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The side chain dynamics of poly(quinoxaline-2,3-diyl)s (PQXs) are expected to influence their conformation. To investigate these dynamics experimentally, quasielastic neutron scattering (QENS) was performed for PQXs in deuterated tetrahydrofuran (THF-d8) and deuterated 1,1,2-trichloroethane/THF (1,1,2-TCE-d3/THF-d8), in which they formed right-handed and left-handed helical structures, respectively. The mean-square displacement of the PQX side chains in 1,1,2-TCE-d3/THF-d8 was lower than that in THF-d8. Furthermore, QENS complementary studies and molecular dynamics simulations unraveled a coupling between the main-chain and side chain dynamics of PQXs, suggesting the possibility of controlling the main-chain helical chirality through the dynamics of chiral side chains. These insights present a novel strategy for the design of synthetic helical macromolecules with precise chirality control.
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AIM: To develop a model using radiomics features extracted from magnetic resonance imaging (MRI) images of Gamma Knife radiosurgery (GKRS) to predict the BRAF mutation in patients with melanoma brain metastases (MBM). MATERIALS AND METHODS: Data of 220 tumours were classified into two groups. One was a group whose BRAF mutation was identified, and the other group whose BRAF mutation was not identified. We extracted 1,962 radiomics features from gadolinium contrast-enhanced T1-weighted MRI treatment-planning images. Synthetic Minority Over-sampling TEchnique (SMOTE) was performed to address the unbalanced data-related issues. A single-layer neural network (NN) was used to build predictive models with radiomics features. The sensitivity, specificity, accuracy, and the area under the curve (AUC) were evaluated to assess the model performance. RESULTS: The prediction performance for the final evaluation without the SMOTE had an accuracy of 77.14%, a specificity of 82.44%, a sensitivity of 81.85%, and an AUC of 0.79. The application of SMOTE improved the prediction model to an accuracy of 83.1%, a specificity of 87.07%, a sensitivity of 78.82%, and an AUC of 0.82. CONCLUSION: The current study showed the feasibility of generating a highly accurate NN model for the BRAF mutation prediction. The prediction performance improved with SMOTE. The model assists physicians to obtain more accurate expectations of the treatment outcome without a genetic test.
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Neoplasias Encefálicas , Melanoma , Radiocirurgia , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Radiocirurgia/métodos , Imageamento por Ressonância Magnética/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Melanoma/diagnóstico por imagem , Melanoma/genética , Melanoma/radioterapia , Mutação/genética , Estudos RetrospectivosRESUMO
SETTING: Japan, an intermediate TB burden country. OBJECTIVE: To review TB-related technical enquiries received at the Research Institute of Tuberculosis, Japan, from January 2017 to December 2019. DESIGN: This was a cohort study. RESULTS: A total of 2,197 enquiries were analysed. On average, 61.0 enquiries/month (range: 42-81) were received. The enquiry rates were highest for the Yamanashi (4.65/100,000 population) and Ishikawa (4.55) Prefectures, and lowest in the Yamagata (0.46) and Tochigi (0.56) Prefectures. The main organisations the enquirers belonged to were local governments (n = 1,585, 72.1%) and healthcare facilities (n = 307, 14.0%). The enquirers were medical doctors (n = 391, 17.8%), nurses (n = 1,207, 54.9%), other healthcare professionals (n = 57, 2.6%), the general public (n = 168, 7.6%) and others/unknown (n = 374, 17.0%). The most frequent enquiries were about TB diagnosis and treatment (n = 501, 22.8%), including laboratory diagnosis (n = 88, 4.0%), TB treatment in general (n = 93, 4.2%) and management of comorbidities (n = 86, 3.9%), followed by contact investigations (n = 385, 17.5%) and TB in foreigners (n = 344, 15.7%). CONCLUSION: As the most frequent enquiries were about diagnosis and treatment of TB, the health ministry of Japan should maintain a few specialised TB institutions with TB physicians to provide technical assistance.
