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Galaxies in the early Universe that are bright at submillimetre wavelengths (submillimetre-bright galaxies) are forming stars at a rate roughly 1,000 times higher than the Milky Way. A large fraction of the new stars form in the central kiloparsec of the galaxy1-3, a region that is comparable in size to the massive, quiescent galaxies found at the peak of cosmic star-formation history4 and the cores of present-day giant elliptical galaxies. The physical and kinematic properties inside these compact starburst cores are poorly understood because probing them at relevant spatial scales requires extremely high angular resolution. Here we report observations with a linear resolution of 550 parsecs of gas and dust in an unlensed, submillimetre-bright galaxy at a redshift of z = 4.3, when the Universe was less than two billion years old. We resolve the spatial and kinematic structure of the molecular gas inside the heavily dust-obscured core and show that the underlying gas disk is clumpy and rotationally supported (that is, its rotation velocity is larger than the velocity dispersion). Our analysis of the molecular gas mass per unit area suggests that the starburst disk is gravitationally unstable, which implies that the self-gravity of the gas is stronger than the differential rotation of the disk and the internal pressure due to stellar-radiation feedback. As a result of the gravitational instability in the disk, the molecular gas would be consumed by star formation on a timescale of 100 million years, which is comparable to gas depletion times in merging starburst galaxies5.
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Intensive systems with two or three rice (Oryza sativa L.) crops per year account for about 50% of the harvested area for irrigated rice in Asia. Any reduction in productivity or sustainability of these systems has serious implications for global food security. Rice yield trends in the world's longest-running long-term continuous cropping experiment (LTCCE) were evaluated to investigate consequences of intensive cropping and to draw lessons for sustaining production in Asia. Annual production was sustained at a steady level over the 50-y period in the LTCCE through continuous adjustment of management practices and regular cultivar replacement. Within each of the three annual cropping seasons (dry, early wet, and late wet), yield decline was observed during the first phase, from 1968 to 1990. Agronomic improvements in 1991 to 1995 helped to reverse this yield decline, but yield increases did not continue thereafter from 1996 to 2017. Regular genetic and agronomic improvements were sufficient to maintain yields at steady levels in dry and early wet seasons despite a reduction in the yield potential due to changing climate. Yield declines resumed in the late wet season. Slower growth in genetic gain after the first 20 y was associated with slower breeding cycle advancement as indicated by pedigree depth. Our findings demonstrate that through adjustment of management practices and regular cultivar replacement, it is possible to sustain a high level of annual production in irrigated systems under a changing climate. However, the system was unable to achieve further increases in yield required to keep pace with the growing global rice demand.
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Produção Agrícola/tendências , Grão Comestível/crescimento & desenvolvimento , Oryza/crescimento & desenvolvimento , Biomassa , Produção Agrícola/estatística & dados numéricos , Oryza/genéticaRESUMO
Greater nitrogen efficiency would substantially reduce the economic, energy and environmental costs of rice production. We hypothesized that synergistic balancing of the costs and benefits for soil exploration among root architectural phenes is beneficial under suboptimal nitrogen availability. An enhanced implementation of the functional-structural model OpenSimRoot for rice integrated with the ORYZA_v3 crop model was used to evaluate the utility of combinations of root architectural phenes, namely nodal root angle, the proportion of smaller diameter nodal roots, nodal root number; and L-type and S-type lateral branching densities, for plant growth under low nitrogen. Multiple integrated root phenotypes were identified with greater shoot biomass under low nitrogen than the reference cultivar IR64. The superiority of these phenotypes was due to synergism among root phenes rather than the expected additive effects of phene states. Representative optimal phenotypes were predicted to have up to 80% greater grain yield with low N supply in the rainfed dry direct-seeded agroecosystem over future weather conditions, compared to IR64. These phenotypes merit consideration as root ideotypes for breeding rice cultivars with improved yield under rainfed dry direct-seeded conditions with limited nitrogen availability. The importance of phene synergism for the performance of integrated phenotypes has implications for crop breeding.
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Nitrogênio , Oryza , Oryza/genética , Fenótipo , Raízes de Plantas , Solo/químicaRESUMO
We search for gravitational-wave signals produced by cosmic strings in the Advanced LIGO and Virgo full O3 dataset. Search results are presented for gravitational waves produced by cosmic string loop features such as cusps, kinks, and, for the first time, kink-kink collisions. A template-based search for short-duration transient signals does not yield a detection. We also use the stochastic gravitational-wave background energy density upper limits derived from the O3 data to constrain the cosmic string tension Gµ as a function of the number of kinks, or the number of cusps, for two cosmic string loop distribution models. Additionally, we develop and test a third model that interpolates between these two models. Our results improve upon the previous LIGO-Virgo constraints on Gµ by 1 to 2 orders of magnitude depending on the model that is tested. In particular, for the one-loop distribution model, we set the most competitive constraints to date: Gµâ²4×10^{-15}. In the case of cosmic strings formed at the end of inflation in the context of grand unified theories, these results challenge simple inflationary models.
