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Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.
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Doença de Crohn/microbiologia , Células Epiteliais/metabolismo , Microbioma Gastrointestinal , Antígenos de Histocompatibilidade Classe II/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Transcriptoma/genética , Animais , Antibacterianos/farmacologia , Relógios Circadianos/fisiologia , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Dieta , Células Epiteliais/citologia , Células Epiteliais/imunologia , Citometria de Fluxo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Perfilação da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Homeostase , Hibridização in Situ Fluorescente , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Intestino Delgado/fisiologia , Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Periodicidade , Linfócitos T/imunologia , Transcriptoma/fisiologiaRESUMO
Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by â¼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.
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Linfócitos B/fisiologia , Imunidade nas Mucosas , Animais , Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Medula Óssea/imunologia , Medula Óssea/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Jejum , Regulação da Expressão Gênica , Glicólise , Imunoglobulina A/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estado Nutricional , Ovalbumina/imunologia , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/patologia , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Transdução de Sinais , Células Estromais/citologia , Células Estromais/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.
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Exorribonucleases , Histonas , Humanos , Exorribonucleases/genética , Histonas/genética , Mutação de Sentido Incorreto/genética , RNA Ribossômico 5,8S , RNA , RNA Mensageiro/genéticaRESUMO
Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman-Handmaker type (DDSH) and nonlethal Rolland-Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz-Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.
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Haplótipos , Proteoglicanas de Heparan Sulfato , Osteocondrodisplasias , Feminino , Humanos , Masculino , Alelos , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/patologia , Efeito Fundador , Proteoglicanas de Heparan Sulfato/genética , Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Doenças FetaisRESUMO
Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.
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Sequenciamento do Exoma , Feminino , Humanos , Gravidez , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Povo Asiático/genética , Variações do Número de Cópias de DNA , População do Leste Asiático , Feto/anormalidades , Hérnia Diafragmática , Meningomielocele/genética , Meningomielocele/diagnóstico por imagem , Mutação , Glicosiltransferases/genéticaRESUMO
Skeletal ciliopathies are a heterogenous group of congenital disorders characterized by multiple internal abnormalities, and distinct radiographic presentation. Pathogenic variants in at least 30 cilia genes are known to cause skeletal ciliopathies. Here we report a fetus with an atypical skeletal ciliopathy phenotype and compound heterozygous variants in the RAB34 gene. The affected fetus had multiple malformations, including posterior neck edema, micrognathia, low-set and small ears, auricular hypoplasia, cleft lip and palate, short extremities, and a combination of rarely occurring pre- and postaxial polydactyly. Genome sequencing identified compound heterozygous variants in the RAB34 gene: maternal c.254T>C, p.(Ile85Thr), and paternal c.691C>T, p.(Arg231*) variants. Only the paternal variant was present in the unaffected sibling. Evidence in the literature indicated that Rab34-/- mice displayed a ciliopathy phenotype with cleft palate and polydactyly. These features were consistent with malformations detected in our patient supporting the pathogenicity of the identified RAB34 variants. Overall, this case report further expands genetic landscape of human ciliopathy syndromes and suggests RAB34 as a candidate gene for skeletal ciliopathies.
