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BACKGROUND: Lesbian, Gay, Bisexual, Transgender, Queer, and more(LGBTQ+) trainees are underrepresented in medicine, and their experiences in surgery have not been well studied. We sought to examine the practices of general surgery residency programs by region regarding representation of LGBTQ+ âsupport online. METHODS: Retrospective, two-person review of 100 general surgery residency programs stratified by Electronic Residency Application Service(ERAS) region comparing data on Diversity, Equity, and Inclusion(DEI) and LGBTQ+ â-specific webpages. RESULTS: The Middle Atlantic and South Atlantic regions had 20% of programs each, with fewer programs found in other regions. Of the 100 institutions, 92% had DEI webpages, and 43% had LGBTQ+ â-specific webpages. There was a significant difference in the likelihood of a program being an Human Rights Campaign(HRC) LGBTQ+ âleader when compared by region(p â< â0.01). CONCLUSIONS: Few general surgery residency programs share LGBTQ+-specific DEI content online with no regional difference observed. Recommendations such as updating websites to highlight LGBTQ+ âinclusion should aid recruitment of a diverse, surgical residency as well as create a welcoming environment for prospective residents.
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BACKGROUND: Bariatric surgery offers effective treatment for morbid obesity and associated medical comorbidities, with excellent short- and long-term outcomes. Although it has been well documented that racial minority bariatric patients have worse outcomes than White patients, it remains unclear whether this recognition has led to improvement. Herein, we assess recent trends in bariatric surgery among Black and White patients and compare early postoperative outcomes by race. METHODS: Primary sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) patients from 2015 to 2021 reported to the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program were studied. Bariatric patients were stratified by race (Black and White) and perioperative outcomes were compared between matched Black and White patients. Primary outcome was 30-day mortality. Secondary outcomes included hospital readmissions, hospital length of stay (LOS), reoperation, and postoperative complications. RESULTS: Overall, there were 193,071 Black and 645,224 White primary bariatric patients, with a higher volume of SG and RGYB performed among White patients. A total of 219,566 Black and White bariatric patients were matched and included in the case-control. Black patients were found to have higher rates of 30-day mortality (0.02% vs. 0.01%; p = 0.03) and readmissions (3.68% vs. 2.65%; p < 0.001). There were no significant differences in LOS, reoperations, or overall postoperative complications. However, there was a higher postoperative pulmonary thromboembolism rate (0.16% vs 0.08%; p < 0.001).). The differences in perioperative outcomes stratified by race persisted over the study period (Fig. 1). CONCLUSION: Black bariatric surgery patients continue to have worse perioperative outcomes compared with their White counterparts. Further work must be done to determine contributing factors in order to effect improvement in outcomes in bariatric surgical care for racial minority patients.
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Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3-4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment.
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BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. RESULTS: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. CONCLUSIONS: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
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Deficiência Intelectual , Transcriptoma , Peixe-Zebra , Animais , Feminino , Humanos , Masculino , Deficiência Intelectual/genética , Mutação com Perda de Função , Mutação de Sentido Incorreto , Fenótipo , Peixe-Zebra/genéticaRESUMO
BACKGROUND: Increasing numbers of women of childbearing age have cardiac disease, including heart failure (HF). In these women, pregnancy can cause significant morbidity and mortality. Contraceptive use and pregnancy counseling in women with HF is an essential part of their medical care. Here, we assess contraceptive use and pregnancy counseling of patients with HF at a single tertiary care center. METHODS AND RESULTS: This was a retrospective, single-center cohort study of female patients with HF with reduced ejection fraction, left ventricular assist devices (LVADs), and heart transplants who were seen in the adult advanced HF outpatient clinics. Patients were identified in the electronic health care record system, and records were reviewed to assess for documentation of contraception and pregnancy counseling. We identified 156 women of childbearing age (aged >18 to <45), seen in the HF clinics between 2018 and 2023. Patients were subdivided by their most recent diagnosis and therapy: HF with reduced ejection fraction (83 [53.2%]), LVAD (18 [11.5%]), and heart transplant (55 [35.3%]). Contraception was documented for 74% of women with HF, 56% of women with LVAD, and 85% of women with heart transplants. Pregnancy counseling was documented for 18.00% of women with HF, 0.06% of women with LVAD, and 29.00% of women with heart transplants. CONCLUSIONS: In our study, many women with HF, LVAD, or transplant have documented contraceptive therapy; however, pregnancy counseling seems to be limited. This vital aspect of medical care should be available for all patients given potential pregnancy-associated risks.
