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OBJECTIVE: To assess the coronary sinus (CS) presence, size, and CS to atrial ratio (CS/A) in the first trimester (FT) compared with the second trimester (ST). METHODS: In this IRB-approved retrospective study, fetuses with adequate FT cardiac sweeps and normal ST hearts were included. Maternal and fetal characteristics were obtained. CS and atrial diameters were measured by a single sonologist. The CS/A ratio was compared between FT and ST. Linear regression assessed the relationship between biparietal diameter (BPD) and CS and atrial diameters. Statistical significance was set at P < .05. RESULTS: Among 99 fetuses, the CS was seen in 42/53 (79.2%) in the FT and 14/32 (43.8%) in the ST. No significant associations were found between CS visualization and the factors analyzed. The CS/A ratio was significantly higher in the FT versus ST (0.43 vs 0.25; P < .0001). Combined FT and ST data revealed positive correlations between BPD and both CS (slope = 0.018, P < .0001) and atrial diameters (slope = 0.135, P < .0001), suggesting differential growth rates, with the atrium exhibiting a faster growth rate as BPD increased. CONCLUSIONS: The CS appears prominent in the FT compared with the ST, likely due to differential growth rates between the CS and atrium. Remnants of embryonic structures, differences in myocardial drainage, and hemodynamics may also be contributing factors. Larger prospective studies are needed to confirm these findings and assess the value of the FT CS/A ratio.
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INTRODUCTION: The calcaneus is the most commonly fractured tarsal bone. Diagnosis is often challenging due to subtle radiographic changes and requires timely identification to prevent complications, including subtalar arthritis, neurovascular injury, malunion, osteomyelitis, and compartment syndrome. Treatment varies based on fracture type, with non-surgical methods for non-displaced stress fractures and surgical interventions for displaced or intra-articular fractures. METHODS: This study utilized the Wisdom in Diagnostic Imaging Simulation (WIDI SIM) platform, an emergency imaging simulation designed to assess radiology resident preparedness for independent call. During an 8-hour simulation, residents were tested on 65 cases across various imaging modalities of varying complexity, including normal studies. A single, unique case of calcaneal fracture was included within the simulation in four separate years of testing. Cases were assessed using a standardized grading rubric by subspecialty radiology faculty, with errors subsequently classified by type. RESULTS: A total of 1279 residents were tested in five separate years on the findings of calcaneal fractures of 5 different patients. Analysis revealed a consistent pattern of missed diagnoses across all training years, primarily attributed to observational errors. There was limited improvement with training progression as all training years exhibited similar average performance levels. CONCLUSIONS: Calcaneal fractures pose a diagnostic challenge due to their frequent subtle radiographic findings, especially in stress fractures. Simulation-based evaluations using WIDI SIM highlighted challenges in radiology residents' proficiency in diagnosing calcaneal fractures. Addressing these challenges through targeted education and exposure to diverse cases is essential to improve diagnostic accuracy and reduce complications with calcaneal fractures.
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Malignant growth relies on rapid protein synthesis frequently leading to endoplasmic reticulum (ER) overload and accumulation of unfolded or misfolded protein in this cellular compartment. In the ER, protein homeostasis is finely regulated by a mechanism called the unfolded protein response (UPR), involving the activation of signalization pathways mediated by three transmembrane proteins, namely PERK, IRE1 and ATF6. IRE1 endoribonuclease activation leads in particular to the splicing of the cytosolic mRNA encoding the key UPR-specific transcription factor XBP1s. Our study shows that sustained activation of XBP1s expression in acute myeloid leukemia (AML) cells induces apoptosis in vitro and in vivo, whereas a moderate XBP1s expression sensitizes cells to chemotherapeutic treatments. ChIP-seq experiments identified specific XBP1s target genes including the MIR22HG lncRNA, the precursor transcript of microRNA-22-3p. miR-22-3p upregulation by XBP1s or forced expression of miR-22 significantly decreases cell's viability and sensitizes leukemic cells to chemotherapy. We found that miR-22-3p intracellular effects result at least partially from the targeting of the mRNA encoding the deacetylase sirtuin-1 (SIRT1), a well-established pro-survival factor. Therefore, this novel XBP1s/miR-22/SIRT1 axis identified could play a pivotal role in the proliferation and chemotherapeutic response of leukemic cells.
