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1.
Int J Mol Sci ; 21(3)2020 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-32024277

RESUMO

BACKGROUND: Morquio A syndrome, mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disorder caused by the deficient activity of N-acetylgalactosamine-6-sulfatase (GalNac6S), due to alterations in the GALNS gene. This disorder results in marked abnormalities in bones and connective tissues, and affects multiple organs. Here, we describe the clinical course of a Japanese boy with MPS IVA who began enzyme replacement therapy (ERT) at the age of 24 months. PATIENT: the patient presented for kyphosis treatment at 22 months of age. An X-ray examination revealed dysostosis multiplex. Uronic acids were elevated in the urine and the keratan sulfate (KS) fraction was predominant. The leukocyte GalNac6S enzyme activity was extremely low. The patient exhibited the c.463G > A (p.Gly155Arg) mutation in GALNS. Based on these findings, his disease was diagnosed as classical (severe) Morquio A syndrome. An elosulfase alfa infusion was initiated at the age of 24 months. The patient's body height improved from -2.5 standard deviation (SD) to -2 SD and his physical activity increased during the first 9 months on ERT. However, he gradually developed paralysis in the lower legs with declining growth velocity, which required cervical decompression surgery in the second year of the ERT. The mild mitral regurgitation, serous otitis media, and mild hearing loss did not progress during treatment. CONCLUSION: early initiation of the elosulfase alfa to our patient showed good effects on the visceral system and muscle strength, while its effect on bones appeared limited. Careful observation is necessary to ensure timely surgical intervention for skeletal disorders associated with neurological symptoms. Centralized and multidisciplinary management is essential to improve the prognosis of pediatric patients with MPS IVA.

2.
Yakugaku Zasshi ; 140(1): 63-79, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-31902887

RESUMO

Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is common in elderly women, and bisphosphonates (BPs) are typical and widely used anti-osteoporotic or anti-bone-resorptive drugs. BRONJ is now a serious concern in dentistry. As BPs are pyrophosphate analogues and bind strongly to bone hydroxyapatite, and the P-C-P structure of BPs is non-hydrolysable, they accumulate in bones upon repeated administration. During bone-resorption, BPs are taken into osteoclasts and exhibit cytotoxicity, producing a long-lasting anti-bone-resorptive effect. BPs are divided into nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). N-BPs have far stronger anti-bone-resorptive effects than non-N-BPs, and BRONJ is caused by N-BPs. Our murine experiments have revealed the following. N-BPs, but not non-N-BPs, exhibit direct and potent inflammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the inflammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by inflammation. N-BPs are taken into soft-tissue cells via phosphate-transporters, while the non-N-BPs etidronate and clodronate inhibit this transportation. Etidronate, but not clodronate, has the effect of expelling N-BPs that have accumulated in bones. Moreover, etidronate and clodronate each have an analgesic effect, while clodronate has an anti-inflammatory effect via inhibition of phosphate-transporters. These findings suggest that BRONJ may be induced by phosphate-transporter-mediated and infection-promoted mechanisms, and that etidronate and clodronate may be useful for preventing and treating BRONJ. Our clinical trials support etidronate being useful for treating BRONJ, although additional clinical trials of etidronate and clodronate are needed.

4.
Int Immunol ; 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31867619

RESUMO

Gain-of-function (GOF) STAT1 mutations account for approximately one-half of patients with chronic mucocutaneous candidiasis (CMC) disease. Patients with GOF-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to CMC, and those with severe infections and/or autoimmunity have a poor prognosis. The establishment of safe and effective treatments based on a precise understanding of the molecular mechanisms of this disorder is required to improve patient care. To tackle this problem, we introduced the human R274Q GOF mutation into mice [GOF-Stat1 knock-in (GOF-Stat1R274Q)]. To investigate the immune responses, we focused on the small intestine, which contains abundant Th17 cells. Stat1R274Q/R274Q mice showed excess phosphorylation of STAT1 in CD4+ T cells upon IFN-γ; stimulation, consistent with the human phenotype in patients with the R274Q mutation. We identified two subpopulations of CD4+ T cells, those with "normal" or "high" level of basal STAT1 protein in Stat1R274Q/R274Q mice. Upon IFN-γ; stimulation, the "normal" level CD4+ T cells were more efficiently phosphorylated than those from WT mice, whereas the "high" level CD4+ T cells were not, suggesting that the level of STAT1 protein does not directly correlate with the level of pSTAT1 in the small intestine. Inoculation of Stat1R274Q/R274Q mice with Candida albicans elicited decreased IL-17-producing CD4+RORγ;t+ cells. Stat1R274Q/R274Q mice also excreted larger amounts of C. albicans DNA in their feces than control mice. Under these conditions, there was upregulation of T-bet in CD4+ T cells. GOF-Stat1R274Q mice thus should be a valuable model for functional analysis of this disorder.