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Anormalidades Múltiplas , Ciliopatias , Fenda Labial , Fissura Palatina , Polidactilia , Humanos , Animais , Camundongos , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/genética , Ciliopatias/diagnóstico por imagem , Ciliopatias/genética , Ciliopatias/patologia , Polidactilia/genética , Anormalidades Múltiplas/genética , Síndrome , Proteínas rab de Ligação ao GTP/genéticaRESUMO
Increasing evidence indicates an interaction between the intestinal microbiota and diseases in distal organs. However, the relationship between pulmonary fibrosis and the intestinal microbiota, especially intestinal fungal microbiota, is poorly understood. Thus, this study aimed to determine the effects of changes in the intestinal fungal microbiota on the pathogenesis of pulmonary fibrosis. Mice with intestinal overgrowth of Candida albicans, which was established by oral administration of antibiotics plus C. albicans, showed accelerated bleomycin-induced pulmonary fibrosis relative to the control mice (i.e. without C. albicans treatment). In addition, the mice with intestinal overgrowth of C. albicans showed enhanced Th17-type immunity, and treatment with IL-17A-neutralizing antibody alleviated pulmonary fibrosis in these mice but not in the control mice. This result indicates that IL-17A is involved in the pathogenesis of C. albicans-exacerbated pulmonary fibrosis. Even before bleomycin treatment, the expression of Rorc, the master regulator of Th17, was already upregulated in the pulmonary lymphocytes of the mice with intestinal overgrowth of C. albicans. Subsequent administration of bleomycin triggered these Th17-skewed lymphocytes to produce IL-17A, which enhanced endothelial-mesenchymal transition. These results suggest that intestinal overgrowth of C. albicans exacerbates pulmonary fibrosis via IL-17A-mediated endothelial-mesenchymal transition. Thus, it might be a potential therapeutic target in pulmonary fibrosis. This study may serve as a basis for using intestinal fungal microbiota as novel therapeutic targets in pulmonary fibrosis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/patologia , Bleomicina/toxicidade , Interleucina-17/metabolismo , Candida albicans/metabolismo , Disbiose , Camundongos Endogâmicos C57BLRESUMO
INTRODUCTION: Small fibre neuropathy (SFN) is an early manifestation of diabetic polyneuropathy. Although oxidative stress, inflammation and change of intestinal bacterial population are assumed to be their pathogenesis, the effects of dietary nutrition have not been evaluated. The relationship between dietary nutrition intake and pain sensation was evaluated in the Japanese population. METHODS: We conducted the Iwaki project, a population-based study recruiting 1,028 individuals, in 2018. The relationships between the pain threshold from intraepidermal electrical stimulation (PINT) and the amount of dietary nutrition evaluated by a brief-type self-administered diet history questionnaire were examined. The odds ratio was further explored after categorizing subjects based on low (< 63.7 µg/day), intermediate (63.7-159.2 µg/day), and high cryptoxanthin levels (> 159.2 µg/day). RESULTS: Univariate linear regression analyses showed significant correlations between PINT and cryptoxanthin intake even after adjustments for other nutritional intakes (ß = 0.107, p < 0.01). Multivariate logistic regression analysis revealed low and high cryptoxanthin intake as significant risk factors for abnormal PINT (≥ 0.20 mA). Multivariate linear regression analyses showed significant correlations between PINT and cryptoxanthin intake levels after adjustment for other clinically PINT-related factors (ß = 0.09, p < 0.01). CONCLUSIONS: Adequate intake of cryptoxanthin is recommended to maintain the pain threshold in the Japanese population.
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BACKGROUND: Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic germline variants in mismatch repair (MMR) genes, which predisposes to various types of cancers showing deficient MMR (dMMR). Identification of LS probands is crucial to reduce cancer-related deaths in affected families. Although universal screening is recommended for colorectal and endometrial cancers, and age-restricted screening is proposed as an alternative, LS screening covering a broader spectrum of cancer types is needed. In the current study, we elucidated the rate of dMMR tumors and evaluated the outcome of LS screening in young-onset extra-colorectal LS-associated cancers. METHODS: Immunohistochemistry for MMR proteins were retrospectively performed in a total of 309 tissue samples of endometrial, non-mucinous ovarian, gastric, urothelial, pancreatic, biliary tract, and adrenal cancers in patients < 50 years of age. Clinicopathological information and the results of genetic testing were obtained from medical charts. RESULTS: There were 24 dMMR tumors (7.8%) including 18 endometrial, three ovarian, two urothelial, and one gastric cancer. Co-occurrence of colorectal cancer and family history of LS-associated cancers was significantly enriched in patients with dMMR tumors. Among the 16 patients with dMMR tumors who were informed of the immunohistochemistry results, five with endometrial and one with urothelial cancer were diagnosed as LS with positive pathogenic variants in MMR genes. CONCLUSIONS: We report the outcome of immunohistochemistry for MMR proteins performed in multiple types of young-onset extra-colorectal LS-associated cancers. Our study demonstrates the feasibility of a comprehensive LS screening program incorporating young-onset patients with various types of extra-colorectal LS-associated cancers.