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Apoptose , Estresse do Retículo Endoplasmático , Leucemia Mieloide Aguda , MicroRNAs , Sirtuína 1 , Proteína 1 de Ligação a X-Box , Humanos , MicroRNAs/genética , Proteína 1 de Ligação a X-Box/metabolismo , Proteína 1 de Ligação a X-Box/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Sirtuína 1/metabolismo , Sirtuína 1/genética , Animais , Camundongos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Linhagem Celular Tumoral , Transdução de Sinais , Proliferação de CélulasRESUMO
ABSTRACT: Among the most common genetic alterations in myelodysplastic syndromes (MDS) are mutations in the spliceosome gene SF3B1. Such mutations induce specific RNA missplicing events, directly promote ring sideroblast (RS) formation, and generally associate with a more favorable prognosis. However, not all SF3B1 mutations are the same, and little is known about how distinct hotspots influence disease. Here, we report that the E592K variant of SF3B1 associates with high-risk disease features in MDS, including a lack of RS, increased myeloblasts, a distinct comutation pattern, and a lack of favorable survival seen with other SF3B1 mutations. Moreover, compared with other hot spot SF3B1 mutations, E592K induces a unique RNA missplicing pattern, retains an interaction with the splicing factor SUGP1, and preserves normal RNA splicing of the sideroblastic anemia genes TMEM14C and ABCB7. These data have implications for our understanding of the functional diversity of spliceosome mutations, as well as the pathobiology, classification, prognosis, and management of SF3B1-mutant MDS.
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Síndromes Mielodisplásicas , Fosfoproteínas , Fatores de Processamento de RNA , Splicing de RNA , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Humanos , Síndromes Mielodisplásicas/genética , Fosfoproteínas/genética , Mutação , Anemia Sideroblástica/genética , Feminino , Prognóstico , Idoso , MasculinoRESUMO
BACKGROUND AND PURPOSE: Suppurative retropharyngeal lymphadenitis is a retropharyngeal space infection almost exclusively seen in the young (4-8 years old) pediatric population. It can be misdiagnosed as a retropharyngeal abscess, leading to unnecessary invasive treatment procedures. This retrospective study aims to assess radiology residents' ability to independently identify CT imaging findings and make a definitive diagnosis of suppurative retropharyngeal lymphadenitis in a simulated call environment. MATERIALS AND METHODS: The Wisdom in Diagnostic Imaging Emergent/Critical Care Radiology Simulation (WIDI SIM) is a computer-aided emergency imaging simulation proven to be a reliable method for assessing resident preparedness for independent radiology call. The simulation included 65 cases across various imaging modalities of varying complexity, including normal studies, with one case specifically targeting suppurative retropharyngeal adenitis identification. Residents' free text responses were manually scored by faculty members using a standardized grading rubric, with errors subsequently classified by type. RESULTS: A total of 543 radiology residents were tested in three separate years on the imaging findings of suppurative retropharyngeal lymphadenitis using the Wisdom in Diagnostic Imaging simulation web-based testing platform. Suppurative retropharyngeal lymphadenitis was consistently underdiagnosed by radiology residents being tested for call readiness irrespective of the numbers of years in training. On average, only 3.5% of radiology residents were able to correctly identify suppurative retropharyngeal lymphadenitis on a contrast-enhanced computed tomography (CT). CONCLUSIONS: Our findings underscore a potential gap in radiology residency training related to the accurate identification of suppurative retropharyngeal lymphadenitis, highlighting the potential need for enhanced educational efforts in this area.