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Anticoncepção , Insuficiência Cardíaca , Centros de Atenção Terciária , Humanos , Feminino , Insuficiência Cardíaca/terapia , Estudos Retrospectivos , Adulto , Centros de Atenção Terciária/tendências , Gravidez , Pessoa de Meia-Idade , Anticoncepção/métodos , Aconselhamento/métodos , Adulto Jovem , Comportamento Contraceptivo/estatística & dados numéricos , Estudos de Coortes , AdolescenteRESUMO
Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. Methods: Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous LoF or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not complement. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring +/+, DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the DN/DN or the LoF/LoF lines. While the same pathways are affected, only about one-third of the differentially expressed genes are common to these homozygote datasets, indicating that AFF3 LoF and DN variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
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BACKGROUND: The Acquisition of Data for Outcomes and Procedure Transfer (ADOPT) program was established by SAGES to develop and expand individual surgeon's comfort with specific, complex operations using hands-on teaching and longitudinal mentoring. The 2022-2023 Foregut (Dominating the Hiatus) section of the course focused on hiatal hernia dissection and gastric fundoplication techniques. Our aim was to describe the experience of surgeons who participated in the course. METHODS: The hands-on component occurred in March 2022 at the SAGES annual meeting. Each expert mentor was matched to two participants. The mentors guided the surgeons through steps of a laparoscopic paraesophageal (PEH) hernia repair and fundoplication using a cadaveric model. Afterwards, monthly group webinars occurred and participants could receive individual coaching from their assigned mentor for a year. Each participant was given a pre-course survey with 3 and 12-month follow-up questionnaires. RESULTS: The majority of the 16 participants were employed in non-academic settings (87.5%). Years in practice ranged from 1 to 26, and 69% completed a fellowship. 100% completed the pre-course survey, and 53.8% responded to the 12-month post-course survey. Participant-reported effectiveness in performing a PEH hernia repair with fundoplication increased from 37.5% pre-course to 85.7% by the conclusion of the course. Confidence levels for the six core steps of the operation also increased: pre-course only 56-75% were confident with each step, this improved to 100% in four out of six steps. 85.7% said the course has changed their practice. DISCUSSION: Since inception, the ADOPT program has aimed to provide expert instruction for practicing surgeons to learn new techniques or improve their confidence in performing operations. The data for the 2022 ADOPT Foregut course shows that 1 year of participation made a positive impact on these surgeons' practices. This helps to fill in the learning gap that occurs after formal surgical training ends.
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Hérnia Hiatal , Laparoscopia , Cirurgiões , Humanos , Cirurgiões/educação , Laparoscopia/educação , Herniorrafia/métodos , Fundoplicatura/métodos , Hérnia Hiatal/cirurgiaRESUMO
Background and Objectives: To report the genetic etiologies of Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), and distal muscular dystrophy (DD) in 6 geographically defined areas of the United States. Methods: This was a cross-sectional, population-based study in which we studied the genes and variants associated with muscular dystrophy in individuals who were diagnosed with and received care for EDMD, LGMD, CMD, and DD from January 1, 2008, through December 31, 2016, in the 6 areas of the United States covered by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Variants of unknown significance (VUSs) from the original genetic test reports were reanalyzed for changes in interpretation. Results: Among 243 individuals with definite or probable muscular dystrophy, LGMD was the most common diagnosis (138 cases), followed by CMD (62 cases), DD (22 cases), and EDMD (21 cases). There was a higher proportion of male individuals compared with female individuals, which persisted after excluding X-linked genes (EMD) and autosomal genes reported to have skewed gender ratios (ANO5, CAV3, and LMNA). The most common associated genes were FKRP, CAPN3, ANO5, and DYSF. Reanalysis yielded more definitive variant interpretations for 60 of 144 VUSs, with a mean interval between the original clinical genetic test of 8.11 years for all 144 VUSs and 8.62 years for the 60 reclassified variants. Ten individuals were found to have monoallelic pathogenic variants in genes known to be primarily recessive. Discussion: This study is distinct for being an examination of 4 types of muscular dystrophies in selected geographic areas of the United States. The striking proportion of resolved VUSs demonstrates the value of periodic re-examinations of these variants. Such re-examinations will resolve some genetic diagnostic ambiguities before initiating repeat testing or more invasive diagnostic procedures such as muscle biopsy. The presence of monoallelic pathogenic variants in recessive genes in our cohort indicates that some individuals with muscular dystrophy continue to face incomplete genetic diagnoses; further refinements in genetic knowledge and diagnostic approaches will optimize diagnostic information for these individuals.
