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The design of three-dimensional (3D) scaffolds should focus on creating highly porous, 3D structures with an interconnected pore network that supports cell growth. The scaffold's pore interconnectivity is directly linked to vascularization, cell seeding, guided cell migration, and transportation of nutrients and metabolic waste. In this study, different types of food flavors including monosodium glutamate, sugar, and sodium chloride were used as the porogens along with PCL/PVP blend polymer for solvent casting/particulate leaching method. The morphology, porosity, interconnectivity, chemical composition, water absorption, and mechanical properties of the fabricated scaffolds are carefully characterized. The scaffolds are biocompatible in bothin vitroandin vivoexperiments and do not trigger any inflammatory response while enhancing new bone formation and vascularization in rabbit calvaria critical-sized defects. The new bone merges and becomes denser along with the experiment timeline. The results indicate that the 3D PCL/PVP scaffolds, using monosodium glutamate as porogen, exhibited suitable biological performance and held promise for bone tissue engineering in oral and maxillofacial surgery.
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Materiais Biocompatíveis , Glutamato de Sódio , Solventes , Engenharia Tecidual , Alicerces Teciduais , Animais , Alicerces Teciduais/química , Coelhos , Engenharia Tecidual/métodos , Porosidade , Solventes/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Poliésteres/química , Teste de Materiais , Crânio/efeitos dos fármacos , Polivinil/química , Regeneração Óssea/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Substitutos Ósseos/química , Substitutos Ósseos/farmacologia , Osso e Ossos/metabolismoRESUMO
BACKGROUND: Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly. METHODS: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members. RESULTS: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. Remarkably, the variant was absent in unaffected individuals within the pedigree, underscoring its association with the polydactyly phenotype. Computational analyses revealed that GLI3 p.Gln494His impacts a residue that is highly conserved across species. CONCLUSION: The GLI3 zinc finger DNA-binding region is an essential part of the Sonic hedgehog signaling pathway, orchestrating crucial aspects of embryonic development through the regulation of target gene expression. This novel finding not only contributes valuable insights into the molecular pathways governing polydactyly during embryonic development but also has the potential to enhance diagnostic and screening capabilities for this condition in clinical settings.
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Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso , Linhagem , Polidactilia , Proteína Gli3 com Dedos de Zinco , Humanos , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismo , Polidactilia/genética , Polidactilia/patologia , Masculino , Feminino , Proteínas do Tecido Nervoso/genética , Dedos de Zinco/genética , Fatores de Transcrição Kruppel-Like/genética , Dedos/anormalidades , Heterozigoto , População do Sudeste AsiáticoRESUMO
Background and Objectives: This study presents results from a survey of physicians performing electrodiagnostic studies to assess average volume. We also assessed how different factors (trainees, technologists, age of the physician, and case complexity) affected volume. Productivity is an important factor for physicians across practice settings. However, unlike evaluation and management services for neurologists, there are no published data for benchmarks of average volume of electrodiagnostic studies. Methods: A 34-question survey was designed collecting information on demographics, electrodiagnostic study volume, technologists, trainees, referrals, and case complexity. The anonymous survey was disseminated through a QR code or hyperlink to multiple online neurology, physical medicine and rehabilitation, electromyography, and neuromuscular forums. The primary outcome was EMG volume including number of EMGs per half-day and EMG volume per year. We conducted bivariate association analysis between primary outcomes and respondent characteristics using the Pearson χ2 test. Multivariable regression models determined factors associated with each of our outcome variables. Results: A total of 201 respondents initiated the survey. 71% were certified in adult neurology, 19.6% in physical medicine and rehabilitation, and 2.7% in pediatric neurology. 37.5% practiced in academic medicine. The remaining respondents were from private practice, group, solo, hospital employed, or other. 83% of respondents allotted a dedicated half-day to performing EMGs. The median number of EMGs scheduled during a half-day was within 3-4 (45%). 30% and 7% scheduled 5-6 or more than 7 patients per half-day, respectively. The median number of EMGs performed per year was within 251-500 (37%). Discussion: This national, cross-sectional survey evaluates average metrics of EMG volume. Our survey showed that the median number of EMGs annually lies between 251 and 500 studies (37%). In addition, for those respondents who allotted a dedicated half-day to performing EMGs, the median number of EMG studies scheduled per half-day lies between 3 and 4 studies (45%). In multivariate analysis, respondent characteristics of age of the physician (older than 45), working with nerve conduction technologists, and holding the position of EMG director were associated with increased EMG volume.