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Internato e Residência , Linfadenite , Radiologia , Humanos , Criança , Pré-Escolar , Estudos Retrospectivos , Radiologia/educação , Competência Profissional , Linfadenite/diagnóstico por imagemRESUMO
PURPOSE: Basilar artery strokes are rare but can have characteristic imaging findings that can often be overlooked. This retrospective study aims to assess radiology residents' ability to identify CT imaging findings of basilar artery occlusion in a simulated call environment. METHODS: The Wisdom in Diagnostic Imaging Emergent/Critical Care Radiology Simulation (WIDI SIM)-a tested and reliable computer-aided emergency imaging simulation-was employed to assess resident readiness for independent radiology call. The simulations include 65 cases of varying complexity, including normal studies, with one case specifically assessing basilar artery stroke. Residents were presented with a single, unique case of basilar artery occlusion in two separate years of testing and were only provided with non-contrast CT images. Residents' free text responses were manually scored by faculty members using a standardized grading rubric, with errors subsequently classified by type. RESULTS: A total of 454 radiology residents were tested in two separate years on the imaging findings of basilar artery occlusion using the Wisdom in Diagnostic Imaging simulation web-based testing platform. Basilar artery occlusion was consistently underdiagnosed by radiology residents being tested for call readiness irrespective of the numbers of years in training. On average, only 14% of radiology residents were able to correctly identify basilar artery occlusion on non-contrast CT. CONCLUSIONS: Our findings underscore a potential gap in radiology residency training related to the detection of basilar artery occlusion, highlighting the potential need for increased educational efforts in this area.
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Internato e Residência , Radiologia , Acidente Vascular Cerebral , Humanos , Artéria Basilar/diagnóstico por imagem , Competência Profissional , Radiologia/educação , Estudos RetrospectivosRESUMO
RATIONALE AND OBJECTIVES: This study explores the implementation and efficacy of an online, interactive, case-based radiology education tool, Wisdom in Diagnostic Imaging (WIDI) Case-Based Intro to Radiology (CBIR). We hypothesize that the WIDI CBIR platform would enhance radiology teaching, foster critical thinking, and provide a comprehensive curriculum in imaging interpretation and utilization. MATERIALS AND METHODS: A focus group consisting of 1 undergraduate, 7 medical students, 9 physician assistant students, and 3 PhD students participated in this study. We tested 3 different teaching methods: a didactic approach without WIDI, a proctored didactic approach using WIDI, and a flipped classroom approach using WIDI. An online survey was conducted to assess student preference and feedback on these methods and the use of WIDI in their curriculum. RESULTS: Most students preferred the proctored didactic approach with WIDI. They reported that the platform complemented their curriculum and encouraged critical thinking. The modules covered adequate clinical and imaging details and enhanced their skills in imaging interpretation. Despite the limitations of a small sample size and reliance on self-reported outcomes, this study indicates that the WIDI platform could be integrated into PA and medical school curricula throughout the US, offering a standardized radiology curriculum. CONCLUSION: The UF WIDI appears to be a promising tool for modernizing radiology education, improving imaging interpretation skills, and enhancing appropriate imaging selection among nonradiologist medical learners. WIDI offers case-based education in imaging use, workflow, search-pattern selection, and interpretation of common radiological findings, potentially bridging the gap in radiology education. Further research and larger studies are required to assess the long-term impact on performance and clinical practice.
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Instrução por Computador , Educação de Graduação em Medicina , Radiologia , Estudantes de Medicina , Humanos , Currículo , Radiologia/educação , Radiografia , Avaliação Educacional , Educação de Graduação em Medicina/métodosRESUMO
Background: The Harvey Cushing Medal, awarded by the American Association of Neurological Surgeons, is the premier accolade in neurosurgery. The study's purpose was to examine the qualities and accomplishments of previous winners, emphasizing potential selection biases, with the aim to promote social justice and guide young neurosurgeons in their career paths. Results: Predominantly, recipients graduated from top-ranked United States News and World Report institutions and specialized in cerebrovascular and neuro-oncologic/skull base neurosurgery. A significant proportion held roles as department or division chairs and led neurosurgical organizations. All awardees were male, and there was a notable trend of increasing publication counts among more recent recipients. Conclusions: Commonalities among Harvey Cushing Medal winners include graduating from top institutions, holding significant leadership roles, and having an extensive publication history. However, the absence of female and underrepresented minority awardees underscores an urgent need for greater diversity in the selection process.
