear cell sarcoma (2), and angiomatoid fibrous histiocytoma (1). DISCUSSION AND CONCLUSION: Our results show that fusion testing can be a helpful diagnostic tool, especially in cases with unusual or uncommon morphology in superficial sites. Furthermore, it can allow for the identification of potential therapeutic targets in some instances.

Intraoperative thermal mapping of mammary tumors in dogs.

In this study, videothermometry's application in detecting mammary tumors in dogs is explored in-depth. The research hypothesizes that this technique can effectively identify cancerous tissues during surgery by analyzing thermal patterns. The methodology involved comparing thermal imaging results from dogs with palpable mammary nodules against a control group, focusing on capturing real-time thermal patterns. Results were significant, showing distinct thermal patterns in carcinomas. This indicates videothermometry's capability in accurately identifying micro metastases and differentiating between neoplastic and non-neoplastic changes. The study concludes that videothermometry has considerable potential in enhancing surgical precision, especially in tumor resection and safety margin definition, but emphasizes the need for further research to thoroughly understand the thermal signatures of various mammary tumors in dogs.

Munchausen Syndrome in the Context of Liaison Psychiatry: A Case Report and a Narrative Review.

Munchausen Syndrome (MS) has been widely recognized as a severe manifestation of factitious disorder, a condition where individuals intentionally fabricate or exaggerate symptoms for psychological gratification. It represents a complex diagnostic challenge due to its elusive nature and intricate relationship with various medical conditions. We present a clinical case of a 44-year-old woman observed in the context of Liaison Psychiatry, demonstrating the intricate interplay between chronic medical conditions, psychiatric factors, and the challenges in diagnosing and managing MS. The patient exhibited a history of recurrent hospitalizations, difficult-to-heal injuries, and a pronounced preference for surgical interventions. Despite diagnostic difficulties and poor therapeutic adherence, a multidisciplinary team approach involving plastic surgery, orthopedics, physical medicine, and rehabilitation, alongside Liaison Psychiatry, led to the diagnosis of MS with chronic osteomyelitis, ultimately necessitating a transtibial amputation. The case underscores the importance of early detection, a multidisciplinary approach, and the role of Liaison Psychiatry in managing MS. While early diagnosis may not alter the disease course, it can prevent unnecessary interventions and mitigate associated risks. The case also highlights the need for continuous psychiatric support and family involvement in addressing the recurrence of self-injurious behaviors. Further research is essential to enhance our understanding and develop effective treatment strategies for MS, contributing to improved diagnostic precision and overall management of this challenging psychiatric disorder.

The impact of chronic and acute problems on sea turtles: The consequences of the oil spill and ingestion of anthropogenic debris on the tropical semi-arid coast of Ceará, Brazil.

Sea turtle mortality is often related to materials that reach the coast from different anthropic activities worldwide. This study aimed to investigate whether sea turtle mortality was related to older marine problems, such as solid waste, or one of the largest oil spill accidents on the Brazilian coast, that occurred in 2019. We posed three questions: 1) Are there solid residues in the digestive tract samples, and which typology is the most abundant? 2) Can meso­ and macro-waste marine pollutants cause mortality? 3) Is the dark material found really oil? A total of 25 gastrointestinal content (GC) samples were obtained, of which 22 ingested waste of anthropogenic origin and 18 were necropsied. These 22 samples were obtained during or after the 2019 oil spill, of which 17 specimens were affected, making it possible to suggest oil ingestion with the cause of death in the animals that could be necropsied. Macroscopic data showed that the most abundant solid waste was plastic (76.05 %), followed by fabrics (12.18 %) and oil-like materials. However, chemical data confirmed only three specimens with oil levels ranging from remnants to high. It was possible to infer possible causes of death in 16 of the total 18 necropsied cases: Most deaths were due to respiratory arrest (62.5 %), followed by pulmonary edema (12.5 %), cachexia syndrome (12.5 %), circulatory shock (6.25 %), and head trauma (6.25 %), which may have been caused by contact with solid waste, oil, or both. The study showed that not all dark material found in the GCs of turtles killed in oiled areas is truly oil, and in this sense, a chemical analysis step to prove the evidence of oil must be added to international protocols.

Mild to moderate post-COVID-19 alters markers of lymphocyte activation, exhaustion, and immunometabolic responses that can be partially associated by physical activity level- an observational sub-analysis fit- COVID study.