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We present our current best estimate of the plausible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next several years, with the intention of providing information to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals for the third (O3), fourth (O4) and fifth observing (O5) runs, including the planned upgrades of the Advanced LIGO and Advanced Virgo detectors. We study the capability of the network to determine the sky location of the source for gravitational-wave signals from the inspiral of binary systems of compact objects, that is binary neutron star, neutron star-black hole, and binary black hole systems. The ability to localize the sources is given as a sky-area probability, luminosity distance, and comoving volume. The median sky localization area (90% credible region) is expected to be a few hundreds of square degrees for all types of binary systems during O3 with the Advanced LIGO and Virgo (HLV) network. The median sky localization area will improve to a few tens of square degrees during O4 with the Advanced LIGO, Virgo, and KAGRA (HLVK) network. During O3, the median localization volume (90% credible region) is expected to be on the order of 10 5 , 10 6 , 10 7 Mpc 3 for binary neutron star, neutron star-black hole, and binary black hole systems, respectively. The localization volume in O4 is expected to be about a factor two smaller than in O3. We predict a detection count of 1 - 1 + 12 ( 10 - 10 + 52 ) for binary neutron star mergers, of 0 - 0 + 19 ( 1 - 1 + 91 ) for neutron star-black hole mergers, and 17 - 11 + 22 ( 79 - 44 + 89 ) for binary black hole mergers in a one-calendar-year observing run of the HLV network during O3 (HLVK network during O4). We evaluate sensitivity and localization expectations for unmodeled signal searches, including the search for intermediate mass black hole binary mergers.
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BACKGROUND: The indications for major hepatectomy for gallbladder cancer either with or without pancreatoduodenectomy remain controversial. The clinical value of these extended procedures was evaluated in this study. METHODS: Patients who underwent major hepatectomy for gallbladder cancer between 1996 and 2016 were identified from a prospectively compiled database. Postoperative outcomes and overall survival were compared between patients undergoing major hepatectomy alone or combined with pancreatoduodenectomy (HPD). RESULTS: Seventy-nine patients underwent major hepatectomy alone and 38 patients had HPD. The patients who underwent HPD were more likely to have T4 disease (P < 0·001), nodal metastasis (P = 0·015) and periaortic nodal metastasis (P = 0·006), but were less likely to receive adjuvant therapy (P = 0·006). HPD was associated with a high incidence of grade III or higher complications (P = 0·002) and death (P = 0·037). Overall survival was longer in patients who underwent major hepatectomy alone than in patients who underwent HPD (median survival time 32 versus 10 months; P < 0·001). In multivariable analysis, surgery in the early period (1996-2006) (P = 0·002), pathological T4 disease (P = 0·005) and distant metastasis (P < 0·001) were associated with shorter overall survival, and cystic duct tumour (P = 0·002) with longer overall survival. CONCLUSION: Major hepatectomy alone for gallbladder cancer contributes to favourable overall survival with low morbidity and mortality, whereas HPD is associated with poor overall survival and high morbidity and mortality rates. HPD may eradicate locally spreading gallbladder cancer; however, the indication for the procedure is questioned from an oncological viewpoint.
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Neoplasias da Vesícula Biliar/cirurgia , Hepatectomia , Pancreaticoduodenectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Hepatectomia/efeitos adversos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: Little is known about the effect of additional resection for a frozen-section-positive distal bile duct margin (DM) in perihilar cholangiocarcinoma. METHODS: Patients who underwent surgical resection for perihilar cholangiocarcinoma between 2001 and 2015 were analysed retrospectively, focusing on the DM. RESULTS: Of 558 consecutive patients who underwent frozen-section examination for a DM, 74 (13·3 per cent) had a frozen-section-positive DM with invasive cancer or carcinoma in situ. Eventually, 53 patients underwent additional resection (bile duct resection in 44 and pancreatoduodenectomy in 9), whereas the remaining 21 patients did not. Ultimately, R0 resection was achieved in 30 of the 53 patients (57 per cent). No patient who underwent additional resection died from surgical complications. The 44 patients with additional bile duct resection had a 5-year overall survival rate of 31 per cent. Overall survival of the nine patients who had pancreatoduodenectomy was better, with a 10-year rate of 67 per cent. Survival of the 21 patients without additional resection was dismal: all died within 5 years. Multivariable analyses identified nodal status and additional resection as independent prognostic factors (lymph node metastasis: hazard ratio (HR) 2·26, 95 per cent c.i. 1·26 to 4·07; bile duct resection versus no additional resection: HR 0·32, 0·17 to 0·60; pancreatoduodenectomy versus no additional resection: HR 0·08, 0·02 to 0·29). CONCLUSION: Additional resection for frozen-section-positive DM in perihilar cholangiocarcinoma frequently yields R0 margins. It offers a better chance of long-term survival, and thus should be performed in carefully selected patients.