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AIM: In Japan, noninvasive prenatal testing (NIPT) has been performed by facilities accredited by the Japanese Society of Obstetrics and Gynecology since 2013. However, since 2016, with the implementation of NIPT, which can only be performed by blood sampling, non-obstetricians have been involved in prenatal testing. Therefore, in July 2022, a new government-involved NIPT certification system based on Health Sciences Council guidelines was introduced to ensure access to prenatal testing information for pregnant women. METHODS: This survey was conducted in February 2023 and was the first survey after the certification system implementation. We conducted a web-based survey of 1227 pregnant women and nursing mothers who underwent NIPT after July 2022 to evaluate their experiences. RESULTS: Respondents were categorized by certification status as certified (C: 56%), non-certified (non-C: 23%), or uncertain (Q: 20%). The C group with a higher mean age at examination (35.0 ± 4.5 years) paid lower examination fees, received longer pre- and post-examination explanations, and underwent more weekday examinations (80%) than the other groups. Most respondents, 67%, 48%, and 53% in the C, non-C, and Q groups, respectively (p < 0.0001), stated that "NIPT needs to be regulated by the government or academic societies." The non-C group was more likely to say, "Insufficient post-test explanations at the laboratory made me more anxious," than the other groups when the testing results were non-negative (p = 0.015). CONCLUSIONS: Despite government regulation, some pregnant women choose convenience over certified facilities, risking inadequate care. The government should ensure that NIPT is a safe option for all pregnant women.
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Background and Objectives: No studies have reported corrugator muscle activity associated with pain in people with pain. This study aimed to develop an objective pain assessment method using corrugator muscle activity with pressure pain stimulation to the skeletal muscle. Methods: Participants were 20 adults (a mean ± SD age of 22.0 ± 3.1 years) with chronic neck/shoulder pain. Surface electromyography (sEMG) of corrugator muscle activity at rest (baseline) and without and with pressure pain stimulation applied to the most painful tender point in the shoulder was recorded. Participants evaluated the intensity of the neck/shoulder pain and the sensory and affective components of pain with pressure stimulation using a visual analogue scale (VAS). The percentages of integrated sEMG (% corrugator activity) without and with pressure pain stimulation to the baseline integrated sEMG were compared, and the relationships between the % corrugator activity and the sensory and affective components of pain VAS scores were evaluated. Results: Without pressure stimulation, an increase in corrugator muscle activity due to chronic neck/shoulder pain was not observed. The % corrugator activity with pressure pain stimulation was significantly higher than that without stimulation (p < 0.01). A significant positive correlation between corrugator muscle activity and the affective components of pain VAS scores with pressure stimulation was found (ρ = 0.465, p = 0.039) and a tendency of positive correlation was found for the sensory component of pain VAS scores (ρ = 0.423, p = 0.063). Conclusions: The increase in corrugator muscle activity with pressure pain stimulation to the tender point in adults with chronic neck/shoulder pain was observed, although increased corrugator muscle activity resulting from the chronic neck/shoulder pain was not. These findings suggest that corrugator muscle activity with pressure pain stimulation can be a useful objective indication for tender point sensitivity assessment in the skeletal muscle with pain.
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Cervicalgia , Dor de Ombro , Adulto , Humanos , Adolescente , Adulto Jovem , Dor de Ombro/etiologia , Músculo Esquelético/fisiologia , Pescoço , EletromiografiaRESUMO
Comprehensive genome analysis may reveal secondary findings (SFs) including pathogenic variants of genes other than those originally targeted. Comprehensive genetic analysis of rare diseases is generally performed as research in Japan. Therefore, the status and difficulties in SF disclosure remain unclear. To obtain information for the appropriate disclosure of SFs in rare diseases, we conducted a survey on how SFs are handled in clinical practice by facilities that outsource comprehensive genetic testing to other facilities. The response rate was 66.7% (40/60). Among the responding facilities, 55% had a policy of disclosing SFs with clinical utility and considered targeting actionable SFs with high penetrance. These facilities had difficulties in determining the disclosure targets (51%) and in genetic counseling (38%). Improving genetic literacy, establishment of surveillance systems, and providing insurance coverage for medical care to unaffected carriers were commonly cited as solutions to these difficulties. A comparison of the willingness to disclose SFs between overseas and in Japan showed more reluctance in Japan (86% vs. 65% for actionable SFs and 62% vs. 16% for non-actionable SFs). The group with difficulty in determining disclosure targets was significantly more likely to discuss this at conferences with other facilities and to refer guidelines. This suggests that the group with difficulties was unable to make decisions solely at their own facility and sought collaboration with other facilities. These findings suggest the necessity for a system that allows consultation with experts across facilities and guidelines that set forth policies for determining SFs.