Aim: This study aimed to evaluate if physical activity is associated with systemic and cellular immunometabolic responses, in young adults after mild-to-moderate COVID-19 infection. Methods: Mild- to- moderate post-COVID-19 patients (70.50 ± 43.10 days of diagnosis; age: 29.4 (21.9- 34.9) years; BMI: 25.5 ± 4.3 kg m2 n = 20) and healthy age-matched controls (age: 29.3 (21.2 - 32.6) years; BMI: 25.4 ± 4.7 kg m2; n = 20) were evaluated. Physical activity levels (PAL), body composition, dietary habits, muscular and pulmonary function, mental health, sleep quality, metabolic parameters, immune phenotypic characterization, stimulated whole blood and PBMC culture (cytokine production), mRNA, and mitochondrial respiration in PBMCs were evaluated. Results: The post-COVID-19 group exhibited lower levels of moderate to vigorous physical activity (MVPA) (p = 0.038); therefore, all study comparisons were performed with adjustment for MVPA. Post-COVID-19 impacted the pulmonary function (FEV1, FEV1%pred, FVC, and FVC %pred) compared with the control (p adjusted by MVPA (p adj) <0.05). Post-COVID-19 exhibited lower levels of serum IL-6 (p adj <0.01), whereas it showed higher serum IL-10, triglyceride, leptin, IgG, ACE activity, TNFRSF1A, and PGE2 (p adj <0.05) levels compared with controls. Post-COVID-19 presented a lower percentage of Treg cells (p adj = 0.03) and altered markers of lymphocyte activation and exhaustion (lower CD28 expression in CD8+ T cells (p adj = 0.014), whereas CD4+T cells showed higher PD1 expression (p adj = 0.037)) compared with the control group. Finally, post- COVID-19 presented an increased LPS-stimulated whole- blood IL-10 concentration (p adj <0.01). When exploring mitochondrial respiration and gene expression in PBMCs, we observed a higher LEAK state value (p adj <0.01), lower OXPHOS activity (complex I) (p adj = 0.04), and expression of the Rev-Erb-α clock mRNA after LPS stimulation in the post-COVID-19 patients than in the control (p adj <0.01). Mainly, PAL was associated with changes in IL-10, triglyceride, and leptin levels in the plasma of post-COVID-19 patients. PAL was also associated with modulation of the peripheral frequency of Treg cells and the expression of PD-1 in CD8+ T cells, although it abrogated the statistical effect in the analysis of TNF-α and IL-6 production by LPS- and PMA-stimulated PBMC of post-COVID-19 patients. Conclusion: Young adults after mild-to-moderate SARS-CoV-2 infection appeared to have lower physical activity levels, which can be associated with clinical and immunometabolic responses in a complex manner.

EWSR1::POU2AF3(COLCA2) Sarcoma: An Aggressive, Polyphenotypic Sarcoma With a Head and Neck Predilection.

EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence-free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of "neuroendocrine-appearing" round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiation.

Natural Killer Cell Activation by Ubiquitin-specific Protease 6 Mediates Tumor Suppression in Ewing Sarcoma.

Ewing sarcoma is a rare and deadly pediatric bone cancer for which survival rates and treatment options have stagnated for decades. Ewing sarcoma has not benefited from immunotherapy due to poor understanding of how its immune landscape is regulated. We recently reported that ubiquitin-specific protease 6 (USP6) functions as a tumor suppressor in Ewing sarcoma, and identified it as the first cell-intrinsic factor to modulate the Ewing sarcoma immune tumor microenvironment (TME). USP6 induces intratumoral infiltration and activation of multiple innate immune lineages in xenografted nude mice. Here we report that natural killer (NK) cells are essential for its tumor-inhibitory functions, as NK cell depletion reverses USP6-mediated suppression of Ewing sarcoma xenograft growth. USP6 expression in Ewing sarcoma cells directly stimulates NK cell activation and degranulation in vitro, and functions by increasing surface levels of multiple NK cell-activating ligands. USP6 also induces surface upregulation of the receptor for the apoptosis-inducing ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), providing an additional route for enhanced sensitivity to NK cell killing. Furthermore, USP6-expressing Ewing sarcoma and NK cells participate in a paracrine immunostimulatory feedforward loop, wherein IFNγ secreted by activated NK cells feeds back on USP6/Ewing sarcoma cells to induce synergistic expression of chemokines CXCL9 and CXCL10. Remarkably, expression of USP6 in subcutaneous Ewing sarcoma xenografts induces systemic activation and maturation of NK cells, and induces an abscopal response in which growth of distal tumors is inhibited, coincident with increased infiltration and activation of NK cells. This work reveals how USP6 reprograms the Ewing sarcoma TME to enhance antitumor immunity, and may be exploited for future therapeutic benefit. Significance: This study provides novel insights into the immunomodulatory functions of USP6, the only cancer cell-intrinsic factor demonstrated to regulate the immune TME in Ewing sarcoma. We demonstrate that USP6-mediated suppression of Ewing sarcoma tumorigenesis is dependent on NK cells. USP6 directly activates NK cell cytolytic function, inducing both intratumoral and systemic activation of NK cells in an Ewing sarcoma xenograft model.