5.
Digestion ; : 1-10, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31671425

RESUMO

BACKGROUND: Major complications in patients with ulcerative colitis (UC) include UC-associated cancer (UCAC) and postoperative pouchitis. We aimed to identify SNPs associated with UCAC/high-grade dysplasia (HGD) and pouchitis. METHODS: Patients with UC who underwent ileal pouch-anal anastomosis (IPAA) with >2 years of follow-up after functioning pouches were included. Pouchoscopies were performed at least once to diagnose pouchitis according to the modified pouchitis disease activity index. SNP genotyping was performed for 8 SNPs reportedly associated with UCAC and pouchitis, namely: ELF1 (rs7329174), FCGR2A, (rs1801274), interleukin-1ß (IL-1B; rs1143627), ITLN1 (rs2274910), MHC (rs7765379), TNFα (rs1799964), TNFSF15 (rs3810936), and UHMK1 (rs768910), using TaqMan genotyping technologies. We investigated the association of these SNPs with UCAC/HGD and pouchitis. Patients' background data were retrospectively collected, including the presence of preoperative extraintestinal manifestation (EIM). RESULTS: A total of 91 Japanese patients with UC were included. None of the 8 SNPs were associated with UCAC/HGD in our cohort. Multivariable analyses proved that the presence of preoperative EIM (hazard ratio [HR] 3.313, 95% CI 1.325-8.289) and IL-1B (rs1143627) TT genotype (HR 2.425, 95% CI 1.049-5.61) were independent predictive factors for the development of overall pouchitis. The presence of preoperative EIM (HR 3.977, 95% CI 1.292-12.24) and IL-1B (rs1143627 TT genotype; HR 3.382, 95% CI 1.101-10.39) were also independent predictive factors for the development of chronic pouchitis. CONCLUSIONS: The IL-1B (rs1143627) TT genotype and preoperative EIM were statistically significant predictors of pouchitis development after IPAA in patients with UC.

6.
Breed Sci ; 69(3): 401-409, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31598072

RESUMO

Sake-brewing cultivars among varieties of Japanese rice (Oryza sativa L.) have traits adapted to the sake-brewing process, such as a high white-core expression rate (WCE). Our previous study detected putative quantitative trait loci (QTLs) associated with a high WCE derived from Yamadanishiki, a popular brewing rice cultivar. Because the occurrence of white-core grains depends on air temperature and the position of the grain on the panicle, phenotyping of WCE must consider these variable conditions. In this study, qWCE6, a QTL for the WCE on chromosome 6, was validated for the first time, and the phenotyping method examined for its suitability in fine-mapping. A clear tendency towards high WCE was observed in late-heading substituted lines which headed under low daily mean temperature at the experimental location. White-core grains were often expressed by the primary spikelets on the upper panicle, producing a high percentage of superior grains. The segregating population for qWCE6 in late heading revealed a distinct difference in WCE between the Koshihikari and Yamadanishiki homozygous alleles at qWCE6 as determined from that locality. Further, two insertion/deletion markers were developed for the marker-assisted selection of qWCE6. Our results will be useful for informing the breeding of sake-brewing rice cultivars.