LIEU: Le Japon, un pays à charge intermédiaire en matière de TB. OBJECTIF: Examiner les demandes de renseignements techniques liées à la TB reçues au Research Institute of Tuberculosis, au Japon, de janvier 2017 à décembre 2019. METHODE: Il s'agissait d'une étude de cohorte. RÉSULTATS: Au total, 2 197 demandes ont été analysées. En moyenne, 61,0 demandes de renseignements/mois (fourchette : 4281) ont été reçues. Les taux de demande étaient les plus élevés dans les préfectures de Yamanashi (4,65/100 000 habitants) et d'Ishikawa (4,55), et les plus faibles dans les préfectures de Yamagata (0,46) et de Tochigi (0,56). Les principales organisations auxquelles appartiennent les enquêteurs sont les administrations locales (n = 1 585 ; 72,1%) et les établissements de santé (n = 307; 14,0%). Les enquêteurs étaient des médecins (n = 391 ; 17,8%), des infirmières (n = 1 207 ; 54,9%), d'autres professionnels de la santé (n = 57 ; 2,6%), le grand public (n = 168 ; 7,6%) et autres/inconnus (n = 374 ; 17,0%). Les demandes les plus fréquentes concernaient le diagnostic et le traitement de la TB (n = 501 ; 22,8%), y compris le diagnostic en laboratoire (n = 88 ; 4,0%), le traitement de la TB en général (n = 93 ; 4,2%) et la prise en charge des comorbidités (n = 86 ; 3,9%), suivis par les enquêtes sur les contacts (n = 385 ; 17,5%) et la TB chez les étrangers (n = 344 ; 15,7%). CONCLUSION: Comme les demandes de renseignements les plus fréquentes concernaient le diagnostic et le traitement de la TB, le ministère de la santé du Japon devrait maintenir quelques institutions spécialisées dans la TB avec des médecins spécialistes de la TB pour fournir une assistance technique.
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STUDY QUESTION: Is oocyte cryopreservation an applicable option for fertility preservation in unmarried patients with haematological malignancies? SUMMARY ANSWER: Oocyte cryopreservation via the vitrification method is accessible and may be considered an option for fertility preservation in unmarried patients with haematological malignancies. WHAT IS KNOWN ALREADY: Haematological malignancies are most commonly observed amongst adolescent and young adult women. Although the survival rate and life expectancy of those with haematological malignancies have improved, chemotherapy and radiotherapy may impair their reproductive potential. Oocyte cryopreservation is thus an ideal option to preserve their fertility. STUDY DESIGN SIZE DURATION: This study retrospectively evaluated 193 unmarried patients (age: 26.2 ± 0.4 years) with haematological malignancies, who consulted for oocyte cryopreservation across 20 different fertility centres in Japan between February 2007 and January 2015. The primary outcome measures were the oocyte retrievals and oocyte cryopreservation outcomes. The secondary outcome measures were the outcomes following oocyte warming for IVF. PARTICIPANTS/MATERIALS SETTING METHODS: The patients had commenced ovarian stimulation cycles via antagonist, agonist, natural and minimal methods for oocyte retrievals, defined according to the treatment strategy of each respective fertility centre. A vitrification method using the Cryotop safety kit was used for oocyte cryopreservation. ICSIs were used for insemination of warmed oocytes. The endometrial preparation method for embryo transfer was hormonal replacement therapy, except in the case of a patient who underwent a spontaneous ovulatory cycle. MAIN RESULTS AND THE ROLE OF CHANCE: Among 193 patients, acute myeloid leukaemia (n = 45, 23.3%) was most common, followed by acute lymphoid leukaemia (n = 38, 19.7%) and Hodgkin's lymphoma (n = 30, 15.5%). In total, 162 patients (83.9%) underwent oocyte retrieval, and oocytes were successfully cryopreserved for 155 patients (80.3%). The mean number of oocyte retrieval cycles and cryopreserved oocytes were 1.7 ± 0.2 and 6.3 ± 0.4, respectively. As of December 2019, 14 patients (9.2%) had requested oocyte warming for IVF. The survival rate of oocytes after vitrification-warming was 85.2% (75/88). The rates of fertilisation and embryo development were 80.0% (60/75) and 46.7% (28/60), respectively. Ten patients (71.4%) had successful embryo transfers, and seven live births (50.0%) were achieved. LIMITATIONS REASONS FOR CAUTION: This study was limited by its retrospective nature. Additionally, there remains an insufficient number of cases regarding the warming of vitrified oocytes to reliably conclude whether oocyte cryopreservation is effective for patients with haematological malignancies. Further long-term follow-up study is required. WIDER IMPLICATIONS OF THE FINDINGS: Oocyte retrieval and oocyte cryopreservation were accessible for patients with haematological malignancies; however, the number of oocyte retrievals may have been limited due to the initiation of cancer treatments. Acceptable embryonic and pregnancy outcomes could be achieved following oocyte warming; therefore, our results suggest that oocyte cryopreservation can be considered an option for fertility preservation in patients with haematological malignancies. STUDY FUNDING/COMPETING INTERESTS: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
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Atoms moving in a static periodic field experience a time-dependent oscillating field in their own rest frame. By tuning the frequency, an atomic transition can be induced. So far, this type of transition has been demonstrated in the EUV region or at higher frequencies by crystalline fields and in the microwave region by artificial fields. Here, we present the observation of the transition of positronium (Ps) in the sub-THz region by using an energy-tunable Ps beam with a multilayered magnetic grating. This grating produces a microsized periodic field, whose amplitude corresponds to a huge energy flux of â¼100 MW cm^{-2}, resulting in the efficient magnetic dipole transition.
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In November 2016, a woman in her 30s who stayed at an insecure, temporary housing facility, a manga café in Tokyo, Japan, for a year was diagnosed with sputum smear-positive tuberculosis (TB). Since the café had 31 staff members and provided with accommodation to many people, the local health office initiated a contact investigation. This study aims to characterise the cases found in the outbreak. A TB case was defined as a person tested bacteriologically positive for TB, or was determined to have TB by a physician. A latent TB infection case was defined as a person tested positive by interferon-γ release assay. From January 2016 through November 2017, there were 31 staff members at the manga café, of which, six developed TB disease (one smear-negative, culture-positive and five smear- and culture-negative) in addition to seven LTBI. Another long-term customer was found having sputum smear-positive TB. Variable numbers tandem repeat (VNTR) test revealed that the index patient and the long-term customer had the identical type of VNTR; however, one staff member had a different VNTR. Local health authorities should intensify screening long-term customers of such facilities for TB regularly as well as once a TB outbreak occurs.
