Exploiting epigenetic targets to overcome taxane resistance in prostate cancer.

The development of taxane resistance remains a major challenge for castration resistant prostate cancer (CR-PCa), despite the effectiveness of taxanes in prolonging patient survival. To uncover novel targets, we performed an epigenetic drug screen on taxane (docetaxel and cabazitaxel) resistant CR-PCa cells. We identified BRPF reader proteins, along with several epigenetic groups (CBP/p300, Menin-MLL, PRMT5 and SIRT1) that act as targets effectively reversing the resistance mediated by ABCB1. Targeting BRPFs specifically resulted in the resensitization of resistant cells, while no such effect was observed on the sensitive compartment. These cells were successfully arrested at the G2/M phase of cell cycle and underwent apoptosis upon BRPF inhibition, confirming the restoration of taxane susceptibility. Pharmacological inhibition of BRPFs reduced ABCB1 activity, indicating that BRPFs may be involved in an efflux-related mechanism. Indeed, ChIP-qPCR analysis confirmed binding of BRPF1 to the ABCB1 promoter suggesting direct regulation of the ABCB1 gene at the transcriptional level. RNA-seq analysis revealed that BRPF1 knockdown affects the genes enriched in mTORC1 and UPR signaling pathways, revealing potential mechanisms underlying its functional impact, which is further supported by the enhancement of taxane response through the combined inhibition of ABCB1 and mTOR pathways, providing evidence for the involvement of multiple BRPF1-regulated pathways. Beyond clinical attributes (Gleason score, tumor stage, therapy outcome, recurrence), metastatic PCa databases further supported the significance of BRPF1 in taxane resistance, as evidenced by its upregulation in taxane-exposed PCa patients.

Aspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection.

Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage. Here, we show that GliT:GFP and GtmA:GFP are localized in the cytoplasm and in vacuoles during GT production. The Mitogen-Activated Protein kinase MpkA is essential for GT production and self-protection, interacts physically with GliT and GtmA and it is necessary for their regulation and subsequent presence in the vacuoles. The sensor histidine kinase SlnASln1 is important for modulation of MpkA phosphorylation. Our work emphasizes the importance of MpkA and compartmentalization of cellular events for GT production and self-defense.

Evaluation of Eustachian tube dimensions by temporal bone computed tomography in patients with chronic otitis media.

OBJECTIVE: To clarify the relationship between Eustachian tube dimensions and chronic otitis media aetiology using temporal bone computed tomography. METHODS: The data of 231 adults who had undergone surgery for unilateral chronic otitis media were reviewed retrospectively. Diseased and healthy ears were enrolled in groups 1 and 2, respectively. Group 1A included chronic otitis media with cholesteatoma (n = 28) and group 1B included chronic otitis media without cholesteatoma (n = 203). The Eustachian tube dimensions of groups 1 and 2 were compared, to clarify the relationship between the Eustachian tube dimensions and chronic otitis media aetiology. Groups 1A and 1B were compared to assess the effect of Eustachian tube dimensions on cholesteatoma development. RESULTS: The Eustachian tube was shorter, narrower and located more horizontally in ears with chronic otitis media. No significant difference was found between groups 1A and 1B. CONCLUSION: Eustachian tube dimensions are closely related to chronic otitis media aetiopathology, but are not related to cholesteatoma development.

The impact of fragmented QRS on clinical findings and outcomes in children with dilated cardiomyopathy with or without left ventricular non-compaction.