7.
Proc Natl Acad Sci U S A ; 116(41): 20376-20381, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31551263

RESUMO

Biomineralization in animals exclusively features oxygen-based minerals with a single exception of the scaly-foot gastropod Chrysomallon squamiferum, the only metazoan with an iron sulfide skeleton. This unique snail inhabits deep-sea hot vents and possesses scales infused with iron sulfide nanoparticles, including pyrite, giving it a characteristic metallic black sheen. Since the scaly-foot is capable of making iron sulfide nanoparticles in its natural habitat at a relatively low temperature (∼15 °C) and in a chemically dynamic vent environment, elucidating its biomineralization pathways is expected to have significant industrial applications for the production of metal chalcogenide nanoparticles. Nevertheless, this biomineralization has remained a mystery for decades since the snail's discovery, except that it requires the environment to be rich in iron, with a white population lacking in iron sulfide known from a naturally iron-poor locality. Here, we reveal a biologically controlled mineralization mechanism employed by the scaly-foot snail to achieve this nanoparticle biomineralization, through δ34 S measurements and detailed electron-microscopic investigations of both natural scales and scales from the white population artificially incubated in an iron-rich environment. We show that the scaly-foot snail mediates biomineralization in its scales by supplying sulfur through channel-like columns in which reaction with iron ions diffusing inward from the surrounding vent fluid mineralizes iron sulfides.

8.
J Am Chem Soc ; 141(40): 15751-15754, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31523957

RESUMO

Neurotransmitter-sensitive contrast agents for magnetic resonance imaging (MRI) have recently been used for mapping signaling dynamics in live animal brains, but paramagnetic sensors for T1-weighted MRI are usually effective only at micromolar concentrations that themselves perturb neurochemistry. Here we present an alternative molecular architecture for detecting neurotransmitters, using superparamagnetic iron oxide nanoparticles conjugated to tethered neurotransmitter analogs and engineered neurotransmitter binding proteins. Interactions between the nanoparticle conjugates result in clustering that is reversibly disrupted in the presence of neurotransmitter analytes, thus altering T2-weighted MRI signals. We demonstrate this principle using tethered dopamine and serotonin analogs, together with proteins selected for their ability to competitively bind either the analogs or the neurotransmitters themselves. Corresponding sensors for dopamine and serotonin exhibit target-selective relaxivity changes of up to 20%, while also operating below endogenous neurotransmitter concentrations. Semisynthetic magnetic particle sensors thus represent a promising path for minimally perturbative studies of neurochemical analytes.

9.
Oxf Med Case Reports ; 2019(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31428771

RESUMO

Pulmonary sclerosing pneumocytoma (PSP) is pathologically classified as an adenoma and behaves in a benign manner. However, some cases of PSP displayed pathologically malignant behavior, such as lymph node metastasis and necrosis. A 64-year-old woman was referred to our hospital complaining of a cough and breathlessness. Histopathological analysis of the resected specimen by left pneumonectomy and lymph node dissection revealed a large PSP measuring 15 × 14 cm in size, with massive necrosis and vascular invasion. This case was the largest ever reported and suggested that clinico-histological presentation of PSP sometimes showed an aggressive phenotype like advanced lung cancer.

10.
Nat Commun ; 10(1): 3608, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444338

RESUMO

Chemical reactions in solution almost always take place via a series of minute intermediates that are often in rapid equilibrium with each other, and hence hardly characterizable at the level of atomistic molecular structures. We found that single-molecule atomic-resolution real-time electron microscopic (SMART-EM) video imaging provides a unique methodology for capturing and analyzing the minute reaction intermediates, as illustrated here for single prenucleation clusters (PNCs) in the reaction mixture of metal-organic frameworks (MOFs). Specifically, we found two different types of PNCs are involved in the formation of MOF-2 and MOF-5 from a mixture of zinc nitrate and benzene dicarboxylates at 95 °C and 120 °C, respectively. SMART-EM identified a small amount of 1-nm-sized cube and cube-like PNCs in the MOF-5 synthesis, but not in the MOF-2 synthesis. In the latter, we instead found only linear and square PNCs, suggesting that the MOF-2/-5 bifurcation takes place at the PNC stage.