A Study of the Current Scenario of the Obstetrics and Gynecology Residency during the COVID-19 Pandemic / Um estudo do cenário atual da residência em obstetrícia e ginecologia durante a pandemia de COVID-19

Abstract Objective To analyze the impact of the COVID-19 pandemic on the residency of gynecology and obstetrics in São Paulo. Methods Cross-sectional study developed by representatives of residents of the Association of Gynecology and Obstetrics of the State of São Paulo (SOGESP, in the Portuguese acronym). Data were collected from questionnaires applied to gynecology and obstetrics residents registered on the SOGESP website in February 2022. The interviewees answered about the repercussions of the pandemic on medical residency and whether they had technical and psychological support during the period. Results A total of 247 questionnaires were collected from residents of gynecology and obstetrics. The residents had an age of 28.3 ± 3 years old, and most of them were female (88.4%). The displacement to COVID care was reported by 62.34% of the students, but only 35.6% reported completely adequate personal protective equipment and only 7.7% reported complete theoretical and technical instruction to support these patients. Almost all of the interviewees stated that the gynecology sector was the most affected. The majority of the interviewees considered that the second-year residents had the greatest loss, and more than half of the residents in the 1st and 2nd year said they wished to give up their residency during the pandemic. More than 80% of the residents reported online theoretical classes and/or presentation of articles, reinforcing the fact that virtual activities gained a greater space within the medical residency. Conclusion The pandemic impacted the residency in greater proportion in outpatient clinics and gynecological surgeries, also interfering with the physician's desire to continue with the program.

Resumo Objetivo Analisar o impacto pandemia de COVID-19 sobre a residência de ginecologia e obstetrícia do Estado de São Paulo. Métodos Estudo transversal desenvolvido por representantes dos residentes da Associação de Ginecologia e Obstetrícia do Estado de São Paulo (SOGESP). Foram coletados dados de questionários aplicados aos residentes de ginecologia e obstetrícia cadastrados no site da SOGESP em fevereiro de 2022. Os entrevistados responderam sobre repercussões da pandemia sobre a residência médica e se tiveram suporte técnico e psicológico durante o período. Resultados Foram levantados 247 questionários de residentes de ginecologia e obstetrícia. Os residentes apresentaram idade de 28,3 ± 3 anos, sendo a maioria do sexo feminino (88,4%). O deslocamento para "covidários" foi referido por 62,34% dos avaliados, porém somente 35,6% referiram equipamento de proteção individual completamente adequado e apenas 7,7% referiram instrução completa teórica e técnica para o suporte destes pacientes. Quase a totalidade dos entrevistados afirmou que o setor de ginecologia foi o mais afetado. A maioria dos entrevistados considerou que o os residentes do segundo ano foram os que tiveram maior prejuízo, sendo que mais da metade dos residentes do 1° e 2° ano afirmou ter desejado desistir da residência durante a pandemia. Mais de 80% dos residentes referiram aulas teóricas e/ou apresentação de artigos online, reforçando o fato de que as atividades virtuais ganharam um espaço maior dentro da residência médica. Conclusão A pandemia impactou nas residências em maior proporção nos ambulatórios e cirurgias ginecológicas, interferindo também sobre o desejo do médico de seguir com o programa.

pH-Sensitive Hybrid System Based on Eu3+/Gd3+ Co-Doped Hydroxyapatite and Mesoporous Silica Designed for Theranostic Applications.