OBJECTIVE: The aim of this study is to investigate the frequency of fragmented QRS and its associations with clinical findings and prognosis in children diagnosed with dilated cardiomyopathy with or without left ventricular non-compaction. METHODS: This retrospective study was conducted between 2010 and 2020. Patients with dilated cardiomyopathy were classified into two groups according to the presence of left ventricular non-compaction: Dilated cardiomyopathy with left ventricular non-compaction and dilated cardiomyopathy without left ventricular non-compaction. Patients were also divided into two groups according to the presence of fragmented QRS (fragmented QRS group and non-fragmented QRS group). RESULTS: Twenty-three of 44 patients (52.3%) were male. Among left ventricular non-compaction patients, the fragmented QRS group had more complex ventricular arrhythmias (p = 0.003). Patients with fragmented QRS had a significantly higher rate of major adverse cardiac events and/or cardiac death in both cardiomyopathy groups (p = 0.003 and p = 0.005). However, the rate of major adverse cardiac events and/or cardiac death was similar between dilated cardiomyopathy patients with and without left ventricular non-compaction. Multivariate logistic regression analysis showed that the presence of fragmented QRS strongly predicts major adverse cardiac events and/or cardiac death (odds ratio, 31.186; 95% confidence interval, 2.347-414.307). Although the survival rates between cardiomyopathy groups were similar, patients with fragmented QRS had a markedly lower survival rate during the follow-up period, as mean of 15 months (p = 0.001). CONCLUSION: Our study showed that the presence of fragmented QRS may be an important ECG sign predicting an major adverse cardiac event and/or cardiac death in patients with dilated cardiomyopathy. We believe that recognising fragmented QRS could be valuable in forecasting patient prognosis and identifying high-risk patients who require additional support.

Cardiovascular manifestations and cardiac magnetic resonance follow-up of multisystem inflammatory syndrome in children (MIS-C).

OBJECTIVE: This study aimed to evaluate the cardiovascular manifestations and surveillance of multisystem inflammatory syndrome in children (MIS-C) and to determine the correlation of echocardiographic findings with cardiac magnetic resonance imaging findings. METHODS: Forty-four children diagnosed as MIS-C with cardiac involvement were enrolled in this observational descriptive study. The diagnosis of MIS-C was made according to the criteria of Centers for Disease Control and Prevention. Clinical findings, laboratory parameters, and electrocardiographic and echocardiographic findings at the time of diagnosis and during follow-up were evaluated. Cardiac magnetic resonance was performed on 28 (64%) cases. The 1-year follow-up imaging was performed in all cases with abnormal initial cardiac magnetic resonance findings. RESULTS: Forty-four patients (56.8% male) with a mean age of 8.5 ± 4.8 years were enrolled in this study. There was a significant positive correlation between high-sensitivity cardiac troponin T (mean: 162 ± 444.4 pg/ml) and N-terminal pro b-type natriuretic peptide (mean: 10,054 ± 11,604 pg/ml) (p < 0.01). Number of cases with an electrocardiographic and echocardiographic abnormality was 34 (77%) and 31 (70%), respectively. Twelve cases (45%) had left ventricular systolic dysfunction and 14 (32%) cases had pericardial effusion on admission. Three cases (11%) had cardiac magnetic resonance findings that may be attributed to the presence of myocardial inflammation, and pericardial effusion was present in seven (25%) cases. Follow-up cardiac magnetic resonances of all cases were normal. Cardiac abnormalities were completely resolved in all except two cases. CONCLUSIONS: Myocardial involvement can be seen during acute disease, but MIS-C generally does not lead to prominent damage during a year of surveillance. Cardiac magnetic resonance is a valuable tool to evaluate the degree of myocardial involvement in cases with MIS-C.

Transcriptional profiling of a fungal granuloma reveals a low metabolic activity of Paracoccidioides brasiliensis yeasts and an actively regulated host immune response.

Granulomas are important immunological structures in the host defense against the fungus Paracoccidioides brasiliensis, the main etiologic agent of Paracoccidioidomycosis (PCM), a granulomatous systemic mycosis endemic in Latin America. We have performed transcriptional and proteomic studies of yeasts present in the pulmonary granulomas of PCM aiming to identify relevant genes and proteins that act under stressing conditions. C57BL/6 mice were infected with 1x106 yeasts and after 8- and 12-weeks of infection, granulomatous lesions were obtained for extraction of fungal and murine RNAs and fungal proteins. Dual transcriptional profiling was done comparing lung cells and P. brasiliensis yeasts from granulomas with uninfected lung cells and the original yeast suspension used in the infection, respectively. Mouse transcripts indicated a lung malfunction, with low expression of genes related to muscle contraction and organization. In addition, an increased expression of transcripts related to the activity of neutrophils, eosinophils, macrophages, lymphocytes as well as an elevated expression of IL-1ß, TNF-α, IFN-γ, IL-17 transcripts were observed. The increased expression of transcripts for CTLA-4, PD-1 and arginase-1, provided evidence of immune regulatory mechanisms within the granulomatous lesions. Also, our results indicate iron as a key element for the granuloma to function, where a high number of transcripts related to fungal siderophores for iron uptake was observed, a mechanism of fungal virulence not previously described in granulomas. Furthermore, transcriptomics and proteomics analyzes indicated a low fungal activity within the granuloma, as demonstrated by the decreased expression of genes and proteins related to energy metabolism and cell cycle.