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A 31-year-old woman with a mechanical aortic valve for congenital aortic stenosis presented to the cardiology clinic for preconception counseling. After experiencing an acute stroke 4 weeks prior, she was subsequently discovered to have prosthetic valve thrombosis requiring replacement of the aortic valve. We discuss her clinical course and preconception considerations.
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Adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, encoding for the adrenoleukodystrophy protein (ALDP), leading to defective peroxisomal ß-oxidation of very long-chain and branched-chain fatty acids (VLCFA). ALD manifests in both sexes with a spectrum of phenotypes, but approximately 35% of affected males develop childhood cerebral adrenoleukodystrophy (CCALD), which is lethal without hematopoietic stem cell transplant performed before symptoms start. Hence, ALD was added to the Recommended Uniform Screening Panel after the successful implementation in New York State (2013-2016). To date, thirty-five states have implemented newborn screening (NBS) for ALD, and a few programs have reported on the successes and challenges experienced. However, the overall impact of NBS on early detection of ALD has yet to be fully determined. Here, we conducted a retrospective analysis of VLCFA testing performed by our reference laboratory (ARUP Laboratories, Salt Lake City, UT, USA) over 10 years. Rate of detection, age at diagnosis, and male-to-female ratio were evaluated in patients with abnormal results before and after NBS implementation. After NBS inclusion, a significant increase in abnormal results was observed (471/6930, 6.8% vs. 384/11,670, 3.3%; p < 0.0001). Patients with ALDP deficiency identified via NBS were significantly younger (median age: 30 days vs. 21 years; p < 0.0001), and males and females were equally represented. ALD inclusion in NBS programs has increased pre-symptomatic detection of this disease, which is critical in preventing adrenal crisis as well as the severe cerebral form.
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OBJECTIVE: Determine locoregional diagnostic yield of 4-site screening (head, neck, chest, and abdomen) to diagnose metastatic disease or clinically significant comorbid diseases in dogs with oral cancer. ANIMALS: 381 dogs with histologically confirmed oral tumors. METHODS: Medical records from 381 dogs with histologically confirmed oral tumors that underwent preoperative screening were retrospectively reviewed. RESULTS: Skull and neck CT scan was performed on 348 patients. Bone lysis was present in 74.4% of tumors. Oral squamous cell carcinoma, sarcomas, and T2-T3 (> 2 cm) tumors had a significantly (P < .05) increased incidence of lysis compared to odontogenic and T1 (< 2 cm) tumors, respectively. Minor incidental findings were present in 60.6% of CT scans. Major incidental findings were found in 4.6% of scans. The risk of diagnosing an incidental finding increased by 10% and 20% per year of age for minor and major findings, respectively. Lymph node metastasis was diagnosed with CT or cytology in 7.5% of cases (10.7% of nonodontogenic tumors, 0% of odontogenic tumors). Oral malignant melanoma, oral squamous cell carcinoma, and T3 tumors had the highest prevalence of metastatic disease at the time of staging. The presence of bone lysis was not associated with cervical metastasis. CLINICAL RELEVANCE: Major incidental findings were rare (< 5%) but primarily included secondary extraoral tumors. Lymphatic metastasis was diagnosed in 10.7% of nonodontogenic tumors, but cytology was not performed in the majority of cases and often included only a single mandibular node. Therefore, these results likely underestimate the incidence of lymphatic metastasis. Guided lymph node sampling is highly recommended, especially for oral malignant melanoma, squamous cell carcinoma, and T2-T3 tumors.