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Obesity is associated with chronic low-level inflammation and is known to contribute to metabolic dysfunction and hypogonadotropic hypogonadism, which we have previously termed the 'Reprometabolic Syndrome.' To investigate potential factors involved in obesity-related reproductive endocrine dysfunction, we conducted a secondary analysis of inflammatory markers in a sample of normal weight women exposed to a one-month eucaloric high-fat diet (HFD), which, as reported earlier, induced the relative hypogonadotropic hypogonadism characteristic of Reprometabolic Syndrome. Eighteen healthy women with a BMI between 18.0-24.9 kg/m2 and regular menstrual cycles participated in the study. Frequent blood sampling was performed during the early follicular phase before and after the one-month eucaloric HFD intervention (48% of calories from fat). Serum samples pooled from each participant were analyzed using immunoassay to measure levels of 30 cytokines, interleukins, and chemokines. Differences between pre- and post-HFD intervention measures were examined by one-sample t-tests. Exposure to the eucaloric HFD did not result in changes in body weight. HFD-induction of Reprometabolic Syndrome in normal weight women was associated with a significant elevation only in the anti- inflammatory cytokine IL-10 (p = 0.04). Eotaxin, IL-6 and MIP-1ß also increased in response to the HFD, but not statistically significantly (p = 0.07). Results suggest that the increase in multiple inflammatory markers, typically associated with obesity, are not primary mediators of the relative hypogonadotropic hypogonadism of Reprometabolic Syndrome. Clinical Trials Registration Number: NCT02653092; Date of Registration: January 6, 2016.
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Background and objective: Prior studies reveal that invited speaker panels, editorial boards, authors of practice guidelines, and senior authors of published articles are disproportionately male in the neurology field. We aimed to analyze a gender gap in authorship of accepted abstracts to the American Academy of Neurology annual meetings in 2020 and 2021. Design/methods: This is a cross-sectional study evaluating the proportions of female first and senior abstract authors in 2020 and 2021. Abstracts were reviewed manually (n = 3,211 in 2020; n = 2,178 in 2021). Data were collected regarding the gender of first and senior authors, subspecialties, and origin of research (USA, international, or corporate-affiliated). Then, we compared the percentages of female first and senior authors in the 2 years to assess for any short-term effects of the COVID-19 pandemic. Results: Accepted abstracts with female first and senior authors comprised 46%, 34% in 2020, and the same in 2021, without change. Female senior authors had a significantly higher proportion of female first authors than their male senior author counterparts. The analysis of subspecialties with more than 100 abstracts showed the lowest percentages of female senior authors was oncology (24.7%), sleep (25.5%), headache (28.7%), and cerebrovascular disease (29%) in 2020. Cerebrovascular disease (29%) and behavioral neurology (24.7%) had the lowest percentage of female senior authors in 2021. In the analysis of the origin of research, corporate-affiliated authors had the lowest percentages of female first (34 and 36%) and senior authors (22.6 and 27.6%). Conclusion: The gender gap in neurology was reaffirmed in regards to female senior authorship overall and in subgroups of abstracts including cerebrovascular disease, headache, behavioral neurology, sleep, oncology, and corporate-affiliated research.
