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The biological heterogeneity of neuroblastoma underscores the need for an in vitro model of each molecularly defined subgroup to investigate tumorigenesis and develop targeted therapies. We have established a permanently growing cell line from a 12-year-old girl who developed a late recurrent stage MS, MDM2-amplified neuroblastoma arising in the liver and performed histological, molecular, cytogenetic, exome, and telomere analyses of the recurrent tumor and the cell line. On histology, the recurrent tumor was immunoreactive for TP53, CDKN1A, and MDM2. A molecular cytogenetic study of the recurrent tumor revealed the amplification of MDM2 but no amplification of MYCN. The established cell line, NBM-SHIM, showed amplification of both MDM2 and MYCN on double-minute chromosomes. A copy number evaluation based on exome data confirmed the finding for MYCN and MDM2 and further identified high ploidy on CDK4 and GLI2 loci in the recurrent tumor and the cell line. The telomere maintenance mechanism on the cell line is unusual in terms of the low expression of TERT despite MYCN amplification and alternative lengthening of telomeres suggested by positive value for C-circle assay and telomere contents quantitative assay. The cell line is unique because it was established from a MYCN-nonamplified, MDM2-amplified, late-relapsed stage MS neuroblastoma, and MYCN amplification was acquired during cell culture. Therefore, the cell line is a valuable tool for investigating neuroblastoma tumorigenesis and new molecular targeted therapies for disrupted ARF-TP53-MDM2 pathway and amplification of MDM2 and CDK4.
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Amplificación de Genes , Proteína Proto-Oncogénica N-Myc , Neuroblastoma , Proteínas Proto-Oncogénicas c-mdm2 , Humanos , Neuroblastoma/genética , Neuroblastoma/patología , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Femenino , Niño , Amplificación de Genes/genética , Línea Celular Tumoral , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Telómero/genética , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Homeostasis del Telómero/genéticaRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0256481.].
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This study aimed to identify severe gastrointestinal ailments in patients with systemic sclerosis (SSc), investigate the role of antibodies in gastrointestinal disorders, and explore the relationship between limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) in terms of gastrointestinal involvement and its association with skin stiffness. We used the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (UCLA SCTC GIT 2.0) questionnaire to assess gastrointestinal disturbances in 100 patients with SSc. Gastrointestinal impairment was categorized into three levels: absence of or minor symptoms, moderate symptoms, and severe symptoms, as indicated by the total gastrointestinal tract (GIT) score. Comparing 27 patients with dcSSc and 73 patients with lcSSc, severe gastrointestinal disturbances were found in 7.4% of patients with dcSSc and 4.1% of patients with lcSSc. A total of 18.0% of anticentromere antibody (ACA)-positive patients exhibited moderate to severe symptoms, while 9.1% of antitopoisomerase 1 antibody-positive patients displayed similar symptoms. The average disease duration in patients with severe symptoms was 15.0 years, in those with moderate symptoms was 10.3 years, and in those who were symptom-free or mildly affected was 8.5 years. Among 16 patients with moderate to severe gastrointestinal disorders, a positive correlation was observed between the modified Rodnan skin thickness score (mRSS) and total GIT score. In addition, a positive correlation was identified between fecal incontinence and mRSS, with weaker correlations for reflux and bloating symptoms. Patients with gastrointestinal disorders showed a tendency to worsen over time, particularly in ACA-positive patients with dcSSc. Furthermore, a correlation was observed between mRSS and fecal incontinence, reflux, and abdominal bloating in patients with moderate to severe gastrointestinal disturbances.