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Revelação , Serviços Terceirizados , Humanos , Medicina Genômica , Doenças Raras/diagnóstico , Doenças Raras/genética , População do Leste Asiático , Testes GenéticosRESUMO
BACKGROUND: The aim of this study was to estimate the impact of respiratory and electrocardiogram (ECG)-gated FDG positron emission tomography (PET)/computed tomography (CT) on the diagnosis of cardiac sarcoidosis (CS). METHODS AND RESULTS: Imaging from thirty-one patients was acquired on a PET/CT scanner equipped with a respiratory- and ECG-gating system. Non-gated PET images and three kinds of gated PET/CT images were created from identical list-mode clinical PET data: respiratory-gated PET during expiration (EX), ECG-gated PET at end diastole (ED), and ECG-gated PET at end systole (ES). The maximum standardized uptake value (SUVmax) and cardiac metabolic volume (CMV) were measured, and the locations of FDG accumulation were analyzed using a polar map. The mean SUVmax of the subjects was significantly higher after application of either respiratory-gated or ECG-gated reconstruction. Conversely, the mean CMV was significantly lower following the application of respiratory-gated or ECG-gated reconstruction. The segment showing maximum accumulation was shifted to the adjacent segment in 25.8%, 38.7%, and 41.9% of cases in EX, ED, and ES images, respectively. CONCLUSION: In FDG PET/CT scanning for the diagnosis of CS, gated scanning is likely to increase quantitative accuracy, but the effect depends on the location and synchronization method.
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Infecções por Citomegalovirus , Sarcoidose , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Eletrocardiografia , Sarcoidose/diagnóstico por imagemRESUMO
PURPOSE: Plasma daptomycin has not been fully characterized in diabetic and obese patients. This study aimed to evaluate the associations of plasma daptomycin with glycation of serum albumin and obesity. METHODS: Infectious patients (n = 70) receiving intravenous daptomycin were enrolled. The plasma concentration of total and free daptomycin were determined using liquid chromatograph-tandem mass spectrometer. The associations of the plasma concentrations of daptomycin with clinical factors including serum albumin fractionations and physical status (obese including overweight, body mass index ≥ 25.0) were investigated. Daptomycin doses were adjusted using total body-weight. RESULTS: The serum albumin level was positively and negatively correlated with the plasma concentration of total daptomycin and its free fraction proportion, respectively. The serum non-glycated albumin was negatively correlated with the free fraction proportion. The dose-normalized plasma concentration of total daptomycin was higher in the obese patients than in non-obese patients when the body-weight was corrected with total and adjusted values. For the dose adjustment with lean body-weight, no difference was observed in the dose-normalized plasma concentration of total daptomycin between the physical statuses. For each body-weight correction method, physical status did not affect the dose-normalized plasma concentration of free daptomycin. CONCLUSION: The glycation of serum albumin and obesity did not associate with dose-normalized plasma free daptomycin. In obese patients, daptomycin dosage adjustment with total body-weight and adjusted body-weight may lead to an apparent excessive exposure resulting in overdosage compared to lean body-weight.
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Daptomicina , Humanos , Daptomicina/uso terapêutico , Obesidade , Albumina Sérica , Índice de Massa CorporalRESUMO
OBJECTIVE: This study examined how clients' selection and preference for noninvasive prenatal testing (NIPT) for aneuploidy changed with genetic counseling (GC) performed by certified geneticists at a primary hospital specializing in obstetrics, where other multiple prenatal genetic tests options were available. METHODS: A total of 334 couples who underwent GC between 2017 and 2019 were included in the study. The average age of the pregnant women who underwent GC was 35.1 years. RESULTS: Among the 95 couples (28.4%) who wanted NIPT at the start of GC, 10 (10.5%) switched to other tests, and 4 (4.2%) chose not to undergo any test. Among the 106 (31.7%) couples who wanted the combination of ultrasonography and the serum marker test, 12 (11.3%) chose not to undergo the test. Among the 92 (27.5%) couples who were undecided before GC, 21 (22.8%) wanted NIPT, 31 (33.7%) selected combined tests, and 18 (19.6%) did not undergo any test. CONCLUSION: We have demonstrated the significance of GC before prenatal genetic testing under widespread use of NIPT. Ideally, obstetric facilities should provide GC, or at least, pre-counseling at their own facilities, and offer multiple prenatal genetic testing options or refer to other facilities for the same.