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INTRODUCTION: Patients with systemic lupus erythematosus (SLE) bear a significant burden of pain. We aimed to identify factors that distinguish patients with SLE referred to comprehensive pain clinics and those who are not. Characterizing this patient population will identify unmet needs in SLE management and inform efforts to improve pain care in rheumatology. METHODS: Among patients with SLE with ≥2 rheumatology clinic visits in a large hospital system from 1998 to 2023 (n = 1319), we examined factors that distinguished those who had at least one visit to multidisciplinary pain clinics (n = 77, 5.8%) from those who did not have any visits (n = 1242, 94.2%) with a focus on biopsychosocial and socioeconomic characteristics. We extracted demographic data and ICD-9/ICD-10 codes from the EHR. RESULTS: Patients with SLE attending the pain clinics exhibited characteristics including average older age (mean age ± SD: 54.1 ± 17.9 vs. 48.4 ± 19.9), a higher likelihood of relying on public health insurance (50.7% vs. 34.2%), and a greater representation of Black patients (9.1% vs. 4.4%) compared to SLE patients not seen in pain clinics. Nearly all patients seen at the pain clinics presented with at least one chronic overlapping pain condition (96.1% vs. 58.6%), demonstrated a higher likelihood of having a mental health diagnosis (76.7% vs. 42.4%), and exhibited a greater number of comorbidities (mean ± SD: 6.0 ± 3.0 vs. 2.9 ± 2.6) compared to those not attending the pain clinic. CONCLUSION: We found notable sociodemographic and clinical differences between these patient populations. Patients presenting with multiple comorbidities might benefit from further pain screening and referral to pain clinics to provide comprehensive care, and earlier referral could mitigate the development and progression of multimorbidities.
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Lúpus Eritematoso Sistêmico , Clínicas de Dor , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/psicologia , Feminino , Masculino , Pessoa de Meia-Idade , Clínicas de Dor/estatística & dados numéricos , Adulto , Idoso , Manejo da Dor/métodos , Manejo da Dor/estatística & dados numéricos , Manejo da Dor/normas , Dor/epidemiologiaRESUMO
BACKGROUND: Osteoarthritis is a significant cause of disability, resulting in increased joint replacement surgeries and health care costs. Establishing benchmarks that more accurately predict surgical duration could help to decrease costs, maximize efficiency, and improve patient experience. We compared the anesthesia-controlled time (ACT) and surgery-controlled time (SCT) of primary total knee (TKA) and total hip arthroplasties (THA) between an academic medical center (AMC) and a community hospital (CH) for 2 orthopedic surgeons. OBJECTIVE: This study aims to validate and compare benchmarking times for ACT and SCT in a single patient population at both an AMC and a CH. METHODS: This retrospective 2-center observational cohort study was conducted at the University of Colorado Hospital (AMC) and UCHealth Broomfield Hospital (CH). Cases with current procedural terminology codes for THA and TKA between January 1, 2019, and December 31, 2020, were assessed. Cases with missing data were excluded. The primary outcomes were ACT and SCT. Primary outcomes were tested for association with covariates of interest. The primary covariate of interest was the location of the procedure (CH vs AMC); secondary covariates of interest included the American Society of Anesthesiologists (ASA) classification and anesthetic type. Linear regression models were used to assess the relationships. RESULTS: Two surgeons performed 1256 cases at the AMC and CH. A total of 10 THA cases and 12 TKA cases were excluded due to missing data. After controlling for surgeon, the ACT was greater at the AMC for THA by 3.77 minutes and for TKA by 3.58 minutes (P<.001). SCT was greater at the AMC for THA by 11.14 minutes and for TKA by 14.04 minutes (P<.001). ASA III/IV classification increased ACT for THA by 3.76 minutes (P<.001) and increased SCT for THA by 6.33 minutes after controlling for surgeon and location (P=.008). General anesthesia use was higher at the AMC for both THA (29.2% vs 7.3%) and TKA (23.8% vs 4.2%). No statistically significant association was observed between either ACT or SCT and anesthetic type (neuraxial or general) after adjusting for surgeon and location (all P>.05). CONCLUSIONS: We observed lower ACT and SCT at the CH for both TKA and THA after controlling for the surgeon of record and ASA classification. These findings underscore the efficiency advantages of performing primary joint replacements at the CH, showcasing an average reduction of 16 minutes in SCT and 4 minutes in ACT per case. Overall, establishing more accurate benchmarks to improve the prediction of surgical duration for THA and TKA in different perioperative environments can increase the reliability of surgical duration predictions and optimize scheduling. Future studies with study populations at multiple community hospitals and academic medical centers are needed before extrapolating these findings.