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Busca de Comunicante/estatística & dados numéricos , Surtos de Doenças/estatística & dados numéricos , Mycobacterium tuberculosis/isolamento & purificação , Habitação Popular/tendências , Tuberculose/epidemiologia , Adulto , Estudos de Coortes , Controle de Doenças Transmissíveis/métodos , Busca de Comunicante/métodos , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites/genética , Pobreza , Prevalência , Estudos Retrospectivos , Medição de Risco , Classe Social , Escarro/microbiologia , Tóquio , Tuberculose/diagnóstico , População Urbana , Adulto JovemRESUMO
Denosumab treatment of osteoporotic patients, except those with severe renal insufficiency, reduced cCa levels. Low baseline cCa, low estimated glomerular filtration rate, and high bone turnover increased the risk of lower cCa, while increasing bone mineral density. Pretreatment with antiresorptive agents was beneficial in reducing the risk of hypocalcemia. INTRODUCTION: Although denosumab-induced hypocalcemia has been frequently observed in patients with chronic kidney disease (CKD) stages 4-5D being treated with denosumab for osteoporosis, few studies have assessed the risk factors for serum-corrected calcium (cCa) reductions in patients with non-severe renal insufficiency. This study assessed the risk factors for reduced cCa concentration following denosumab administration and analyzed factors predictive of changes in bone mineral density (BMD). METHODS: Seventy-seven osteoporotic patients, not including those with CKD stages 4-5D, were treated with 60 mg denosumab once every 6 months. Biochemical parameters and BMD were analyzed from prior to the initial dose until 1 month after the second dose. RESULTS: Following the first administration of denosumab, cCa levels decreased, reaching a minimum on day 7. Multiple linear regression analyses showed that baseline cCa, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, tartrate-resistant acid phosphatase-5b (TRACP-5b), and bone alkaline phosphatase (BAP) or pretreatment with antiresorptive agents were significant factors independently associated with the absolute reduction in cCa from baseline to day 7 (ΔcCa0-7 days). ΔcCa0-7 days after the second dose of denosumab was significantly lower than that after the first dose. After 6 months of denosumab treatment, both LS-BMD and FN-BMD significantly increased from baseline. LS-BMD and FN-BMD correlated significantly with baseline TRACP-5b or BAP and eGFR, respectively. CONCLUSIONS: Both low eGFR and high bone turnover were independent risk factors for denosumab-induced cCa decrement, and for increases in BMD. Pretreatment with antiresorptive agents may reduce the risk of hypocalcemia.
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Conservadores da Densidade Óssea/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Denosumab/efeitos adversos , Hipocalcemia/induzido quimicamente , Insuficiência Renal/complicações , Absorciometria de Fóton , Idoso , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Cálcio/sangue , Denosumab/uso terapêutico , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Hipocalcemia/sangue , Hipocalcemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Osteoporose/fisiopatologia , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologia , Fatores de RiscoRESUMO
Background: Japan had a tuberculosis (TB) notification rate of 13.9 per 100 000 population in 2016. Objectives: To characterise TB-related enquiries received by the Research Institute of Tuberculosis, Tokyo, Japan, between January 2014 and December 2016. Design: A descriptive study of the time, place and other attributes of the enquiries. Results: A total of 1864 enquiries were listed for analysis. On average, 51.8 enquiries (range 30-77) were received per month. The enquiry rates were highest for Yamanashi (5.87/100 000) and Kochi (5.77) Prefectures, and lowest in Miyazaki (0.45) and Saga (0.48) Prefectures. Enquirers belonged mostly to local governments (n = 1212, 65%) and health care facilities (n = 386, 21%), and included medical doctors (n = 412, 22%), nurses (n = 926, 50%) and the general public (n = 150, 8.0%). Most enquiries concerned TB diagnosis and treatment (n = 475, 25%), including diagnosis in general (n = 38, 2.0%), laboratory diagnosis (n = 83, 4.5%), anti-tuberculosis treatment in general (n = 62, 3.3%) and the management of comorbidities or adverse events (n = 60, 3.2%), followed by contact investigations (n = 371, 20%). Conclusions: As most enquiries concerned the diagnosis and treatment of TB, the Ministry of Health of Japan should maintain a number of specialised TB institutions with TB clinicians to provide technical assistance.