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Autosomal-dominant tubulointerstitial kidney disease caused by UMOD (encoding uromodulin) mutation (ADTKD-UMOD) is a rare hereditary disease. A strong family history of hyperuricemia or gout and inherited kidney disease raises the suspicion of ADTKD-UMOD. Genetic testing can confirm the diagnosis without a kidney biopsy. However, when complicated by other diseases that can cause tubulointerstitial disease, renal biopsy is indispensable for the diagnosis and decisions on treatment strategy. We report the case of a 44-year-old woman referred for evaluation of kidney dysfunction. She had an attack of gout 1 month before referral and a family history of hyperuricemia. She was diagnosed with primary Sjogren's syndrome through an immune workup and ophthalmological examination. However, a kidney biopsy revealed histological features suggesting ADTKD rather than gouty kidney or tubulointerstitial nephritis associated with Sjogren's syndrome, and immunostaining revealed a characteristic staining pattern with UMOD. Comprehensive genetic testing of 93 genes responsible for polycystic kidney disease revealed a novel heterozygous missense variant (c.649 T > A:p. Cys217Ser) in UMOD, and the patient was diagnosed with ADTKD-UMOD. In this case, kidney biopsy contributed to the correct diagnosis of tubulointerstitial kidney disease. This case emphasizes the importance of suspecting ADTKD-UMOD based on family history and careful evaluation of kidney biopsy findings.
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BACKGROUND: While research has explored the risk of periodontal disease in various eye conditions, the link between dry eye and periodontal disease remains underexplored, especially in Japanese adults. This study aims to investigate the association between dry eye and periodontal disease in community-dwelling Japanese adults. METHODS: This study is a subset of the Uonuma cohort study, which includes Japanese adults aged 40 years and older residing in the Uonuma area of Niigata Prefecture, Japan. Participants completed a self-administered, paper-based questionnaire. Statistical analyses, including the chi-square test, independent t test, ANOVA test, and logistic regressions, were employed to assess the association of periodontal disease with independent variables. RESULTS: Among 36,488 participants (average age 63.3 years, 47.4% men), 39.3% had a history of periodontal disease, and gender differences were statistically significant (p < 0.001). Significant associations were found between periodontal disease and dry eye diagnosis or symptoms. Univariable logistic regression revealed links between periodontal disease and age, gender, living status, alcohol consumption, remaining teeth, bite molar availability, and history of dry eye disease or symptoms. Multiple-adjusted regression found that doctor-diagnosed dry eye was associated with a higher likelihood of periodontal disease (odds ratio, 1.12; 95% confidence interval, 1.03-1.22). Participants who never experienced dryness or foreign body sensation had lower ORs of periodontal disease than those who always experienced such symptoms across all models. CONCLUSION: A significant correlation was found between dry eye and periodontal disease in Japanese adults. Regular check-ups, early detection, and effective management of both conditions are strongly recommended.
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Síndromes de Ojo Seco , Enfermedades Periodontales , Adulto , Masculino , Humanos , Persona de Mediana Edad , Femenino , Japón/epidemiología , Estudios de Cohortes , Vida Independiente , Síndromes de Ojo Seco/complicaciones , Síndromes de Ojo Seco/epidemiología , Enfermedades Periodontales/complicaciones , Enfermedades Periodontales/epidemiologíaRESUMEN
Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.
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Predisposición Genética a la Enfermedad , Esclerodermia Sistémica , Humanos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Receptores de IgG/genética , Puntuación de Riesgo Genético , Esclerodermia Sistémica/genética , Polimorfismo de Nucleótido Simple , Factores Reguladores del Interferón/genética , Sitios GenéticosRESUMEN
This case study illustrates a 63-year-old Japanese woman who presented with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis. She was administered a therapeutic regimen consisting of corticosteroids, tacrolimus, and cyclophosphamide. However, after a month of treatment, symptoms of confusion and depressive tendencies emerged, followed by the manifestation of hematuria, thrombocytopenia, and fragmented erythrocytes. A disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13 activity was 45%. Thrombotic microangiopathy was contemplated, yet a definitive diagnosis remained elusive. She died 2 months after admission. Although the occurrence of thrombotic microangiopathy in patients with dermatomyositis is rare, the prognosis is poor, emphasizing the importance of prompt diagnosis and treatment.