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Tomada de Decisões , Aconselhamento Genético , Teste Pré-Natal não Invasivo , Adulto , Feminino , Humanos , Gravidez , Aneuploidia , População do Leste Asiático , MaternidadesRESUMO
Recently, utilization of genetic data has become routine in medicine. It is important to consider the use of genetic information in different situations based on the principles of medical ethics. Furthermore, it is necessary to understand the features of genetic information and to adhere to various guidelines in research and clinical practices. In genomic medicine, which will become the mainstream of medicine using comprehensive genetic information, it will be crucial to fully comprehend the suitable handling of secondary results, and to prioritize benefits to the patients. Moreover, developing a system that incorporates appropriate legislation to ensure nondiscrimination of patients on the basis of their genetic information and to provide a forum for ethical issues that will arise in the future is essential.
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Ética Médica , Medicina Genômica , HumanosRESUMO
We herein describe our experience with patients who had been diagnosed with BRCA1/2 pathogenic variants and metastatic breast cancer. Three patients who experienced postoperative recurrences had received chemotherapy before recurrence, while an additional patient with stage â £ disease at diagnosis required chemotherapy before olaparib administration. Prior anthracycline and/or taxane-based therapies needed prior to administration of poly(adenosine diphosphate ribose) polymerase inhibitors might still be controversial in terms of patient benefits.
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Proteína BRCA1 , Neoplasias da Mama , Ftalazinas , Piperazinas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Proteína BRCA2/genética , Prognóstico , Poli(ADP-Ribose) PolimerasesRESUMO
Nineteen non-small cell lung cancer patients admitted for chemotherapy were investigated for cognitive dysfunction and factors affecting cognitive function. The results showed that the patients experienced some decline in cognitive function, and fatigue affected cognitive function and quality of life. Cognitive function in cancer patients affects their treatment choices, employment, and social life. We need to be aware of the cognitive dysfunction of cancer patients, and at the same time, we need to intervene with consideration for cognitive function, as fatigue can easily lead to a sense of cognitive decline.
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Carcinoma Pulmonar de Células não Pequenas , Disfunção Cognitiva , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Fadiga , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Qualidade de Vida/psicologiaRESUMO
Small fibre neuropathy (SFN) is an initial pathology of diabetic polyneuropathy (DPN). Serum lipopolysaccharide binding protein levels are positively correlated with the pain threshold in the foot, suggesting that the abundance of gut Gram-negative bacilli, which are a source of lipopolysaccharides, may be involved in the development of DPN. Furthermore, the abundance of the gut and oral microbiota is assumed to be involved in the pathogenesis of diabetes. Nevertheless, the association between SFN and the microbiota has not been clarified. A total of 1056 individuals were recruited in the 2018 Iwaki Health Promotion Project. Pain sensation was evaluated based on the pain threshold from intraepidermal electrical stimulation (PINT). Patients with PINT scores <0.15 mA were categorized into the low-PINT group (n = 718); otherwise, they were categorized into the high-PINT group (n = 283). Furthermore, each group was divided into the subjects with or without glucose tolerance based on HbA1c levels, fasting blood glucose levels and diabetic history. Principal coordinate analysis and α- and ß-diversity of the microbiota were evaluated. The correlation between clinical and microbiota data was examined. Oral microbiota diversity showed no structural differences according to PINT scores, whereas principal coordinate analysis and α- and ß-diversity revealed significant structural differences in gut microbiota (p < 0.01, p < 0.05 and p < 0.05, respectively), even after the participants with glucose intolerance were excluded (p < 0.01, p < 0.05 and p < 0.05, respectively). The relative abundance of the genus Bacteroides was significantly lower in high-PINT participants compared with low-PINT participants (10 ± 6.7% vs. 11.3 ± 7.0%, p < 0.01), even after the exclusion of subjects with diabetes and impaired fasting glucose (10.0 ± 6.5% vs. 11.2 ± 6.9%, p < 0.05). In univariate linear regression analyses, PINT was significantly correlated with metabolic syndrome parameters, eGFR, uric acid level and the abundance of Bacteroides. The correlation between Bacteroides and PINT scores remained significant after adjustment for multiple factors (ß = -0.07181, p < 0.05). Changes of bacterial diversity and a low abundance of gut Bacteroides were correlated with elevated PINT scores in the Japanese population. This correlation may represent a new therapeutic option for SFN.
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Neuropatias Diabéticas , Microbioma Gastrointestinal , Humanos , Bacteroides , Glicemia , Hemoglobinas Glicadas , Japão , Lipopolissacarídeos , Limiar da Dor , Ácido ÚricoRESUMO
BACKGROUND: Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. CONCLUSION: Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).