The KdmB-EcoA-RpdA-SntB (KERS) chromatin regulatory complex controls development, secondary metabolism and pathogenicity in Aspergillus flavus.

The filamentous fungus Aspergillus flavus is a plant and human pathogen predominantly found in the soil as spores or sclerotia and is capable of producing various secondary metabolites (SM) such as the carcinogenic mycotoxin aflatoxin. Recently, we have discovered a novel nuclear chromatin binding complex (KERS) that contains the JARID1-type histone demethylase KdmB, a putative cohesion acetyl transferase EcoA, a class I type histone deacetylase RpdA and the PHD ring finger reader protein SntB in the model filamentous fungus Aspergillus nidulans. Here, we show the presence of the KERS complex in A. flavus by immunoprecipitation-coupled mass spectrometry and constructed kdmBΔ and rpdAΔ strains to study their roles in fungal development, SM production and histone post-translational modifications (HPTMs). We found that KdmB and RpdA couple the regulation of SM gene clusters with fungal light-responses and HPTMs. KdmB and RpdA have opposing roles in light-induced asexual conidiation, while both factors are positive regulators of sclerotia development through the nsdC and nsdD pathway. KdmB and RpdA are essential for the productions of aflatoxin (similar to findings for SntB) as well as cyclopiazonic acid, ditryptophenaline and leporin B through controlling the respective SM biosynthetic gene clusters. We further show that both KdmB and RpdA regulate H3K4me3 and H3K9me3 levels, while RpdA also acts on H3K14ac levels in nuclear extracts. Therefore, the chromatin modifiers KdmB and RpdA of the KERS complex are key regulators for fungal development and SM metabolism in A. flavus.

The use of immunoaffinity purification approaches coupled with LC-MS/MS offers a powerful strategy to identify protein complexes in filamentous fungi.

Fungi are a diverse group of organisms that can be both beneficial and harmful to mankind. They have advantages such as producing food processing enzymes and antibiotics, but they can also be pathogens and produce mycotoxins that contaminate food. Over the past two decades, there have been significant advancements in methods for studying fungal molecular biology. These advancements have led to important discoveries in fungal development, physiology, pathogenicity, biotechnology, and natural product research. Protein complexes and protein-protein interactions (PPIs) play crucial roles in fungal biology. Various methods, including yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC), are used to investigate PPIs. However, affinity-based PPI methods like co-immunoprecipitation (Co-IP) are highly preferred because they represent the natural conditions of PPIs. In recent years, the integration of liquid chromatography coupled with mass spectrometry (LC-MS/MS) has been used to analyse Co-IPs, leading to the discovery of important protein complexes in filamentous fungi. In this review, we discuss the tandem affinity purification (TAP) method and single affinity purification methods such as GFP, HA, FLAG, and MYC tag purifications. These techniques are used to identify PPIs and protein complexes in filamentous fungi. Additionally, we compare the efficiency, time requirements, and material usage of Sepharose™ and magnetic-based purification systems. Overall, the advancements in fungal molecular biology techniques have provided valuable insights into the complex interactions and functions of proteins in fungi. The methods discussed in this review offer powerful tools for studying fungal biology and will contribute to further discoveries in this field.

Complications of epicutaneo-caval catheters: Pericardial effusion and cardiac tamponade in three preterm infants.