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Neoplasias dos Ductos Biliares/cirurgia , Ducto Hepático Comum/patologia , Tumor de Klatskin/cirurgia , Margens de Excisão , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Feminino , Secções Congeladas , Hepatectomia , Ducto Hepático Comum/cirurgia , Humanos , Tumor de Klatskin/mortalidade , Tumor de Klatskin/patologia , Masculino , Pessoa de Meia-Idade , Pancreaticoduodenectomia , Reoperação , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: In the eighth edition of the AJCC cancer staging classification, the T system for distal cholangiocarcinoma (DCC) has been revised from a layer-based to a depth-based approach. The aim of this study was to propose an optimal T classification using a measured depth in resectable DCC. METHODS: Patients who underwent pancreatoduodenectomy for DCC at 32 hospitals between 2001 and 2010 were included. The distance between the level of the naive bile duct and the deepest cancer cells was measured as depth of invasion (DOI). Invasive cancer foci were measured as invasive tumour thickness (ITT). Log rank χ2 scores were used to determine the cut-off points, and concordance index (C-index) to assess the survival discrimination of each T system. RESULTS: Among 404 patients, DOI was measurable in 182 (45·0 per cent) and ITT was measurable in all patients, with median values of 2·3 and 5·6 mm respectively. ITT showed a positive correlation with DOI (rS = 0·854, P < 0·001), and the cut-off points for prognosis were 1, 5 and 10 mm. Median survival time was shorter with increased ITT: 12·4 years for ITT below 1 mm, 5·2 years for ITT at least 1 mm but less than 5 mm, 3·0 years for ITT at least 5 mm but less than 10 mm, and 1·5 years for ITT 10 mm or more (P < 0·001). This classification exhibited more favourable prognostic discrimination than the T systems of the seventh and eighth editions of the AJCC (C-index 0·646, 0·622 and 0·624 respectively). CONCLUSION: ITT is an accurate approach for depth assessment in DCC. The four-tier ITT classification with cut-off points of 1, 5 and 10 mm seems to be a better T system than those in the seventh and eighth editions of the AJCC classification.
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Neoplasias dos Ductos Biliares/classificação , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/classificação , Colangiocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Pancreaticoduodenectomia , Estudos RetrospectivosRESUMO
BACKGROUND: Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. METHODS: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. RESULTS: Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse-free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare. CONCLUSION: The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/).
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Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Procedimentos Cirúrgicos do Sistema Biliar , Carcinoma Adenoescamoso/tratamento farmacológico , Desoxicitidina/análogos & derivados , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/cirurgia , Quimioterapia Adjuvante , Desoxicitidina/uso terapêutico , Esquema de Medicação , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND AND PURPOSE: X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), caused by mutations in gap junction protein beta 1 (GJB1), is characterized by various central nervous system symptoms and gender differences of clinical severity. The aim of this study was to identify the frequency and mutation spectrum of CMTX1 patients in Japan and to demonstrate their phenotypic diversities. METHODS: Using three high-throughput sequencing systems, targeted gene panel sequencing on 1483 unrelated index patients with suspected Charcot-Marie-Tooth (CMT) disease was performed. The peripheral and central nervous system involvements of all patients with GJB1 variants were assessed retrospectively and a detailed gender comparison was conducted with the CMT examination score. RESULTS: Twenty-three novel and 36 described GJB1 variants were identified from 88 pedigrees, in which 34 female and 78 male patients were enrolled. Mean age at onset of the male patients was much younger than the females, 21.56 ± 17.63 years vs. 35.53 ± 23.72 years (P = 0.007). Male patients presented with more severe phenotypes in every examination item, but statistical differences were observed only in motor dysfunctions of the lower extremities and vibration sensation. No significant sensory difference was identified between genders, either clinically or electrophysiologically. Central nervous system dysfunctions were found in 15 patients from 12 pedigrees. Therein, six patients developed stroke-like phenotypes, with dysarthria as the leading symptom. CONCLUSIONS: A relatively lower frequency of CMTX1 (5.9%) was demonstrated and a broad mutation spectrum of GJB1 was described. Detailed clinical differences between genders and various central nervous system symptoms were also illustrated, even in the same pedigree.