Nanomaterials such as pH-responsive polymers are promising for targeted drug delivery systems, due to the difference in pH between tumor and healthy regions. However, there is a significant concern about the application of these materials in this field due to their low mechanical resistance, which can be attenuated by combining these polymers with mechanically resistant inorganic materials such as mesoporous silica nanoparticles (MSN) and hydroxyapatite (HA). Mesoporous silica has interesting properties such as high surface area and hydroxyapatite has been widely studied to aid in bone regeneration, providing special properties adding multifunctionality to the system. Furthermore, fields of medicine involving luminescent elements such as rare earth elements are an interesting option in cancer treatment. The present work aims to obtain a pH-sensitive hybrid system based on silica and hydroxyapatite with photoluminescent and magnetic properties. The nanocomposites were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), nitrogen adsorption methods, CHN elemental analysis, Zeta Potential, scanning electron microscopy (SEM), and transmission electron microscopy (TEM), vibrational sample magnetometry (VSM), and photoluminescence analysis. Incorporation and release studies of the antitumor drug doxorubicin were performed to evaluate the potential use of these systems in targeted drug delivery. The results showed the luminescent and magnetic properties of the materials and showed suitable characteristics for application in the release of pH-sensitive drugs.

Transcriptomic and immunophenotypic characterization of two cases of adamantinoma-like Ewing sarcoma of the thyroid gland.

INTRODUCTION: Adamantinoma-like Ewing sarcoma (ALES) is a rare aggressive malignancy occasionally diagnosed in the thyroid gland. ALES shows basaloid cytomorphology, expresses keratins, p63, p40, frequently CD99, and harbours the t(11;22) EWSR1::FLI1 translocation. There is debate on whether ALES resembles more sarcoma or carcinoma. METHODS: We performed RNA sequencing from two ALES cases and compared findings with skeletal Ewing's sarcomas and nonneoplastic thyroid tissue. ALES was investigated by in situ hybridization (ISH) for high-risk human papillomavirus (HPV) DNA and immunohistochemistry for the following antigens: keratin 7, keratin 20, keratin 5, keratins (AE1/AE3 and CAM5.2), CD45, CD20, CD5, CD99, chromogranin, synaptophysin, calcitonin, thyroglobulin, PAX8, TTF1, S100, p40, p63, p16, NUT, desmin, ER, FLI1, INI1, and myogenin. RESULTS: An uncommon EWSR1::FLI transcript with retained EWSR1 exon 8 was detected in both ALES cases. Regulators of EWSR1::FLI1 splicing (HNRNPH1, SUPT6H, SF3B1) necessary for production of a functional fusion oncoprotein, as well as 53 genes (including TNNT1, NKX2.2) activated downstream to the EWSR1::FLI1 cascade, were overexpressed. Eighty-six genes were uniquely overexpressed in ALES, most of which were related to squamous differentiation. Immunohistochemically, ALES strongly expressed keratins 5, AE1/AE3 and CAM5.2, p63, p40, p16, and focally CD99. INI1 was retained. The remaining immunostains and HPV DNA ISH were negative. CONCLUSION: Comparative transcriptomic profiling reveals overlapping features of ALES with skeletal Ewing's sarcoma and an epithelial carcinoma, as evidenced by immunohistochemical expression of keratin 5, p63, p40, CD99, the transcriptome profile, and detection of EWSR1::FLI1 fusion transcript by RNA sequencing.

Cytotoxic and immunomodulatory potential of a novel [2-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazol-3-yl)pyridine] in myeloid leukemia.