In the neonatal intensive care units (NICU), epicutaneo-caval catheters (ECCs) are common alternative vascular routes. Pericardial effusion (PCE) and cardiac tamponade (CT) are rare but serious complications in infants with ECCs. It may be asymptomatic or present with a variety of significant clinical signs, including dyspnea, bradycardia, sudden asystole, and hypotension. If untreated, PCE can be fatal. This report presents, three cases of ECC-associated PCE/CT during NICU stay. All three patients were born before 30 weeks of gestation and weighed less than 1500 g. Echocardiography was used for diagnosis all patients. PCE/CT was detected incidentally in one patient and after hemodynamic deterioration in the other two. In one patient, CT was developed due to catheter malposition, and the other two patient, the catheter tip was found in the right atrium. PCE did not recur in any of the patients after pericardial fluid was drained and the catheters were removed. No PCE/CT-related deaths were observed. In all three patients, X-ray was used to evaluate the location of the catheter tips. However, after clinical deterioration, echocardiography showed that in the first two cases the tips were actually in the right atrium. Real-time ultrasound was suggested with strong evidence to evaluate the location of the catheter tip and to detect secondary malapposition. PCE/CT should be considered in the presence of unexplained and refractory respiratory distress, abnormal heart rate and blood pressure, and metabolic acidosis in a neonate with ECC. Early diagnosis and prompt pericardiocentesis are essential to reduce mortality and improve prognosis. Prospective studies with educational interventions should be designed to demonstrate that the use of point-of-care ultrasound (POCUS) can be easily acquired and may reduce complications.

Vacuoles and peroxisomes are involved in Aspergillus fumigatus gliotoxin production and self-protection.

Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage. Here, we show that GliT:GFP and GtmA:GFP are localized in the cytoplasm and in vacuoles during GT production. Peroxisomes are also required for proper GT production and self-defense. The Mitogen-Activated Protein (MAP) kinase MpkA is essential for GT production and self-protection, interacts physically with GliT and GtmA and it is necessary for their regulation and subsequent presence in the vacuoles. Our work emphasizes the importance of dynamic compartmentalization of cellular events for GT production and self-defense.

An Anatomy of Fungal Eye: Fungal Photoreceptors and Signalling Mechanisms.

Organisms have developed different features to capture or sense sunlight. Vertebrates have evolved specialized organs (eyes) which contain a variety of photosensor cells that help them to see the light to aid orientation. Opsins are major photoreceptors found in the vertebrate eye. Fungi, with more than five million estimated members, represent an important clade of living organisms which have important functions for the sustainability of life on our planet. Light signalling regulates a range of developmental and metabolic processes including asexual sporulation, sexual fruit body formation, pigment and carotenoid production and even production of secondary metabolites. Fungi have adopted three groups of photoreceptors: (I) blue light receptors, White Collars, vivid, cryptochromes, blue F proteins and DNA photolyases, (II) red light sensors, phytochromes and (III) green light sensors and microbial rhodopsins. Most mechanistic data were elucidated on the roles of the White Collar Complex (WCC) and the phytochromes in the fungal kingdom. The WCC acts as both photoreceptor and transcription factor by binding to target genes, whereas the phytochrome initiates a cascade of signalling by using mitogen-activated protein kinases to elicit its cellular responses. Although the mechanism of photoreception has been studied in great detail, fungal photoreception has not been compared with vertebrate vision. Therefore, this review will mainly focus on mechanistic findings derived from two model organisms, namely Aspergillus nidulans and Neurospora crassa and comparison of some mechanisms with vertebrate vision. Our focus will be on the way light signalling is translated into changes in gene expression, which influences morphogenesis and metabolism in fungi.

Proteomic dissection of the role of GliZ in gliotoxin biosynthesis in Aspergillus fumigatus.