11.
Surg Today ; 49(12): 1066-1073, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31309329

RESUMO

PURPOSE: We evaluated the recent incidence of surgery and the changing surgery trends for ulcerative colitis (UC) in Japan due to the increasing use of anti-tumor necrosis factor (TNF) agents. METHODS: A questionnaire survey was performed to assess the number of surgeries, surgical indications, surgical timing, and immunosuppressive treatments before surgery between 2007 and 2017. RESULTS: A total of 3801 surgical cases were reported over 11 years. The prevalence of UC surgery decreased over the period studied. The rate of prednisolone (PSL) use did not change. The prevalence of both calcineurin inhibitors (CNIs) and anti-TNF agents increased during the period studied (p < 0.01). The prevalence of urgent/emergent surgery did not change. The most distinctive change in surgical indications was the increase in cancer/dysplasia (CAC), the prevalence of which increased from 20.2% in 2007 to 34.8%. CONCLUSION: The prevalence of UC surgery seems to be decreasing according to the increasing rate of anti-TNF agent and CNI administration. However, the indication of CAC significantly increased. Further research should evaluate whether or not long-term remission maintained with several agents can lead to increasing CAC.

12.
J Rheumatol ; 46(6): 655-656, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31154449
13.
J Thorac Oncol ; 14(8): 1408-1418, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31055075

RESUMO

INTRODUCTION: Current nodal staging of NSCLC is defined only by anatomical location of lymph nodes (LNs). The aim of this study is to investigate prognostic impacts of the number of metastatic LNs by stratifying the present N classification. METHODS: We analyzed 1989 patients with NSCLC who underwent complete resection by lobectomy or pneumonectomy involving dissection of the hilar and mediastinal LNs from 2003 to 2012. We classified patients according to the number of metastatic nodes and stations and their current category of metastatic LNs. We analyzed the overall survival in each group and assessed the survival impact of the combination of them. RESULTS: In the multivariate analyses of all patients, pathological N1 (pN1) (reference [ref.] pN2) and single-node metastasis (ref. multiple-node) were independent prognostic factors whereas single-station metastasis (ref. multiple-station) was not. In the respective multivariate analyses of pN1 and pN2 disease, multiple-node metastasis (ref. single-node) was an independent prognostic factor in pN1 disease (hazard ratio: 1.41, p = 0.04), but not in pN2 disease. Investigation for other boundaries of a number of metastatic LNs of three or more (ref. one to two), four or more (ref. one to three), and five or more (ref. one to four) found that all of them were independent prognostic factors in both pN1 and pN2 diseases. CONCLUSIONS: The number of metastatic LNs had a strong impact on survival in addition to the current pN classification. To clarify its prognostic impact, further study is needed in other datasets including patients treated by nonsurgical modalities.

14.
Am J Hum Genet ; 104(6): 1233-1240, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31130285

RESUMO

Noonan syndrome (NS) is characterized by distinctive craniofacial appearance, short stature, and congenital heart disease. Approximately 80% of individuals with NS harbor mutations in genes whose products are involved in the RAS/mitogen-activating protein kinase (MAPK) pathway. However, the underlying genetic causes in nearly 20% of individuals with NS phenotype remain unexplained. Here, we report four de novo RRAS2 variants in three individuals with NS. RRAS2 is a member of the RAS subfamily and is ubiquitously expressed. Three variants, c.70_78dup (p.Gly24_Gly26dup), c.216A>T (p.Gln72His), and c.215A>T (p.Gln72Leu), have been found in cancers; our functional analyses showed that these three changes induced elevated association of RAF1 and that they activated ERK1/2 and ELK1. Notably, prominent activation of ERK1/2 and ELK1 by p.Gln72Leu associates with the severe phenotype of the individual harboring this change. To examine variant pathogenicity in vivo, we generated zebrafish models. Larvae overexpressing c.70_78dup (p.Gly24_Gly26dup) or c.216A>T (p.Gln72His) variants, but not wild-type RRAS2 RNAs, showed craniofacial defects and macrocephaly. The same dose injection of mRNA encoding c.215A>T (p.Gln72Leu) caused severe developmental impairments and low dose overexpression of this variant induced craniofacial defects. In contrast, the RRAS2 c.224T>G (p.Phe75Cys) change, located on the same allele with p.Gln72His in an individual with NS, resulted in no aberrant in vitro or in vivo phenotypes by itself. Together, our findings suggest that activating RRAS2 mutations can cause NS and expand the involvement of RRAS2 proto-oncogene to rare germline disorders.