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Carcinoma de Células Escamosas , Doenças do Cão , Neoplasias de Cabeça e Pescoço , Melanoma , Neoplasias Bucais , Humanos , Cães , Animais , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/veterinária , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/veterinária , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/veterinária , Metástase Linfática , Estudos Retrospectivos , Estadiamento de Neoplasias , Detecção Precoce de Câncer , Melanoma/veterinária , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/veterinária , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/patologia , Melanoma Maligno CutâneoRESUMO
OBJECTIVE: Determine diagnostic yield of chest, abdomen, and 4-site screening to diagnose metastatic disease and secondary diseases of prognostic significance in dogs with oral cancer. SAMPLE: Medical records from 381 dogs with histologically confirmed oral tumors that underwent preoperative screening were retrospectively reviewed. RESULTS: Thoracic metastasis was diagnosed in 4.9% (0.9% odontogenic, 6.5% nonodontogenic) of oral tumors. Oral malignant melanoma and multilobular osteochondrosarcoma were most at risk. Abdominal metastasis was diagnosed in 2% of oral tumors (0% odontogenic, 3.1% nonodontogenic) and cytologically confirmed in 2 cases (0.6% [2/295)] of all abdominal ultrasounds (AUS) 5.5% [2/36] of all AUS that had cytology). Both cases had oral malignant melanoma. Incidental disease was diagnosed in 53.1% and 81.3% of thoracic and abdominal screenings, respectively. Major findings were more common in AUS (7.8%) compared to thoracic screening (1.9%). The prevalence of incidental findings was similar for odontogenic and nonodontogenic tumors. Both metastasis and major findings were diagnosed more commonly with thoracic CT compared to radiographs. Metastasis or a major finding of prognostic significance was diagnosed in at least 1 test in 27.8% of patients that had head CT, lymph node cytology, thoracic screening, and AUS (n = 115). CLINICAL RELEVANCE: Major incidental findings were more commonly detected with AUS and were diagnosed in 1 in every 12 patients. However, metastatic disease was most commonly detected with thoracic screening. When all 4 screening tests are performed, there is an approximately 1 in 4 chance of diagnosing metastasis or major significant disease regardless of tumor type.
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Doenças do Cão , Melanoma , Neoplasias Bucais , Humanos , Cães , Animais , Estudos Retrospectivos , Estadiamento de Neoplasias , Detecção Precoce de Câncer , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/veterinária , Neoplasias Bucais/patologia , Melanoma/veterinária , Linfonodos/patologia , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/patologia , Melanoma Maligno CutâneoRESUMO
The case of a 67-year-old man who presented for elective gastroenterology procedures and was in atrial fibrillation is discussed. Transthoracic echocardiography revealed a large atrial mass. Preoperative coronary angiography revealed a heavily vascularized mass. Use of cardiac magnetic resonance identified the cardiac mass as likely an atrial myxoma. (Level of Difficulty: Beginner.).
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PURPOSE: Simulation-based education (SBE) provides experiential learning, improvement in quality of care, and reduction in errors. In 2011, the Association of American Medical Colleges described adoption of SBE in 68.0% of medical schools and 25.0% of teaching hospitals. We sought to examine current trends of SBE integration in American undergraduate medical education since previous publications. METHODS: From 2016 to 2019, University of Texas Southwestern Medical Center postgraduate year 1 residents were invited to participate in a survey assessing medical school simulation experience with 26 clinical tasks from three categories: procedural, communication, and other. Deidentified results were analyzed to assess demographics including sex, specialty, residency program type, allopathic versus osteopathic medical school, and medical school region. RESULTS: Nine hundred sixty-seven of 1047 (92.3%) responses were obtained, representing 139 US medical schools, 91% from allopathic training. Of procedural tasks, most simulated was suturing (n = 848, 89.6%) and least simulated was thoracentesis (n = 737, 80.9%). Of communication tasks, most simulated was taking a history (n = 475, 51.1% reporting simulation >30) and least simulated (never or ≤1) were obtaining a consent (n = 669, 73.2%) and disclosing a medical error (n = 666, 72.4%). Of other tasks, most simulated was chest compressions (n = 898, 96.0%) and least simulated was operating a defibrillator (n = 206, 22.1%). Results were similar regardless of procedural or nonprocedural program. There was no significant difference in SBE exposure between allopathic and osteopathic students ( P = 0.89). Two participants (0.002%) reported no simulation exposure. CONCLUSIONS: Our study is the first to describe a high prevalence of SBE adoption in medical schools nationwide since the Association of American Medical Colleges' 2011 publication, with overall equal exposure for students regardless of residency type and allopathic or osteopathic medical school. Despite widespread adoption of simulation, opportunities remain to expand SBE use to teach critically important communication skills.