Gliotoxin (GT) biosynthesis in fungi is encoded by the gli biosynthetic gene cluster. While GT addition autoinduces biosynthesis, Zn2+ has been shown to attenuate cluster activity, and it was speculated that identification of Zn2Cys6 binuclear transcription factor GliZ binding partners might provide insight into this observation. Using the Tet-ON induction system, doxycycline (DOX) presence induced GliZ fusion protein expression in, and recovery of GT biosynthesis by, A. fumigatus ΔgliZ::HA-gliZ and ΔgliZ::TAP-gliZ strains, respectively. Quantitative RT-PCR confirmed that DOX induces gli cluster gene expression (n = 5) in both A. fumigatus HA-GliZ and TAP-GliZ strains. GT biosynthesis was evident in Czapek-Dox and in Sabouraud media, however tagged GliZ protein expression was more readily detected in Sabouraud media. Unexpectedly, Zn2+ was essential for GliZ fusion protein expression in vivo, following 3 h DOX induction. Moreover, HA-GliZ abundance was significantly higher in either DOX/GT or DOX/Zn2+, compared to DOX-only. This suggests that while GT induction is still intact, Zn2+ inhibition of HA-GliZ production in vivo is lost. Co-immunoprecipitation revealed that GT oxidoreductase GliT associates with GliZ in the presence of GT, suggesting a potential protective role. Additional putative HA-GliZ interacting proteins included cystathionine gamma lyase, ribosomal protein L15 and serine hydroxymethyltransferase (SHMT). Total mycelial quantitative proteomic data revealed that GliT and GtmA, as well as several other gli cluster proteins, are increased in abundance or uniquely expressed with GT addition. Proteins involved in sulphur metabolism are also differentially expressed with GT or Zn2+ presence. Overall, we disclose that under DOX induction GliZ functionality is unexpectedly evident in zinc-replete media, subject to GT induction and that GliT appears to associate with GliZ, potentially to prevent dithiol gliotoxin (DTG)-mediated GliZ inactivation by zinc ejection.

Investigation of factors affecting pediatric type 1 endoscopic tympanoplasty results and success rates of surgery.

OBJECTIVE: There are many factors that affect the results of tympanoplasty in children. Recurrent ear infections, hearing loss, and more serious complications due to cholesteatoma may be observed. This study examined factors affecting the success of type 1 endoscopic tympanoplasty surgery in pediatric patients and investigated recommended procedures to increase the success of the operation. METHODS: Our study included pediatric patients who underwent type 1 endoscopic tympanoplasty operation for chronic otitis media. Patient files were analyzed retrospectively. Hearing results before and after the operations were recorded.. Patients were divided into groups according to gender, age (<12 age group, ≥12 age group), and perforation type. Hearing results and physical examination findings were compared for each group. RESULTS: A total of 204 pediatric patients were included in our study: 114 were male and 90 were female. Patients' hearing results were compared according to the size and location of their tympanic membrane perforations. Hearing loss was found to increase as the size of the tympanic membrane perforation increased. In addition, it was observed that perforations in the posterior quadrant caused more severe hearing loss than in the other quadrants. The postoperative results of the two groups <12 years old, and ≥12 years old were evaluated according to age. Postoperative improvement was higher in the ≥12 age group compared to the <12 age group. CONCLUSION: According to the results of this study, tympanoplasty surgeries performed on patients younger than 12 have a decreased success rate. Among the many factors that affect the success of an operation, age is one of the most important. There are many factors that affect the results of the operation, perforation size and localization is one of them. There are many factors that affect the success of surgery such as pediatric patients and adult patients. It is useful to make a personal evaluation and to plan the surgery by evaluating the obstacles such as eustachian tube maturation and difficulty in postoperative care in pediatric patients.

F-box receptor mediated control of substrate stability and subcellular location organizes cellular development of Aspergillus nidulans.

Fungal growth and development are coordinated with specific secondary metabolism. This coordination requires 8 of 74 F-box proteins of the filamentous fungus Aspergillus nidulans. F-box proteins recognize primed substrates for ubiquitination by Skp1-Cul1-Fbx (SCF) E3 ubiquitin RING ligases and degradation by the 26S proteasome. 24 F-box proteins are found in the nuclear fraction as part of SCFs during vegetative growth. 43 F-box proteins interact with SCF proteins during growth, development or stress. 45 F-box proteins are associated with more than 700 proteins that have mainly regulatory roles. This corroborates that accurate surveillance of protein stability is prerequisite for organizing multicellular fungal development. Fbx23 combines subcellular location and protein stability control, illustrating the complexity of F-box mediated regulation during fungal development. Fbx23 interacts with epigenetic methyltransferase VipC which interacts with fungal NF-κB-like velvet domain regulator VeA that coordinates fungal development with secondary metabolism. Fbx23 prevents nuclear accumulation of methyltransferase VipC during early development. These results suggest that in addition to their role in protein degradation, F-box proteins also control subcellular accumulations of key regulatory proteins for fungal development.