15.
Front Pediatr ; 7: 160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114772

RESUMO

In this report, we describe a novel T437N STAT1 mutation found in a mother and 3 of her 4 children which we demonstrate yields gain-of-function. All of the four patients with the T437N STAT1 mutation experienced lymphadenopathy. However, two of the children developed Nodular Lymphocyte Predominant Hodgkin Lymphoma (NHLPL) and have responded to chemotherapeutic regimens. The fourth sibling had neither the STAT1 variant nor lymphadenopathy or malignancy. To our knowledge this is the first description of a potential association between STAT1 GOF mutations and lymphoma development.

16.
Langmuir ; 35(18): 6169-6178, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-30991804

RESUMO

Some aphids that live in the leaf galls of the host plant are known to fabricate liquid marbles consisting of honeydew and wax particles as an inner liquid and a stabilizer, respectively. In this study, the liquid marbles fabricated by the galling aphids, Eriosoma moriokense, were extensively characterized with respect to size and size distribution, shape, nanomorphology, liquid/solid weight ratio, and chemical compositions. The stereo microscopy studies confirmed that the liquid marbles have a near-spherical morphology and that the number-average diameter was 368 ± 152 µm, which is 1 order of magnitude smaller than the capillary length of the honeydew. The field emission scanning electron microscopy studies indicated that micrometer-sized wax particles with fiber- and dumpling-like shapes coated the honeydew droplets, which rendered the liquid marbles hydrophobic and nonwetting. Furthermore, the highly magnified scanning electron microscopy images confirmed that the wax particles were formed with assemblage of submicrometer-sized daughter fibers. The contact angle measurements indicated that the wax was intrinsically hydrophobic and that the liquid marbles were stabilized by the wax particles in the Cassie-Baxter model. The weight ratio of the honeydew and the wax particles was determined to be 96/4, and the honeydew consisted of 19 wt % nonvolatile components and 81 wt % water. The 1H nuclear magnetic resonance, Fourier transform infrared spectroscopy, and mass spectroscopy studies confirmed that the wax mainly consisted of triglycerides and that the honeydew mainly consisted of saccharides (glucose and fructose) and ribitol. The atomic force microscopy studies confirmed that honeydew is sticky in nature.

17.
Medicine (Baltimore) ; 98(12): e14781, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30896620

RESUMO

RATIONALE: The prevalence of anastomotic recurrence (AR) in colorectal cancer (CRC) after resection of the primary tumor (PT) is 5% to 14%. However, no association has been observed between specific somatic genetic alterations and AR. Such associations may shed light on the mechanism of AR. PATIENT CONCERNS: We experienced 2 patients with AR of CRC. The first patient was a 42-year-old woman who underwent resection of an AR of rectal cancer 2 times within 19 months after resection of the PT. The second patient was a 77-year-old woman who underwent resection of an AR of ascending colon cancer twice within 38 months after resection of the PT. DIAGNOSIS: Both cases were diagnosed as repetitive AR. INTERVENTIONS: Loss of heterozygosity analysis, microsatellite instability (MSI) study of 9 microsatellite loci, and mutational analysis of KRAS, BRAF, APC, TP53, and SMAD4 were performed. OUTCOMES: All the lesions, except 1, harbored mutations in APC, KRAS, and TP53, without MSI, after neoadjuvant chemoradiotherapy. The APC, KRAS, and TP53 mutations were pathogenic or likely pathogenic in the PTs and ARs. Both women harbored the same KRAS G13D mutation, which accounts for 8% of all KRAS mutations in sporadic CRC s. The probability of the incidental occurrence of KRAS G13D mutations in both cases is 0.64%, provided that the mutations were independent of AR. LESSONS: Our findings may shed light on the mechanism of AR in CRC, namely, that the PT harbored the same mutations as the AR and the lesions in both cases harbored the KRAS G13D mutation.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Recidiva Local de Neoplasia/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Feminino , Humanos , Instabilidade de Microssatélites , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Proteína Supressora de Tumor p53/genética
18.
Anticancer Res ; 39(3): 1425-1432, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842178