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Dermatomiositis , Microangiopatías Trombóticas , Femenino , Humanos , Persona de Mediana Edad , Dermatomiositis/complicaciones , Dermatomiositis/diagnóstico , Dermatomiositis/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/complicaciones , Tacrolimus/uso terapéutico , PronósticoRESUMEN
We describe the case of a 61-year-old woman with anti-signal recognition particle (SRP) antibody-positive immune-mediated necrotizing myopathy (IMNM) who exhibited biopsy-confirmed thrombotic microangiopathy (TMA). The patient developed proximal-dominant muscle weakness and was diagnosed with anti-SRP antibody-positive IMNM based on muscle biopsy results and serological examination. A high-dose corticosteroid prescription was initiated, followed by intravenous methylprednisolone and intravenous immunoglobulin therapy (IVIg). The patient showed IVIg-induced hemolytic anemia with preserved ADAMTS13 activity. Transient oral tacrolimus administration was initiated. Approximately 8 weeks after admission, the serum creatinine levels gradually increased. Renal histological examination revealed TMA, including ischemic changes in the renal tubules, stenosis, and occlusion of the interlobular arteries with fibrinoid necrosis of the afferent arteriolar walls. The arteriolar walls demonstrated an accumulation of C1q and C3c. Myofiber damage in patients with IMNM accounts for the activation of the classical pathway of the complement cascade in the sarcolemma due to antibody deposition. Additionally, a membrane attack complex is observed on capillaries in the muscle tissues of patients with anti-SRP antibody-positive IMNM. Although drug-induced pathomechanisms, such as IVIg and tacrolimus, can trigger the development of TMA, we suggest that the presence of serum anti-SRP antibodies would be implicated in complement-associated kidney vascular damage.
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Enfermedades Autoinmunes , Miositis , Microangiopatías Trombóticas , Femenino , Humanos , Persona de Mediana Edad , Inmunoglobulinas Intravenosas/uso terapéutico , Músculo Esquelético/patología , Partícula de Reconocimiento de Señal , Tacrolimus , Autoanticuerpos , Miositis/inducido químicamente , Miositis/diagnóstico , Miositis/tratamiento farmacológico , Microangiopatías Trombóticas/inducido químicamente , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/tratamiento farmacológicoRESUMEN
Physical activity is crucial to prevent sarcopenia, but there is scant data on the link between sarcopenia and physical activity in rural communities. Therefore, this study investigated associations of farming activity and snow removal with sarcopenia in a middle-aged and older population in rural Japan. This cross-sectional study enrolled 3,056 residents aged ≥ 40 years (49.2% men; mean age, 64.2 years) in Yuzawa, Japan. Information on farming activity and snow removal were collected via questionnaire from May through November and from December through April, respectively. Sarcopenia was assessed by the SARC-F (strength, ambulation, rising from a chair, stair climbing, and history of falling) score. Associations of farming activity and snow removal with sarcopenia were assessed using multivariable logistic regression analysis with adjustment for potential confounders. Participants who engaged in farming activity, snow removal, and both accounted for 3.8%, 40.5%, and 29.4% of the total, respectively. In the multivariable logistic regression analysis, adjusted odds ratios [95% confidence intervals (CI)] of sarcopenia for farming activity and snow removal were 0.80 (0.63-1.03) and 0.68 (0.53-0.87), respectively. Compared with participants who did not engage in farming activity or snow removal, participants who engaged in both had a significantly lower adjusted odds ratio of sarcopenia [0.63 (95% CI 0.47-0.86)]. Participants who engaged in snow removal and those who engaged in both farming activity and snow removal showed inverse associations with sarcopenia. Our findings further support the importance of physical activity in preventing or mitigating sarcopenia in rural communities.
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Sarcopenia , Masculino , Persona de Mediana Edad , Humanos , Anciano , Femenino , Sarcopenia/epidemiología , Japón/epidemiología , Estudios Transversales , Vida Independiente , Población Rural , Ejercicio FísicoRESUMEN
A 69-year-old woman was referred to our hospital because of an acute kidney injury with macroscopic hematuria. She had been taking dabigatran for atrial flutter for six years. Based on the typical histological findings of her kidney biopsy and her history of dabigatran use with prolonged activated partial thromboplastin time, she was diagnosed with dabigatran-related nephropathy complicated by tubulointerstitial nephritis with IgA nephropathy. After prednisolone therapy, the renal function improved. Direct-acting oral anticoagulants, including dabigatran, may cause anticoagulant-related nephropathy similar to warfarin, even in patients with a normal renal function. Tubulointerstitial nephritis may coexist with dabigatran-related nephropathy, and prednisolone therapy should be considered in such cases. IgA nephropathy has been reported as a background disease, and caution should be exercised when encountering it.