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IMPORTANCE: Weight loss before conception is recommended for women with overweight or obesity to improve fertility outcomes, but evidence supporting this recommendation is mixed. OBJECTIVE: To examine the effectiveness of weight loss interventions using lifestyle modification and/or medication in women with overweight or obesity on pregnancy, live birth, and miscarriage. DATA SOURCES: An electronic search of MEDLINE, Embase, Cochrane Library, including Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature was conducted through July 6, 2022, via Wiley. STUDY SELECTION AND SYNTHESIS: Randomized controlled trials examining weight loss interventions through lifestyle and/or medication in women with overweight or obesity planning pregnancy were included. Random-effects meta-analysis was conducted, reporting the risk ratio (RR) for each outcome. Subgroup analyses were conducted by intervention type, type of control group, fertility treatment, intervention length, and body mass index (BMI). MAIN OUTCOME(S): Clinical pregnancy, live birth, and miscarriage events. RESULT(S): A narrative review and meta-analysis were possible for 16 studies for pregnancy (n = 3,588), 13 for live birth (n = 3,329), and 11 for miscarriage (n = 3,248). Women randomized and exposed to a weight loss intervention were more likely to become pregnant (RR = 1.24, 95% CI 1.07-1.44; I2 = 59%) but not to have live birth (RR = 1.19, 95% CI 0.97-1.45; I2 = 69%) or miscarriage (RR = 1.17, 95% CI 0.79-1.74; I2 = 31%) compared with women in control groups. Subgroup analyses revealed women randomized to weight loss interventions lasting 12 weeks or fewer (n = 9, RR = 1.43; 95% CI 1.13-1.83) and women with a BMI ≥ 35 kg/m2 (n = 7, RR = 1.54; 95% CI, 1.18-2.02) were more likely to become pregnant compared with women in the control groups. Miscarriage was higher in intervention groups who underwent fertility treatment (n = 8, RR 1.45; 95% CI 1.07-1.96). CONCLUSION(S): Pregnancy rates were higher in women undergoing preconception weight loss interventions with no impact on live birth or miscarriage rates. Findings do not support one-size-fits-all recommendation for weight loss through lifestyle modification and/or medication in women with overweight or obesity immediately before conception to improve live birth or miscarriage outcomes.
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Fertilidade , Nascido Vivo , Cuidado Pré-Concepcional , Redução de Peso , Humanos , Feminino , Gravidez , Cuidado Pré-Concepcional/métodos , Resultado do Tratamento , Taxa de Gravidez , Aborto Espontâneo/epidemiologia , Obesidade/terapia , Obesidade/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Infertilidade Feminina/terapiaRESUMO
Low back pain (LBP) significantly affects global health, with associated detrimental outcomes such as physical impairment, emotional distress, and exacerbated mental health symptoms. This study evaluated the representation of marginalized groups, including racialized, gender minority, pregnant/lactating, and elderly individuals in randomized controlled trials for pharmacological interventions treating LBP from 2011 to 2020. We searched Embase, MEDLINE, and CINAHL in December 2021, and 139 studies were eligible. Most trials (n = 113, 81%) reported participant sex; however, no study collected data on sexual and gender minorities, and the majority (n = 99, 71%) excluded pregnant/lactating individuals. Most trials (n = 105, 76%) reported no data on participant race or ethnicity. We limited within-country analyses of race and ethnicity to US-based trials because US-based trials were more likely to report race and/or ethnicity (48%) compared to non-US-based trials (8%). Black participants were the only racialized group whose composition was comparable to US Census estimates. About half (n = 73, 53%) of all trials had an upper age limit for eligibility (range: 40-85 years old) and 24% (n = 33) excluded adults aged >65 years. Our findings confirm that trials for pharmacological LBP interventions underreport demographic data, and the trials that include this data have unrepresentative samples. There is an urgent need for more inclusive and representative patient samples to ensure generalizability and equitable benefits. Standardizing demographic data reporting and integrating community-based participatory research methods can help foster inclusive research practices. This review was registered with prospective register of systematic reviews (PROSPERO), ID 296017. PERSPECTIVE: This systematic review investigates patient representation in pharmacological-based clinical trials for low back pain, LBP, the most prevalent pain condition worldwide. Improvements in reporting demographic data and recruiting diverse participant populations-across different racialized, gender and sexual minority, and age groups-will help clinical research generalizability and provide equitable benefits.