Contexte : Le Japon avait un taux de notification de la tuberculose (TB) de 13,9 par 100 000 habitants en 2016.Objectif : Caractériser les demandes liées à la TB reçues par le Research Institute of Tuberculosis, Tokyo, Japon, de janvier 2014 à décembre 2016.Schéma : Une étude descriptive en termes de date, lieu et autres caractéristiques des demandes.Résultats : Un total de 1864 demandes ont été listées pour l'analyse. En moyenne, 51,8 demandes (fourchette 3077) par mois ont été reçues. Les taux de demande ont été les plus élevés pour les préfectures de Yamanashi (5,87/100 000 habitants) et de Kochi (5,77) et les plus bas dans les préfectures de Miyazaki (0,45) et de Saga (0,48). Les organisations principales auxquelles appartenaient les demandeurs ont été les gouvernements locaux (n = 1212 ; 65%) et les structures de soins de santé (n = 386 ; 21%). Les demandeurs ont été des médecins (n = 412 22%), des infirmiers (n = 926 ; 50%) et le public général (n = 150 ; 8,0%). Les demandes les plus fréquentes ont été liées au diagnostic et au traitement de la TB (n = 475 ; 25%), incluant le diagnostic en général (n = 38 ; 2.0%), le diagnostic de laboratoire (n = 83 ; 4,5%), le traitement de la TB en général (n = 62 ; 3,3%) et la prise en charge des comorbidités ou des effets secondaires (n = 60 ; 3,2%), suivies par la recherche des contacts (n = 371 ; 20%).Conclusion : Comme les demandes les plus fréquentes ont été relatives au diagnostic et au traitement de la TB, le Ministère de la santé du Japon devrait maintenir quelques institutions spécialisées dans la TB avec des cliniciens qui pourraient fournir une assistance technique.
Marco de referencia: En el Japón, la tasa de notificación de tuberculosis (TB) fue 13,9 por 100 000 habitantes en el 2016.Objetivos: Caracterizar las consultas relacionadas con la TB que se recibieron en el Instituto de Investigación en Tuberculosis, Tokyo, Japón, de enero del 2014 a finales de diciembre del 2016.Método: Se llevó a cabo un estudio descriptivo de las consultas con respecto al tiempo, el lugar y otros atributos de las mismas.Resultados: Se registraron 1864 consultas para análisis. En promedio, se recibieron 51,8 consultas por mes (entre 30 y 77). La tasa de consultas más alta correspondió a las prefecturas de Yamanashi (5,87/100 000 habitantes) y Kochi (5,77) y la más baja a las prefecturas de Miyazaki (0,45) y Saga (0,48). Las principales organizaciones de los solicitantes pertenecían a los gobiernos locales (n = 1212; 65%) y a los establecimientos de salud (n = 386; 21%). Los solicitantes fueron médicos (n = 412; 22%), enfermeros (n = 926; 50%) y el público en general (n = 150; 8,0%). Las consultas más frecuentes se relacionaban con el diagnóstico y el tratamiento de la TB (n = 475; 25%), entre otros, el diagnóstico en general (n = 38; 2,0%), el diagnóstico en el laboratorio (n = 83; 4,5%), el tratamiento antituberculoso en general (n = 62; 3,3%) y el manejo de las enfermedades intercurrentes o las reacciones adversas (n = 60; 3,2%), seguidos de la investigación de contactos (n = 371; 20%).Conclusiones: Dado que las consultas más frecuentes se referían al diagnóstico y el tratamiento de la TB, el Ministerio de Salud del Japón debe conservar algunas instituciones especializadas en TB con médicos experimentados que presten asistencia técnica en esta esfera.
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The goal of the ASACUSA-CUSP collaboration at the Antiproton Decelerator of CERN is to measure the ground-state hyperfine splitting of antihydrogen using an atomic spectroscopy beamline. A milestone was achieved in 2012 through the detection of 80 antihydrogen atoms 2.7 m away from their production region. This was the first observation of 'cold' antihydrogen in a magnetic field free region. In parallel to the progress on the antihydrogen production, the spectroscopy beamline was tested with a source of hydrogen. This led to a measurement at a relative precision of 2.7×10-9 which constitutes the most precise measurement of the hydrogen hyperfine splitting in a beam. Further measurements with an upgraded hydrogen apparatus are motivated by CPT and Lorentz violation tests in the framework of the Standard Model Extension. Unlike for hydrogen, the antihydrogen experiment is complicated by the difficulty of synthesizing enough cold antiatoms in the ground state. The first antihydrogen quantum states scan at the entrance of the spectroscopy apparatus was realized in 2016 and is presented here. The prospects for a ppm measurement are also discussed.This article is part of the Theo Murphy meeting issue 'Antiproton physics in the ELENA era'.