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INTRODUCTION: Artificial intelligence (AI) has the potential to transform oncologic care. There have been significant developments in AI applications in medical imaging and increasing interest in multimodal models. These are likely to enable improved oncologic care through more precise diagnosis, increasingly in a more personalized and less invasive manner. In this review, we provide an overview of the current state and challenges that clinicians, administrative personnel and policy makers need to be aware of and mitigate for the technology to reach its full potential. AREAS COVERED: The article provides a brief targeted overview of AI, a high-level review of the current state and future potential AI applications in diagnostic radiology and to a lesser extent digital pathology, focusing on oncologic applications. This is followed by a discussion of emerging approaches, including multimodal models. The article concludes with a discussion of technical, regulatory challenges and infrastructure needs for AI to realize its full potential. EXPERT OPINION: There is a large volume of promising research, and steadily increasing commercially available tools using AI. For the most advanced and promising precision diagnostic applications of AI to be used clinically, robust and comprehensive quality monitoring systems and informatics platforms will likely be required.
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Inteligência Artificial , Neoplasias , Humanos , Diagnóstico por Imagem , Oncologia , Previsões , Cuidados Paliativos , Neoplasias/diagnóstico por imagem , Neoplasias/terapiaRESUMO
Neurointerventional Radiology (NIR), encompassing neuroendovascular surgery, endovascular neurosurgery, and interventional neurology, is an innovative and rapidly evolving multidisciplinary specialty focused on minimally invasive therapies for a wide range of neurological disorders. This review provides a comprehensive overview of NIR, discussing the three routes into the field, highlighting their distinct training paradigms, and emphasizing the importance of unified approaches through organizations like the Society of Neurointerventional Surgery (SNIS). The paper explores the benefits of co-managed care and its potential to improve patient outcomes, as well as the role of interdisciplinary collaboration and cross-disciplinary integration in advancing the field. We discuss the various contributions of neurosurgery, radiology, and neurology to cerebrovascular surgery, aiming to inform and educate those interested in pursuing a career in neurointervention. Additionally, the review examines the adoption of innovative technologies such as robotic-assisted techniques and artificial intelligence in NIR, and their implications for patient care and the future of the specialty. By presenting a comprehensive analysis of the field of neurointervention, we hope to inspire those considering a career in this exciting and rapidly advancing specialty, and underscore the importance of interdisciplinary collaboration in shaping its future.
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Aging is associated with an abnormal increase in DNA methylation (DNAm) in human gene promoters, including in bone marrow stem cells. DNAm patterns are further perturbed in hematological malignancies such as acute myeloid leukemia but the physiological significance of such epigenetic changes is unknown. Using epigenetic editing of human stem/progenitor cells (HSPCs), we show that p15 methylation affects hematopoiesis in vivo. We edited the CDKN2B (p15) promoter and ARF (p14) using dCas9-3A3L and observed DNAm spreading beyond the gRNA location. We find that despite a transient delivery system, DNAm is maintained during myeloid differentiation in vitro, and hypermethylation of the p15 promoter reduces gene expression. In vivo, edited human HSPCs can engraft the bone marrow of mice and targeted DNAm is maintained in HSPCs long term. Moreover, epigenetic changes are conserved and inherited in both myeloid and lymphoid lineages. Although the proportion of myeloid (CD33+) and lymphoid (CD19+) cells is unaffected, monocyte (CD14+) populations decreased and granulocytes (CD66b+) increased in mice engrafted with p15 hypermethylated HSPCs. Monocytes derived from p15 hypermethylated HSPCs appear to be activated and show increased inflammatory transcriptional programs. We believe these findings have clinical relevance since we found p15 promoter methylation in the peripheral blood of patients with clonal hematopoiesis. Our study shows DNAm can be targeted and maintained in human HSPCs and demonstrated functional relevance of aberrant DNAm on the p15 locus. As such, other aging-associated aberrant DNAm may impact hematopoiesis in vivo.