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Dor Lombar , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Dor Lombar/tratamento farmacológico , Seleção de PacientesRESUMO
OBJECTIVE: The aim of this study was to investigate and compare different case definitions for chronic pain to provide estimates of possible misclassification when researchers are limited by available electronic health record and administrative claims data, allowing for greater precision in case definitions. METHODS: We compared the prevalence of different case definitions for chronic pain (N = 3042) in patients with autoimmune rheumatic diseases. We estimated the prevalence of chronic pain based on 15 unique combinations of pain scores, diagnostic codes, analgesic medications, and pain interventions. RESULTS: Chronic pain prevalence was lowest in unimodal pain phenotyping algorithms: 15% using analgesic medications, 18% using pain scores, 21% using pain diagnostic codes, and 22% using pain interventions. In comparison, the prevalence using a well-validated phenotyping algorithm was 37%. The prevalence of chronic pain also increased with the increasing number (bimodal to quadrimodal) of phenotyping algorithms that comprised the multimodal phenotyping algorithms. The highest estimated chronic pain prevalence (47%) was the multimodal phenotyping algorithm that combined pain scores, diagnostic codes, analgesic medications, and pain interventions. However, this quadrimodal phenotyping algorithm yielded a 10% overestimation of chronic pain compared to the well-validated algorithm. CONCLUSION: This is the first empirical study to our knowledge that shows that established common modes of phenotyping chronic pain can lead to substantially varying estimates of the number of patients with chronic pain. These findings can be a reference for biases in case definitions for chronic pain and could be used to estimate the extent of possible misclassifications or corrections in using datasets that cannot include specific data elements.
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Doenças Autoimunes , Dor Crônica , Reumatologia , Humanos , Dor Crônica/diagnóstico , Dor Crônica/epidemiologia , Registros Eletrônicos de Saúde , Algoritmos , AnalgésicosRESUMO
Fruit trees and other fruiting hardwood perennials are economically valuable, and there is interest in developing improved varieties. Both conventional breeding and biotechnology approaches are being utilized towards the goal of developing advanced cultivars. Increased knowledge of the effectiveness and efficiency of biotechnology approaches can help guide use of the CRISPR gene-editing technology. Here, we examined CRISPR-Cas9-directed genome editing in the valuable commodity fruit tree Malus x domestica (domestic apple). We transformed two cultivars with dual CRISPR-Cas9 constructs designed to target two AGAMOUS-like genes simultaneously. The main goal was to determine the effectiveness of this approach for achieving target gene changes. We obtained 6 Cas9 control and 38 independent CRISPR-Cas9 events. Of the 38 CRISPR-Cas9 events, 34 (89%) had gene edits and 14 (37%) showed changes to all alleles of both target genes. The most common change was large deletions, which were present in 59% of all changed alleles, followed by small deletions (21%), small insertions (12%), and a combination of small insertions and deletions (8%). Overall, a high rate of successful gene alterations was found. Many of these changes are predicted to cause frameshifts and alterations to the predicted peptides. Future work will include monitoring the floral development and floral form.
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BACKGROUND: There is minimal data of health outcomes for Type 1 Diabetes (T1D) in Southeast Asia (SEA) where government funding of insulin and blood glucose monitoring either do not exist or is limited. The full impact of Covid-19 pandemic on the national economies of SEA remain unknown. In the midst of the pandemic, in 2021, HelloType1 was developed by Action4Diabetes (A4D), a non-government organisation charity in collaboration with Southeast Asia local healthcare professionals as an innovative digital educational resource platform of T1D in local languages. HelloType1 was launched in Cambodia, Vietnam, Thailand and Malaysia in 2021 to 2022 with Memorandums of Understandings (MOUs) signed between A4D and each country. Internet data analytics were undertaken between the 1st of January 2022 to 31st of December 2022. AIMS: The aims of this study were to explore the usability and internet data analytics of the HelloType1 online educational platform within each country. METHODS: The data analytics were extracted Google analytics that tracks data from the website hellotype1.com and Facebook analytics associated with the website. RESULTS: There was a 147% increase in the number of HelloType1 users between the first 6 months versus the latter 6 months in 2022 and a 15% increase in the number of pages visited were noted. The majority of traffic source were coming from organic searches with a significant increase of 80% growth in 2022. CONCLUSIONS: The results of the analytics provide important insights on how an innovative diabetes digital educational resource in local languages may be optimally delivered in low-middle income countries with limited resources.