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PURPOSE: To investigate the association between plasma antibody levels against Porphyromonas gingivalis (PG) and atrial fibrillation (AF) history in community-dwelling older individuals in Japan. MATERIALS AND METHODS: This study was a subset of the Uonuma cohort study, including 3091 participants aged 60-79 years. Data were collected, including AF history as a dependent variable, plasma immunoglobulin G antibody levels against PG as an independent variable, and previously reported AF risk factors and demographic information as covariates. RESULTS: The median age of the participants was 69 years. Of the 3091 participants, 1411 (45.6%) were men, and 56 (1.8%) had an AF history. AF prevalence was significantly higher in participants with higher antibody levels against PG than in those with lower antibody levels (3.0% vs 1.4%; p = 0.005). Multivariable logistic regression analysis showed that participants with higher antibody levels against PG had twofold higher odds of having AF (odds ratio = 2.13; 95% confidence interval = 1.23-3.69). Restricted cubic spline analysis indicated a nonlinear relationship between antibody levels against PG and AF history. CONCLUSION: Plasma antibody levels against PG were associated with AF history in community-dwelling older individuals in Japan.
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Fibrilación Atrial , Masculino , Humanos , Anciano , Femenino , Fibrilación Atrial/epidemiología , Porphyromonas gingivalis , Estudios Transversales , Estudios de Cohortes , Japón/epidemiología , Vida IndependienteRESUMEN
BACKGROUND: Liquid-based cytology (LBC), now used globally for the head and neck region, has been used at our hospital since 2011. This study was designed to analyze the efficacy of LBC with immunocytochemical staining on preoperative diagnosis of salivary gland tumors. METHODS: This retrospective analysis of fine-needle aspiration (FNA) performance for salivary gland tumors was conducted at Fukui University Hospital. Salivary gland tumor operations conducted during April 2006 - December 2010 (84 cases) were classified as the Conventional Smear (CS) group, which were diagnosed morphologically by Papanicolaou and Giemsa staining. Those done during January 2012 - April 2017 (112 cases) were classified as the LBC group, which were diagnosed using LBC samples with immunocytochemical staining. The FNA results and pathological diagnosis of both groups were analyzed to calculate the FNA performance. RESULTS: Compared to the CS group, cases of inadequate and indeterminate FNA sample were not reduced significantly by LBC with immunocytochemical staining. As for FNA performance, the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CS group were, respectively, 88.7%, 53.3%, 100%, 100%, and 87.0%. Those of LBC group were all 100%, representing significant improvement over the CS group. CONCLUSIONS: Analysis results indicated the usefulness of LBC with immunocytochemical staining for preoperative diagnosis of salivary gland tumors.
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Neoplasias de las Glándulas Salivales , Humanos , Biopsia con Aguja Fina/métodos , Estudios Retrospectivos , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/patología , Citodiagnóstico , Coloración y Etiquetado , Sensibilidad y EspecificidadRESUMEN
AIM: Despite global efforts in public health campaigns concerning chronic kidney disease (CKD), awareness of the condition remains low. We evaluated CKD awareness and related factors to identify an effective way to raise awareness. METHODS: This study assessed laboratory-confirmed CKD and self-reported CKD using a population-based cohort (baseline from 2012 to 2014, age ≥40 years) in Niigata, Japan. Self-reported CKD was obtained at a 5-year follow-up survey and laboratory-confirmed CKD was diagnosed when an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or dipstick urinary protein ≥1+ was observed in at least two health check-ups during the 5-year period. CKD awareness was defined as a match between laboratory-confirmed and self-reported CKD. The association between characteristics and CKD awareness was tested by multivariable logistic regression analysis with adjustment for eGFR and other potential confounders. RESULTS: The analytic population comprised 7472 individuals (mean age, 65.6 years old, 51.2% women) and 19.4% with laboratory-confirmed CKD. The sensitivity and specificity of the survey question concerning self-reported CKD were 12.4% and 98.2%, respectively. Among the participants with laboratory-confirmed CKD, significant factors associated with CKD awareness were male sex (adjusted odds ratio [95% confidence interval], 1.81 [1.27, 2.59]), a history of urinary tract stone (1.86 [1.06, 3.26]), age (0.97 [0.95, 0.99]), and married status (0.66 [0.44, 0.99]). CONCLUSION: Our findings suggest that known lifestyle-related diseases that could cause CKD are not associated with CKD awareness independently of kidney function and that a sex-dependent approach may help to raise CKD awareness in community-dwelling Japanese adults.