The KdmB-EcoA-RpdA-SntB chromatin complex binds regulatory genes and coordinates fungal development with mycotoxin synthesis.

Chromatin complexes control a vast number of epigenetic developmental processes. Filamentous fungi present an important clade of microbes with poor understanding of underlying epigenetic mechanisms. Here, we describe a chromatin binding complex in the fungus Aspergillus nidulans composing of a H3K4 histone demethylase KdmB, a cohesin acetyltransferase (EcoA), a histone deacetylase (RpdA) and a histone reader/E3 ligase protein (SntB). In vitro and in vivo evidence demonstrate that this KERS complex is assembled from the EcoA-KdmB and SntB-RpdA heterodimers. KdmB and SntB play opposing roles in regulating the cellular levels and stability of EcoA, as KdmB prevents SntB-mediated degradation of EcoA. The KERS complex is recruited to transcription initiation start sites at active core promoters exerting promoter-specific transcriptional effects. Interestingly, deletion of any one of the KERS subunits results in a common negative effect on morphogenesis and production of secondary metabolites, molecules important for niche securement in filamentous fungi. Consequently, the entire mycotoxin sterigmatocystin gene cluster is downregulated and asexual development is reduced in the four KERS mutants. The elucidation of the recruitment of epigenetic regulators to chromatin via the KERS complex provides the first mechanistic, chromatin-based understanding of how development is connected with small molecule synthesis in fungi.

EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities.

Dysregulation of the epigenome due to alterations in chromatin modifier proteins commonly contribute to malignant transformation. To interrogate the roles of epigenetic modifiers in cancer cells, we generated an epigenome-wide CRISPR-Cas9 knockout library (EPIKOL) that targets a wide-range of epigenetic modifiers and their cofactors. We conducted eight screens in two different cancer types and showed that EPIKOL performs with high efficiency in terms of sgRNA distribution and depletion of essential genes. We discovered novel epigenetic modifiers that regulate triple-negative breast cancer (TNBC) and prostate cancer cell fitness. We confirmed the growth-regulatory functions of individual candidates, including SS18L2 and members of the NSL complex (KANSL2, KANSL3, KAT8) in TNBC cells. Overall, we show that EPIKOL, a focused sgRNA library targeting ~800 genes, can reveal epigenetic modifiers that are essential for cancer cell fitness under in vitro and in vivo conditions and enable the identification of novel anti-cancer targets. Due to its comprehensive epigenome-wide targets and relatively high number of sgRNAs per gene, EPIKOL will facilitate studies examining functional roles of epigenetic modifiers in a wide range of contexts, such as screens in primary cells, patient-derived xenografts as well as in vivo models.

Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis.

Epithelial-mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E-M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance into and continued residence in these various states, and which of these states favour the process of metastasis. Here we characterize a layer of EMT-regulating machinery that governs E-M plasticity (EMP). This machinery consists of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, which operate as critical regulators to maintain a stable epithelial state. Interestingly, loss of these two complexes unlocks two distinct EMT trajectories. Dysfunction of PRC2, but not KMT2D-COMPASS, yields a quasi-mesenchymal state that is associated with highly metastatic capabilities and poor survival of patients with breast cancer, suggesting that great caution should be applied when PRC2 inhibitors are evaluated clinically in certain patient cohorts. These observations identify epigenetic factors that regulate EMP, determine specific intermediate EMT states and, as a direct consequence, govern the metastatic ability of carcinoma cells.

Is there a relationship between middle concha bullosa and ethmoid roof asymmetry? / Existe uma relação entre a concha média bolhosa e a assimetria do teto etmoidal?