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Diabetes Mellitus Tipo 1 , Internet , Humanos , Sudeste Asiático/epidemiologia , Glicemia , Automonitorização da Glicemia , Atenção à Saúde , Diabetes Mellitus Tipo 1/epidemiologia , Pandemias , Educação de Pacientes como AssuntoRESUMO
Objectives: It is uncertain whether concurrent mitral valve repair or replacement for moderate or greater secondary mitral regurgitation at the time of coronary artery bypass graft or aortic valve replacement surgery improves long-term survival. Methods: Patients undergoing coronary artery bypass graft and/or aortic valve replacement surgery with moderate or greater secondary mitral regurgitation were reviewed. The effect of concurrent mitral valve repair or replacement upon long-term mortality was assessed while accounting for patient and operative characteristics and mitral regurgitation severity. Results: Of 1,515 patients, 938 underwent coronary artery bypass graft or aortic valve replacement surgery alone and 577 underwent concurrent mitral valve repair or replacement. Concurrent mitral valve repair or replacement did not alter the risk of postoperative mortality for patients with moderate mitral regurgitation (hazard ratio = 0.93; 0.75-1.17) or more-than-moderate mitral regurgitation (hazard ratio = 1.09; 0.74-1.60) in multivariable regression. Patients with more-than-moderate mitral regurgitation undergoing coronary artery bypass graft-only surgery had a survival advantage from concurrent mitral valve repair or replacement in the first two postoperative years (P = 0.028) that did not persist beyond that time. Patients who underwent concurrent mitral valve repair or replacement had a higher rate of later mitral valve operation or reoperation over the five subsequent years (1.9% vs. 0.2%; P = 0.0014) than those who did not. Conclusions: These observations suggest that mitral valve repair or replacement for more-than-moderate mitral regurgitation at the time of coronary artery bypass grafting may be reasonable in a suitably selected coronary artery bypass graft population but not for aortic valve replacement, with or without coronary artery bypass grafting. Our findings are supportive of 2021 European guidelines that severe secondary mitral regurgitation "should" or be "reasonabl[y]" intervened upon at the time of coronary artery bypass grafting but do not support 2020 American guidelines for performing mitral valve repair or replacement concurrent with aortic valve replacement, with or without coronary artery bypass grafting.
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Acute myeloid leukemia (AML) is the most aggressive hematopoietic malignancy characterized by uncontrolled proliferation of myeloid progenitor cells within the bone marrow. Tumor suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme, which suppresses inflammatory response in macrophages. Macrophages have a central role in the defense against foreign substances and circulating cancer cells by their professional phagocytic capacity. Little is known about contributions of CYLD to changes in biological properties of human macrophages and its involvement in AML. The present study, therefore, explored whether macrophage functions in healthy individuals and AML patients are influenced by CYLD. To this end, ninety-two newly diagnosed AML patients and 80 healthy controls were recruited. The mRNA expression levels of inflammation-related genes were evaluated by real-time PCR, cell maturation, phagocytosis and apoptosis assays by flow cytometry and secretion of inflammatory cytokines by ELISA. As a result, AML patients with the low CYLD expression were significantly higher in M4/M5 than other subtypes according to the FAB type. The low CYLD expression was also closely associated with older patients and enhanced level of LDH in AML. Moreover, treatment of normal macrophages with CYLD siRNA enhanced activation of STAT-1, leading to increases in expressions of maturation markers and IL-6 production as well as suppression in cell apoptosis and phagocytosis, while macrophage phagocytosis from AML M4/M5b was higher than that from healthy controls upon CYLD siRNA transfection through STAT1 signalling. In conclusion, the inhibitory effects of CYLD on macrophage functions are expected to affect the immune response in AML.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Macrófagos/metabolismo , Citocinas/metabolismo , Fagocitose , RNA Interferente Pequeno , Enzima Desubiquitinante CYLD/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismoRESUMO
Male infertility is a growing health problem, which affects approximately 7% of the global male population. Nonobstructive azoospermia (NOA) is one of the most severe forms of male infertility caused by genetic defects, including chromosome structural abnormalities, Y chromosome microdeletions, or single-gene alterations. However, the etiology of up to 40% of NOA cases is unidentified. By whole-exome sequencing, we detected a homozygous 5-bp-deletion variant in exon 4 of the TEX12 gene (c.196-200del, p.L66fs, NM_031275.4) in two brothers with NOA of a nonconsanguineous Vietnamese family. This deletion variant of 5 nucleotides (ATTAG) results in a premature stop codon in exon 4 and truncation of the C-terminal. Segregation analysis by Sanger sequencing confirmed that the deletion variant was inherited in an autosomal recessive pattern. The 1st and 3rd infertile sons were homozygous for the deletion, whereas the 2nd fertile son and both parents were heterozygous. The new deletion mutation identified in TEX12 gene caused loss of function of TEX12 gene. The loss of TEX12 function has already caused infertility in male mice. Therefore, we concluded that the loss of TEX12 function may cause infertility in men. To our knowledge, this is the first case reported so far indicating disruption of human TEX12, which leads to infertility in men.