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Pueblos del Este de Asia , Insuficiencia Renal Crónica , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Cohortes , Estudios de Seguimiento , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Concienciación , Vida Independiente , Japón , Salud Pública , Promoción de la SaludRESUMEN
The eponymous history of Warthin tumor (WT) is a fascinating issue in the field of salivary gland pathology. The late decades of the nineteenth century and the turn of the century saw notable German and French contributions on WT. Especially, the seminal 1910 paper of Albrecht and Arzt of Vienna is the foundation for the current knowledge of WT. It is generally believed that prior to this pioneering study, Hildebrand of Göttingen accurately described the lesion of WT in 1895. However, the historical origins of WT appear to be unsettled, and only a few German pathologists and surgeons are aware that dating back to 1885, the first recognizable reference to WT was that by the renowned German-Swiss pathologist Zahn, whose name is eponymously associated with "Zahn infarct" and "lines of Zahn". Two noted French surgeons with a major interest in pathology, Albarrán in 1885 and Lecéne in 1908, did not contribute to the topic. Since the 1950s, a mostly American group of pathologists and surgeons gradually adopted the term WT to replace the very accurate histologic descriptor "papillary cystadenoma lymphomatosum" coined by Warthin himself in 1929. It is our opinion that from a historical viewpoint, there is no particular reason why this tumor should have been named WT.
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Adenolinfoma , Neoplasias de la Parótida , Humanos , Adenolinfoma/patología , Neoplasias de la Parótida/patología , Epónimos , Glándula Parótida/patologíaRESUMEN
The combination therapy of atezolizumab, an anti-programmed cell death ligand-1 antibody, plus bevacizumab (Atz/Bev) is widely used to treat patients with advanced hepatocellular carcinoma (HCC). The development of polymyalgia rheumatica (PMR) during immune checkpoint inhibitor therapy for patients with HCC has not been reported to date. Two patients who developed PMR during Atz/Bev therapy for advanced HCC are reported. Both patients developed fever, bilateral symmetrical shoulder pain, morning stiffness, and an elevated C-reactive protein level. Their symptoms improved rapidly with prednisolone (PSL) 15-20 mg/d, and their C-reactive protein levels decreased. In PMR, long-term low-dose PSL should be administered. In the present patients who developed PMR as immune-related adverse events, starting with a small dose of PSL resulted in rapid improvement of symptoms.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Polimialgia Reumática , Humanos , Polimialgia Reumática/tratamiento farmacológico , Polimialgia Reumática/diagnóstico , Carcinoma Hepatocelular/tratamiento farmacológico , Bevacizumab/efectos adversos , Proteína C-Reactiva/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Prednisolona/uso terapéuticoRESUMEN
We present a family of two female Alport syndrome patients with a family history of impaired glucose tolerance. Whole exome sequencing identified a novel heterozygous variant of COL4A5 NM_033380.3: c.2636 C > A (p.S879*) and a rare variant of GCK NM_001354800.1: c.1135 G > A (p.A379T) as the causes of Alport syndrome and monogenic diabetes, respectively. Two independent pathogenic variants affected the clinical phenotypes. Clinical next-generation sequencing is helpful for identifying the causes of patients' manifestations.
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Idiopathic nodular glomerulosclerosis has a poor renal prognosis and is characterized by diffuse nodular glomerulosclerotic lesions in the absence of diabetic mellitus. Here, we report the case of a 69-year-old woman with no smoking history who developed renal dysfunction and proteinuria in the absence of overt diabetes or obesity. A biopsy specimen showed nodular mesangial sclerosis with arteriolar hyalinosis and severe large-vessel arteriosclerosis, leading to a diagnosis of idiopathic nodular glomerulosclerosis. Addition of esaxerenone to her existing renin-angiotensin-aldosterone inhibitor therapy led to a rapid decrease in the proteinuria levels and the maintenance of renal function without any complications for more than a year. The results suggest that intensive renin-angiotensin-aldosterone blockade might be an effective treatment for idiopathic nodular glomerulosclerosis.