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Metilação de DNA , Leucemia Mieloide Aguda , Humanos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Hematopoese/genética , Leucemia Mieloide Aguda/genética , Regiões Promotoras GenéticasRESUMO
INTRODUCTION: Crises like the COVID-19 pandemic create blood product shortages. Patients requiring transfusions are placed at risk and institutions may need to judiciously administer blood during massive blood transfusions protocols (MTP). The purpose of this study is to provide data-driven guidance for the modification of MTP when the blood supply is severely limited. METHODS: This is a retrospective cohort study of 47 Level I and II trauma centers (TC) within a single healthcare system whose patients received MTP from 2017 to 2019. All TC used a unifying MTP protocol for balanced blood product transfusions. The primary outcome was mortality as a function of volume of blood transfused and age. Hemoglobin thresholds and measures of futility were also estimated. Risk-adjusted analyses were performed using multivariable and hierarchical regression to account for confounders and hospital variation. RESULTS: Proposed MTP maximum volume thresholds for three age groupings are as follows: 60 units for ages 16-30 y, 48 units for ages 31-55 y, and 24 units for >55 y. The range of mortality under the transfusion threshold was 30%-36% but doubled to 67-77% when the threshold was exceeded. Hemoglobin concentration differences relative to survival were clinically nonsignificant. Prehospital measures of futility were prehospital cardiac arrest and nonreactive pupils. In hospital risk factors of futility were mid-line shift on brain CT and cardiopulmonary arrest. CONCLUSIONS: Establishing MTP threshold practices under blood shortage conditions, such as the COVID pandemic, could sustain blood availability by following relative thresholds for MTP use according to age groups and key risk factors.
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COVID-19 , Ferimentos e Lesões , Humanos , Estudos Retrospectivos , Pandemias , COVID-19/terapia , Transfusão de Sangue/métodos , Protocolos Clínicos , Centros de TraumatologiaRESUMO
The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer types. For our purposes, the focused metastatic malignancies include breast cancer, lung cancer, melanoma, primary central nervous system tumors, and hematologic cancers (lymphoma, leukemia, and multiple myeloma). Of note, our discussion was limited to cancer-specific leptomeningeal metastases secondary to the aforementioned primary cancers. LMD mechanisms secondary to non-cancerous pathologies, such as infection or inflammation of the leptomeningeal layer, were excluded from our scope of review. Furthermore, we intended to characterize general leptomeningeal disease, including the specific anatomical infiltration process/area, CSF dissemination, manifesting clinical symptoms in patients afflicted with the disease, detection mechanisms, imaging modalities, and treatment therapies (both preclinical and clinical). Of these parameters, leptomeningeal disease across different primary cancers shares several features. Pathophysiology regarding the development of CNS involvement within the mentioned cancer subtypes is similar in nature and progression of disease. Consequently, detection of leptomeningeal disease, regardless of cancer type, employs several of the same techniques. Cerebrospinal fluid analysis in combination with varied imaging (CT, MRI, and PET-CT) has been noted in the current literature as the gold standard in the diagnosis of leptomeningeal metastasis. Treatment options for the disease are both varied and currently in development, given the rarity of these cases. Our review details the differences in leptomeningeal disease as they pertain through the lens of several different cancer subtypes in an effort to highlight the current state of targeted therapy, the potential shortcomings in treatment, and the direction of preclinical and clinical treatments in the future. As there is a lack of comprehensive reviews that seek to characterize leptomeningeal metastasis from various solid and hematologic cancers altogether, the authors intended to highlight not only the overlapping mechanisms but also the distinct patterning of disease detection and progression as a means to uniquely treat each metastasis type. The scarcity of LMD cases poses a barrier to more robust evaluations of this pathology. However, as treatments for primary cancers have improved over time, so has the incidence of LMD. The increase in diagnosed cases only represents a small fraction of LMD-afflicted patients. More often than not, LMD is determined upon autopsy. The motivation behind this review stems from the increased capacity to study LMD in spite of scarcity or poor patient prognosis. In vitro analysis of leptomeningeal cancer cells has allowed researchers to approach this disease at the level of cancer subtypes and markers. We ultimately hope to facilitate the clinical translation of LMD research through our discourse.
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Neoplasias da Mama , Neoplasias Hematológicas , Carcinomatose Meníngea , Humanos , Feminino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Carcinomatose Meníngea/terapia , Carcinomatose Meníngea/epidemiologia , Carcinomatose Meníngea/secundário , Neoplasias da Mama/patologia , Imageamento por Ressonância MagnéticaRESUMO
Focused ultrasound is a novel technique for the treatment of aggressive brain tumors that uses both mechanical and thermal mechanisms. This non-invasive technique can allow for both the thermal ablation of inoperable tumors and the delivery of chemotherapy and immunotherapy while minimizing the risk of infection and shortening the time to recovery. With recent advances, focused ultrasound has been increasingly effective for larger tumors without the need for a craniotomy and can be used with minimal surrounding soft tissue damage. Treatment efficacy is dependent on multiple variables, including blood-brain barrier permeability, patient anatomical features, and tumor-specific features. Currently, many clinical trials are currently underway for the treatment of non-neoplastic cranial pathologies and other non-cranial malignancies. In this article, we review the current state of surgical management of brain tumors using focused ultrasound.