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Azoospermia , Infertilidade Masculina , Humanos , Masculino , Animais , Camundongos , Azoospermia/genética , Irmãos , Infertilidade Masculina/genética , HomozigotoRESUMO
Pediatric solid and central nervous system tumors are the leading cause of cancer-related death among children. Identifying new targeted therapies necessitates the use of pediatric cancer models that faithfully recapitulate the patient's disease. However, the generation and characterization of pediatric cancer models has significantly lagged behind adult cancers, underscoring the urgent need to develop pediatric-focused cell line resources. Herein, we establish a single-site collection of 261 cell lines, including 224 pediatric cell lines representing 18 distinct extracranial and brain childhood tumor types. We subjected 182 cell lines to multi-omics analyses (DNA sequencing, RNA sequencing, DNA methylation), and in parallel performed pharmacological and genetic CRISPR-Cas9 loss-of-function screens to identify pediatric-specific treatment opportunities and biomarkers. Our work provides insight into specific pathway vulnerabilities in molecularly defined pediatric tumor classes and uncovers biomarker-linked therapeutic opportunities of clinical relevance. Cell line data and resources are provided in an open access portal.
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Neoplasias Encefálicas , Criança , Humanos , Neoplasias Encefálicas/patologia , Linhagem Celular TumoralRESUMO
Background: In Asia, diabetes-associated death due to cardiorenal diseases were 2-3 times higher in women than men which might be due to gender disparity in quality of care and health habits. Methods: Adults with type 2 diabetes (T2D) from 11 Asian countries/areas were assessed using the same protocol (2007-2015). We compared treatment target attainment (HbA1c < 7%, blood pressure [BP] < 130/80 mmHg, risk-based LDL-cholesterol, lack of central obesity [waist circumference <90 cm in men or <80 cm in women), use of cardiorenal-protective drugs (renin-angiotensin system [RAS] inhibitors, statins), and self-reported health habits including self-monitoring blood glucose (SMBG) by gender. Analyses were stratified by countries/areas, age of natural menopause (<50 vs. ≥50 years), and comorbidities (atherosclerotic cardiovascular disease [ASCVD], heart failure, kidney impairment [eGFR < 60 mL/min/1.73 m2]). Findings: Among 106,376 patients (53.2% men; median (interquartile range) diabetes duration: 6.0 (2.0-12.0) years; mean ± SD HbA1c 8.0 ± 1.9%; 27% insulin-treated), women were older and less likely to receive college education than men (28.9% vs. 48.8%). Women were less likely to smoke/drink alcohol and were physically less active than men. Women had lower BP (<130/80 mmHg: 29.4% vs. 25.7%), less general obesity (54.8% vs. 57.8%) but more central obesity than men (77.5% vs. 57.3%). Women were less likely to have ASCVD (12.8% vs. 17.0%) or heart failure (1.3% vs. 2.3%), but more likely to have kidney impairment (22.3% vs. 17.6%) and any-site cancer than men (2.5% vs. 1.6%). In most countries/areas, more men attained HbA1c <7% and risk-based LDL-cholesterol level than women. After adjusting for potential confounders including countries and centres, men had 1.63 odds ratio (95% CI 1.51, 1.74) of attaining ≥3 treatment targets than women. Interpretation: Asian women with T2D had worse quality of care than men especially in middle-income countries/areas, calling for targeted implementation programs to close these care gaps. Sponsor: Asia Diabetes Foundation. Funding: Nil.