Cancer ranks among the leading causes of mortality worldwide. However, the efficacy of commercially available anticancer drugs is compromised by the emerging challenge of drug resistance. This study aimed to investigate the anticancer and immunomodulatory potential of a recently developed a novel [2-(4-(2,5-dimethyl-1 H-pyrrol-1-yl)- 1 H-pyrazol-3-yl) pyridine]. The cytotoxic potential of the compound was assessed using the MTT assay on both cancerous HL60 (acute myeloid leukemia) and K562 (chronic myeloid leukemia) cell lines, as well as non-cancerous Vero cells and human peripheral blood mononuclear cells (PBMCs). A clonogenic assay was employed to evaluate the anticancer efficacy of the compound, while flow cytometry was utilized to investigate its effect on cell cycle arrest. Furthermore, the immunomodulatory potential of the compound was assessed by quantifying inflammatory and anti-inflammatory biomarkers in the supernatant of PBMCs previously treated with the compound. Our study revealed that the novel pyridine ensemble exhibits selective cytotoxicity against HL60 (IC50 = 25.93 µg/mL) and K562 (IC50 = 10.42 µg/mL) cell lines, while displaying no significant cytotoxic effect on non-cancerous cells. In addition, the compound induced a decrease of 18% and 19% in the overall activity of COX-1 and COX-2, respectively. Concurrently, it upregulated the expression of cytokines including IL4, IL6, IL10, and IL12/23p40, while downregulating INFγ expression. These findings suggest that the compound has the potential to serve as a promising candidate for the treatment of acute and chronic myeloid leukemias due to its effective antiproliferative and immunomodulatory activities, without causing cytotoxicity in non-cancerous cells.

Distinctive Nested Glomoid Neoplasm: Clinicopathologic Analysis of 20 Cases of a Mesenchymal Neoplasm With Frequent GLI1 Alterations and Indolent Behavior.

Recently, it has been recognized that a subset of primary soft tissue neoplasms with GLI1 gene alterations exhibit nested architecture and can mimic glomus tumors or well-differentiated neuroendocrine tumors. Here, we report a series of 20 such neoplasms, which we have provisionally termed "distinctive nested glomoid neoplasm." Eleven patients (55%) were female and 9 were male. The median age at presentation was 41.5 years (range: congenital to 74 y). The anatomic distribution was wide, with body sites including the trunk (7 tumors), lower extremity (5), tongue (4), upper extremity (3), and neck (1). Excluding tumors of the tongue, 10 tumors (62%) arose in deep soft tissue and 6 (38%) arose primarily in the subcutis. Tumor size ranged from 0.9 to 11.1 cm (median: 3 cm). Distinctive nested glomoid neoplasms are composed of nests of round-to-ovoid cells with scant, palely eosinophilic cytoplasm and monomorphic nuclei with vesicular chromatin and small nucleoli. The nests are invested by prominent capillary networks, and they are situated within large lobules separated by irregular, thick fibrous septa. Among 18 tumors for which adjacent non-neoplastic tissue could be assessed, perivascular proliferation of tumor cells was identified in 16 tumors (89%). Microcystic architecture was present at least focally in 8 tumors (40%), and myxoid stroma was identified at least focally in 5 (25%). Seven tumors (35%) showed clear cell features. By immunohistochemistry, some tumors expressed MDM2 (7/15; 47%), S100 (5 of 19; 26%), STAT6 (2 of 5; 20%), and AE1/AE3 (1/5; 20%). Tumors rarely expressed pan-keratin (1/10; 10%) or CAM5.2 (1/10), and all tumors were negative for ß-catenin (12 tumors), chromogranin (12), synaptophysin (11), epithelial membrane antigen (10), desmin (10), smooth muscle actin (9), INSM1 (7), and CD34 (6). GLI1 break-apart fluorescence in situ hybridization was performed on 7 tumors, and next-generation sequencing was performed on 15 tumors (10 DNA sequencing only, 1 RNA sequencing only, 4 both DNA and RNA sequencing). Sixteen tumors, including all 15 tested by next-generation sequencing and an additional case tested by fluorescence in situ hybridization only, were found to harbor GLI1 gene alterations: 10 harbored GLI1 gene rearrangements (3 ACTB :: GLI1 , 2 PTCH1 :: GLI1 , 1 HNRNPA1 :: GLI1 , 1 NEAT1 :: GLI1 , 1 TXNIP :: GLI1 , 2 undetermined fusion partners), and 6 harbored GLI1 amplification. Clinical follow-up was available for 10 patients (50%; range: 3 mo to 10 y; median: 6.4 y), including 8 with >1 year of follow-up. Three patients (30%) experienced local recurrence (at intervals of 3 mo to 10 y). None developed distant metastases or died of disease as yet. Overall, our findings support the notion that a subset of GLI1 -altered soft tissue neoplasms are indolent, morphologically distinctive nested glomoid neoplasms that should not be classified as sarcomas.