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Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgiaRESUMO
Health informatics and artificial intelligence (AI) are expected to transform the healthcare enterprise and the future practice of radiology. There is an increasing body of literature on radiomics and deep learning/AI applications in medical imaging. There are also a steadily increasing number of FDA cleared AI applications in radiology. It is therefore essential for radiologists to have a basic understanding of these approaches, whether in academia or private practice. In this article, we will provide an overview of the field and familiarize the readers with the fundamental concepts behind these approaches.
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Inteligência Artificial , Radiologia , Humanos , Radiologistas , Radiologia/métodos , Radiografia , PrevisõesRESUMO
There are many impactful applications of artificial intelligence (AI) in the electronic radiology roundtrip and the patient's journey through the healthcare system that go beyond diagnostic applications. These tools have the potential to improve quality and safety, optimize workflow, increase efficiency, and increase patient satisfaction. In this article, we review the role of AI for process improvement and workflow enhancement which includes applications beginning from the time of order entry, scan acquisition, applications supporting the image interpretation task, and applications supporting tasks after image interpretation such as result communication. These non-diagnostic workflow and process optimization tasks are an important part of the arsenal of potential AI tools that can streamline day to day clinical practice and patient care.
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Inteligência Artificial , Radiologia , Humanos , Fluxo de Trabalho , Radiologia/métodosRESUMO
Among the most common genetic alterations in the myelodysplastic syndromes (MDS) are mutations in the spliceosome gene SF3B1. Such mutations induce specific RNA missplicing events, directly promote ring sideroblast (RS) formation, generally associate with more favorable prognosis, and serve as a predictive biomarker of response to luspatercept. However, not all SF3B1 mutations are the same, and here we report that the E592K variant of SF3B1 associates with high-risk disease features in MDS, including a lack of RS, increased myeloblasts, a distinct co-mutation pattern, and decreased survival. Moreover, in contrast to canonical SF3B1 mutations, E592K induces a unique RNA missplicing pattern, retains an interaction with the splicing factor SUGP1, and preserves normal RNA splicing of the sideroblastic anemia genes TMEM14C and ABCB7. These data expand our knowledge of the functional diversity of spliceosome mutations, and they suggest that patients with E592K should be approached differently from low-risk, luspatercept-responsive MDS patients with ring sideroblasts and canonical SF3B1 mutations.
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Cerebral venous sinus stenting (CVSS) is a minimally invasive procedure using endovascular stent placement to relieve elevated intracranial pressure secondary to venous sinus stenosis. Increased venous sinus pressure secondary to stenosis is commonly associated with elevated intracranial pressure without intracranial lesions on imaging or idiopathic intracranial hypertension (IIH). While the etiology of IIH remains unknown, stenosis of one or more of the dural sinuses has been implicated as a possible underlying mechanism. The manifestations of IIH include headaches, transient vision loss, pulsatile tinnitus, and neck pain. In this review, we discuss the recent studies that have demonstrated the e!ectiveness of CVSS for patients with IIH and also the indications, technical challenges, potential complications, and emerging developments in CVSS.
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Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.
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Leucemia Mieloide Aguda , Manose , Humanos , Morte Celular , Citarabina/farmacologia , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/metabolismo , Apoptose , Tirosina Quinase 3 Semelhante a fmsRESUMO
Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we report how mis-splicing of coenzyme A synthase (COASY), induced by mutations in SF3B1, affects heme biosynthesis and erythropoiesis. Our data revealed that COASY was up-regulated during normal erythroid differentiation, and its silencing prevented the formation of erythroid colonies, impeded erythroid differentiation, and precluded heme accumulation. In patients with MDS-RS, loss of protein due to COASY mis-splicing led to depletion of both CoA and succinyl-CoA. Supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1mut cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the COASY pathway in erythroid maturation and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.