RESUMO

BACKGROUND: We aimed to investigate the molecular features of synchronous colorectal cancer (CRC). MATERIALS AND METHODS: Out of 1,262 patients with CRC, 130 lesions in 59 patients with synchronous CRC were retrospectively analyzed. Microsatellite, v-Ki-Ras2 Kristen rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), tumor protein 53 (TP53) and ß-catenin status were evaluated and compared between synchronous CRC lesions in each patient. RESULTS: The subtypes of instability, BRAF and ß-catenin subtypes was significant but low. Patients with discordant KRAS and TP53 were not concordant between lesions in the same patient, and concordance of microsatellite KRAS/BRAF subtypes comprised 50.8% of those with synchronous CRC. The rate of patients with lesions containing both mutL homolog 1 (MLH1) methylation and microsatellite stable status was 66.7% in those with synchronous CRC, with at least one lesion with high microsatellite instability. CONCLUSION: The present study on synchronous CRC demonstrated a low concordance of molecular subtypes between lesions in the same patient. A molecular analysis of metastatic lesions is warranted for molecular targeted therapy of metastatic synchronous CRC.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
19.
Thorac Cancer ; 10(4): 832-838, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30821130

RESUMO

BACKGROUND: Tumor spread through alveolar spaces (STAS) is a recently described invasive pattern associated with the prognosis and recurrence of lung adenocarcinoma. This study was performed to determine whether the presence and distance of STAS can be predicted by the immunohistochemical intensity of SLX, a well-known cell adhesion protein. METHODS: In total, 245 patients with pathological stage I lung adenocarcinoma who underwent lobectomy with radical mediastinal lymph node dissection were identified from 1998 to 2012. Recurrence-free survival (RFS) was compared between patients stratified by STAS and the immunohistochemical intensity of SLX in the main tumor. Patients were divided into three groups based on the intensity of SLX staining: high (n = 108), moderate (n = 48), and low (n = 89). RESULTS: STAS was observed in 71 patients (29.0%). Patients with STAS had significantly poorer five-year RFS (67.1%) than those without STAS (84.8%). Although no relationship was observed between the existence of STAS and SLX intensity, the distance between STAS cells and the main tumor was significantly shorter in the moderate group (median 0.9 mm, range: 0.2-1.2 mm) than in the other two groups (median 1.2 mm, range: 0.4-5.0 mm). The five-year RFS rates in the high, moderate, and low groups were 80.0%, 96.0%, and 75.8%, respectively. Multivariate analysis revealed that pathological stage, lymphatic/vascular invasion, and SLX intensity were independent predictors of recurrence. CONCLUSION: SLX staining cannot predict the presence of STAS; however, it can predict the distance between STAS and the main tumor in stage I lung adenocarcinoma.

20.
Int J Hematol ; 109(4): 382-389, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30758723

RESUMO

Mutation in the gene encoding tRNA nucleotidyl transferase, CCA-adding 1 (TRNT1), an enzyme essential for the synthesis of the 3'-terminal CCA sequence in tRNA molecules, results in a disorder that features sideroblastic anemia, B-cell immunodeficiency, periodic fever, and developmental delay. Mutations in TRNT1 are also linked to phenotypes including retinitis pigmentosa, cataracts, and cardiomyopathy. To date, it has remained unclear how defective TRNT1 is linked to B-cell deficiency. Here we report the case of a 12-year-old boy without sideroblastic anemia who harbors novel compound heterozygous mutations in TRNT1. Immunophenotypic analysis revealed severely decreased levels of B cells and follicular helper T cells. In the bone marrow, B-cell maturation stopped at the CD19+CD10+CD20+/- pre-B-cell stage. Severe combined immunodeficiency mice transplanted with bone marrow hematopoietic stem cells from the patient showed largely normal B-cell engraftment and differentiation in the bone marrow and periphery at 24 weeks post-transplantation, comparable to those in mouse transplanted with healthy hematopoietic stem cells. Biochemical analysis revealed augmented endoplasmic reticulum (ER) stress response in activated T cells. Peripheral B-cell deficiency of TRNT1 deficiency may be associated with augmented ER stress in immature B cells in the bone marrow.


Assuntos
Heterozigoto , Síndromes de Imunodeficiência , Nucleotidiltransferases , Antígenos CD/sangue , Antígenos CD/genética , Linfócitos B/metabolismo , Linfócitos B/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Lactente , Masculino , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/patologia
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