Abstract Introduction The middle turbinate and ethmoid roof are intranasal structures and may have many anatomical variations. These structures, which serve as anatomical markers during functional sinus surgery, are important for preventing complications and performing a proper surgery. Knowledge of anatomical variations will increase surgical success and reduce complications. Objective We aimed to investigate the presence of asymmetry in the ethmoidal roof and anatomical variation in patients with and without concha bullosa. Methods In this study, the files of patients who underwent paranasal computed tomography between 2012 and 2018 were analyzed retrospectively. The patients were divided into two groups, as patients with and without concha bullosa. Differences between the two groups in terms of age, gender, septum deviation, ethmoid artery dehiscence, ethmoid roof asymmetry were examined. Results The 369 patients included in our study were divided into two groups; those with concha bullosa and those without concha bullosa. The mean age of the patients with concha bullosa was 36.1 ± 13.4 (min-max: 12-74) and the mean age of patients without concha bullosa was 37.5 ± 14.3 (min-max: 10-81). The ethmoid roof depths were compared between the two groups and a significant difference was observed (p < 0.001). The ethmoid roof depth was higher in the group with concha bullosa (p < 0.001). Conclusion The results of our study indicate that the ethmoidal roof tends to be higher in patients with middle concha bullosa.

Resumo Introdução A concha média e o teto etmoidal são estruturas intranasais e podem apresentar muitas variações anatômicas. Essas estruturas, usadas como marcadores anatômicos durante a cirurgia sinusal funcional, são importantes para evitar complicações e para a feitura adequada da cirurgia. O conhecimento das variações anatômicas aumenta o sucesso cirúrgico e reduz as complicações. Objetivo Investigar a presença de assimetria no teto etmoidal e variações anatômicas em pacientes com e sem concha bolhosa. Método Os prontuários dos pacientes submetidos à tomografia computadorizada de seios paranasais entre 2012 e 2018 foram analisados retrospectivamente. Os pacientes foram divididos em dois grupos, pacientes com e sem concha bolhosa. As diferenças entre os dois grupos em termos de idade, sexo, desvio do septo, deiscência da artéria etmoidal e assimetria do teto etmoidal foram avaliadas. Resultados Os 369 pacientes incluídos em nosso estudo foram divididos em dois grupos: com concha bolhosa e sem concha bolhosa. A média de idade dos pacientes com concha bolhosa foi de 36,1 ± 13,4 (mín-máx: 12-74 anos) e a média de idade dos pacientes sem concha bolhosa foi de 37,5 ± 14,3 (mín-máx: 10-81 anos). As profundidades do teto etmoidal foram comparadas entre os dois grupos, observou-se diferença significante (p < 0,001). Observou-se que a profundidade do teto etmoidal foi maior no grupo com concha bolhosa (p < 0,001). Conclusão O resultado do nosso estudo indica que pacientes com concha média bolhosa tendem a apresentar uma maior profundidade do teto etmoidal.

The role and efficacy of routine high-sensitivity troponin T screening in paediatric COVID-19.

OBJECTIVE: We aimed to evaluate the efficacy and role of high-sensitivity troponin T in children with a confirmed SARS-CoV-2 infection and also the correlation of troponin T levels with symptoms, and echocardiographic findings were analysed. METHODS: Two hundred and fourteen patients with a confirmed SARS-CoV-2 infection between the dates of 28 March and 15 August 12020 were enrolled in this retrospective single-centre study. Patients with comorbidities and diagnosed as multisystem inflammatory syndrome in children were excluded. Demographic data, clinical and laboratory parameters were evaluated. The patients were classified and compared according to the troponin positivity. The correlation of troponin T with symptoms and echocardiographic findings was analysed. RESULTS: The most common symptoms in the whole study group were fever (53.3%) and cough (24.8%). Troponin T levels were elevated in 15 (7%) patients. The most common symptom in patients with troponin positivity was also fever (73.3%). Troponin T positivity was significantly higher in patients under the age of 12 months and troponin T levels were negatively correlated with age. C-reactive protein levels were elevated in 77 (36%) of the patients in the whole group and 7 (46.7%) of 15 patients with troponin positivity. C-reactive protein levels were similar between groups. CONCLUSION: Routine troponin screening does not yield much information in previously healthy paediatric COVID-19 patients without any sign of myocardial dysfunction. Elevated troponin levels may be observed but it is mostly a sign of myocardial injury without detectable myocardial dysfunction in this group of patients.