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Educação de Graduação em Medicina , Internato e Residência , Medicina Osteopática , Humanos , Estados Unidos , Educação de Graduação em Medicina/métodos , Medicina Osteopática/educação , Inquéritos e Questionários , Faculdades de MedicinaRESUMO
Objectives: Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is a recently described autosomal recessive leukoencephalopathy caused by pathogenic variants in the SLC13A3 gene. ARLIAK is characterized by acute neurologic involvement, often precipitated by febrile illness, with largely reversible clinical symptoms and imaging findings. Three patients have been reported in the literature to date. Our objective is to report newly identified patients and their genetic variants and phenotypes and review published literature on ARLIAK. Methods: This report contributes 4 additional patients to the literature; describes novel variants in SLC13A3; and reviews genetic, biochemical, clinical, and radiologic features of all published patients with ARLIAK. Results: We provide additional genetic, imaging, and laboratory insights into ARLIAK, an atypical leukodystrophy with clinical and radiologic findings that can normalize. Discussion: Our case series highlights the importance of reanalysis of next-generation sequencing in the diagnostic workup.
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DNMT1 maintains the parental DNA methylation pattern on newly replicated hemimethylated DNA. The failure of this maintenance process causes aberrant DNA methylation that affects transcription and contributes to the development and progression of cancers such as acute myeloid leukemia. Here, we structurally characterized a set of newly discovered DNMT1-selective, reversible, non-nucleoside inhibitors that bear a core 3,5-dicyanopyridine moiety, as exemplified by GSK3735967, to better understand their mechanism of inhibition. All of the dicyanopydridine-containing inhibitors examined intercalate into the hemimethylated DNA between two CpG base pairs through the DNA minor groove, resulting in conformational movement of the DNMT1 active-site loop. In addition, GSK3735967 introduces two new binding sites, where it interacts with and stabilizes the displaced DNMT1 active-site loop and it occupies an open aromatic cage in which trimethylated histone H4 lysine 20 is expected to bind. Our work represents a substantial step in generating potent, selective, and non-nucleoside inhibitors of DNMT1.
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DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , Sítios de Ligação , Domínio Catalítico , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferases/química , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismoRESUMO
DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia.
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Azacitidina , Leucemia Mieloide Aguda , Animais , Azacitidina/farmacologia , DNA/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/genética , Decitabina/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , CamundongosRESUMO
BACKGROUND: Artificial Intelligence (AI) is making a continuous progression into the field of Radiation Oncology in Canada and globally. While this field continues to evolve, there is no clear understanding about how radiation oncologists, radiation therapists, medical physicists and radiation trainees perceive AI and its' impact on radiation oncology as a discipline. The purpose of this study was to investigate the perception of these four Canadian professional groups about AI. and how AI will affect radiation oncology as a specialty. METHODS: Following an in-depth scientific review of the existing literature, a 29 Likert-scale questionnaire was developed using Google Survey. The questionnaire was piloted and distributed through national organizations including the Canadian Association for Radiation Oncology (CARO), the Canadian Association of Medical Radiation Therapy (CAMRT) and the Canadian Organization of Medical Physicists (COMP), initially in February, and again between March and June 2020. The results were analyzed using descriptive statistics. RESULTS: 159 responses were received from 10 Canadian provinces. Knowledge about AI was moderate with an average of 5/10, but 91% responded interest in learning more about it. The negative implications of AI were related to fear of losing jobs and shift of practice. The majority of participants agreed AI would positively impact on patient treatment. CONCLUSION: Radiation oncology professionals believe AI will be an important part of patient treatment in their future practices. The fear about AI may be mitigated with further education programs about AI, which can gain more confidence in the acceptance of AI.