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Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; one-sided P = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. Clinical trials registration: UMIN Clinical Trial Registry, number UMIN000000819.
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Carcinoma de Células Escamosas/radioterapia , Glote/patologia , Neoplasias Laríngeas/radioterapia , Radioterapia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Fracionamento da Dose de Radiação , Feminino , Humanos , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVES: In Japan, approximately 7000 smear-positive tuberculosis (TB) cases were reported in 2014. According to the law, such patients must be isolated in a TB ward until they become at least sputum smear-negative. However, there are some recalcitrant patients who are difficult to isolate because of problematic behaviors. This study was conducted to characterize recalcitrant TB patients and determine why they left the hospitals and how they were followed up after they left. STUDY DESIGN: Cross-sectional study. METHODS: We sent a self-administered questionnaire to the hospitals in Japan with over 11 TB isolation beds, asking about recalcitrant TB inpatients from April 2013 through March 2014, in terms of demographic information, the reasons why they left, and how they were followed up. RESULTS: A total of 38 recalcitrant patients were reported, of whom 15 (39.5%) self-discharged, eight (21.0%) were discharged, and 15 (39.5%) were transferred. Thirty-three (86.8%) were males. The main reason (52.6%) why the patients were considered recalcitrant was related to psychiatric problems. However, nine (23.6%) patients physically assaulted or insulted the staff members. Thirty-six (94.7%) were able to continue anti-TB treatment after they left the original hospital. CONCLUSION: Although the number of recalcitrant TB patients who were abusive was small, there should be TB facilities with law enforcement officials readily available to enforce isolation.
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Hospitalização/estatística & dados numéricos , Isolamento de Pacientes/estatística & dados numéricos , Tuberculose/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Alta do Paciente/estatística & dados numéricos , Inquéritos e Questionários , Adulto JovemRESUMO
Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.
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Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proliferação de Células/genética , Células Clonais , Exoma , Humanos , Taxa de Mutação , Nucleofosmina , Sequências de Repetição em Tandem , Fatores de TempoRESUMO
Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.
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Análise Mutacional de DNA/métodos , Leucemia Promielocítica Aguda/genética , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Exoma/genética , Perfilação da Expressão Gênica , Humanos , Proteínas Nucleares/genética , Recidiva , Fatores de Transcrição/genéticaRESUMO
Definitive chemoradiotherapy (CRT) with docetaxel (DOC) and 5-fluorouracil (5-FU) is a unique regimen for esophageal cancer. In this prospective phase II study, antitumor effect and safety of CRT using DOC and 5-FU for inoperable locally advanced esophageal cancer were evaluated. DOC 7.5 mg/m2 was infused on days 1, 8, 22, and 29. 5-FU 250 mg/m2 /day was infused continuously on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-45. Radiotherapy was given to 66 Gy in 33 fractions. Eleven patients with thoracic and five with cervical esophageal cancer were eligible. All patients had esophageal squamous cell carcinoma (ESCC). The response rate was 94%, with complete response in five patients (31%) and partial response in 10 (63%). Hematologic toxicity was mild; only one patient (6%) had Grade 1 leukopenia. Nonhematologic Grade 3 or higher adverse events were esophagitis (31%), anorexia (6%), and esophago-bronchial fistula (6%). No treatment-related deaths occurred. The median time to progression was 20 months and overall 3-year and 5-year survival were 44% and 31%, respectively. Definitive CRT using DOC and 5-FU could be performed safely, and it demonstrated a favorable antitumor effect for ESCC. This regimen might be indicated in patients in whom it is desirable to avoid myelosuppression and progression of renal impairment.