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PURPOSE: Small cell lung cancer (SCLC) is one of the malignant cancers with aggressive progression and poor prognosis. Bronchoalveolar lavage fluid (BALF) has been arising recently as a potential source of biomarkers for lung cancers. In this study, we performed quantitative BALF proteomic analysis to identify potential biomarkers for SCLC. EXPERIMENTAL DESIGN: BALF were collected from tumor-bearing lungs and non-tumor lungs of five SCLC patients. Then, BALF proteomes were prepared for a TMT-based quantitative mass spectrometry analysis. Differentially expressed proteins (DEP) were identified when considering individual variation. Potential SCLC biomarker candidates were validated by immunohistochemistry (IHC). A public database of multiple SCLC cell lines was used to evaluate the correlation of these markers with SCLC subtypes and chemo-drug responses. RESULTS: We identified 460 BALF proteins in SCLC patients and observed considerable individual variation among the patients. Immunohistochemical analysis and bioinformatics resulted in the identification of CNDP2 and RNPEP as potential subtype markers for ASCL1 and NEUROD1, respectively. In addition, CNDP2 was found to be positively correlated with responses to etoposide, carboplatin, and irinotecan. CONCLUSIONS AND CLINICAL RELEVANCE: BALF is an emerging source of biomarkers, making it useful for the diagnosis and prognosis of lung cancers. We characterized the proteomes of paired BALF samples collected from tumor-bearing and non-tumor lungs of SCLC patients. Several proteins were found elevated in tumor-bearing BALF, and especially CNDP2 and RNPEP appeared to be potential indicators for ASLC1-high and NEUROD1-high subtypes of SCLC, respectively. The positive correlation of CNDP2 with chemo-drug responses would help to make decisions for treatment of SCLC patients. These putative biomarkers could be comprehensively investigated for a clinical use towards precision medicine.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Líquido da Lavagem Broncoalveolar , Proteômica , Proteoma , Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/metabolismoRESUMO
AIM: Although Graves' disease (GD) is common in endocrine practices worldwide, global differences in diagnosis and management remain. We sought to assess the current practices for GD in countries across Asia and the Pacific (APAC), and to compare these with previously published surveys from North America and Europe. METHODS: A web-based survey on GD management was conducted on practicing clinicians. Responses from 542 clinicians were received and subsequently analysed and compared to outcomes from similar surveys from other regions. RESULTS: A total of 542 respondents participated in the survey, 515 (95%) of whom completed all sections. Of these, 86% were medical specialists, 11% surgeons, and 3% nuclear medicine physicians. In addition to serum thyroid-stimulating hormone (TSH) and free thyroxine assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (68%) during initial work-up. Thyroid ultrasound is requested by about half of respondents (53%), while the use of nuclear medicine scans is limited. The preferred first-line treatment is anti-thyroid drug (ATD) therapy (79%) with methimazole (MMI) or carbimazole (CBZ), followed by radioiodine (RAI; 19%) and surgery (2%). In case of surgery, one-third of respondents would opt for a subtotal rather than a total thyroidectomy. In case of mild Graves orbitopathy (GO), ATDs (67%) remains the preferred treatment, but a larger proportion of clinicians prefer surgery (20%). For a patient with intention to conceive, the preferred treatment pattern remained unchanged, although propylthiouracil (PTU) became the preferred ATD-agent during the first trimester. In comparison to European and American practices, marked differences were noted in the relatively infrequent usage of nuclear medicine scans and the overall higher use of a ATDs and ß-blockers and adjunctive ATD-treatment during RAI in the APAC-group. CONCLUSION: Although regional differences regarding the diagnosis and management of GD are apparent in this first pan-Asia-Pacific survey, this study reveals the overall approach to the management of this disease in Asia-Pacific generally tends to fall between the trends appreciated in the American and European cohorts.