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Doença de Charcot-Marie-Tooth/diagnóstico , Conexinas/genética , Disartria/diagnóstico , Mutação , Fenótipo , Adolescente , Adulto , Idade de Início , Doença de Charcot-Marie-Tooth/genética , Criança , Pré-Escolar , Disartria/genética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Retrospectivos , Fatores Sexuais , Adulto Jovem , Proteína beta-1 de Junções ComunicantesRESUMO
Efficacy and safety of testosterone gel 2% (TG) were evaluated in two phase 3, open-labelled, single-arm, multicentre studies (000023 and extension study 000077). Hypogonadal men having serum testosterone levels <300 ng/dl at two consecutive measurements were included. Study duration was 9 months (000023: 3 months; 000077: 6 months). Starting dose of TG (46 mg) was applied on upper arm/shoulder. The primary endpoint (000023) was responder rate (subjects with average 24-hour serum testosterone concentration 300-1050 ng/dl on Day 90). Study 000077 evaluated the safety of TG in patients rolling over from study 000023 over a period of 6 months. Of 180 subjects in 000023, 172 completed and 145 rolled over to 000077, with 127 completers. The responder rate was 85.5%. Fewer subjects in 000077 (12.7%) versus 000023 (31.8%) had maximum testosterone concentration (Cmax ) >1500 ng/dl, with no significant safety concerns. Significant improvements in sexual function and quality of life were noted in both studies. Subjects experienced few skin reactions without notable increases in prostate-specific antigen and haematocrit levels. TG was efficacious with an acceptable safety profile. Cmax >1500 ng/dl did not exhibit distinct impact on safety parameters. However, further optimisation of titration schema to reduce Cmax is warranted while maintaining the average steady state total testosterone concentration.
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Androgênios/uso terapêutico , Terapia de Reposição Hormonal/efeitos adversos , Hipogonadismo/tratamento farmacológico , Testosterona/uso terapêutico , Administração Cutânea , Adolescente , Adulto , Idoso , Androgênios/administração & dosagem , Androgênios/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and [Formula: see text] credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5-[Formula: see text] requires at least three detectors of sensitivity within a factor of [Formula: see text] of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.
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Rice is the staple food for almost half of the world population. In South and South East Asia, about 40% of rice production is from deltaic regions that are vulnerable to salt stress. A quantitative approach was developed for characterizing genotypic variability in biomass production, leaf transpiration rate and leaf net photosynthesis responses to salinity during the vegetative stage, with the aim of developing efficient screening protocols to accelerate breeding varieties adapted to salt-affected areas. Three varieties were evaluated in pots under greenhouse conditions and in the field, with average soil salinity ranging from 2 to 12 dS m-1. Plant biomass, net photosynthesis rate, leaf transpiration rate and leaf conductance were measured at regular intervals. Crop responses were fitted using a logistic function with three parameters: 1) maximum rate under control conditions (Ymax), 2) salinity level for 50% of reduction (b), and 3) rate of reduction (a). Variation in the three parameters correlated significantly with variation in plant biomass production under increasing salinity. Salt stress levels that caused 50% reduction in net leaf photosynthesis and transpiration rates were higher in the tolerant genotype BRRI Dhan47 (16.5 dS m-1 and 14.3 dS m-1, respectively) than the sensitive genotype IR29 (11.1 dS m-1 and 6.8 dS m-1). In BRRI Dhan47, the threshold beyond which growth was significantly reduced was above 5 dS m-1 and the rate of growth reduction beyond this threshold was as low as 4% per unit increase in salinity. This quantitative approach to screening for salinity tolerance in rice offers a means to better understand rice growth under salt stress and, using simulation modelling, can provide an improved tool for varietal characterization.
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The rice model ORYZA v3 has been recently improved to account for salt stress effect on rice crop growth and yield. This paper details subsequent studies using the improved model to explore opportunities for improving salinity tolerance in rice. The objective was to identify combinations of plant traits influencing rice responses to salinity and to quantify yield gains by improving these traits. The ORYZA v3 model was calibrated and validated with field experimental data collected between 2012 and 2014 in Satkhira, Bangladesh and Infanta, Quezon, Philippines, then used for simulations scenario considering virtual varieties possessing different combinations of crop model parameter values related to crop salinity response and the soil salinity dynamic observed at Satkhira site. Simulation results showed that (i) short duration varieties could escape end of season increase in salinity, while long duration varieties could benefit from an irrigated desalinization period occurring during the later stages of crop growth in the Satkhira situation; (ii) combining short duration growth with salt tolerance (bTR and bPN) above 12 dS m-1 and a resilience trait (aSalt) of 0.11 in a variety, allows maintenance of 65-70% of rice yield under increasing salinity levels of up to 16 dS m-1; and (iii) increasing the value of the tolerance parameter b by 1% results in 0.3-0.4% increase in yield. These results are relevant for defining directions to increase rice productivity in saline environments, based on improvements in phenology and quantifiable salt tolerance traits.
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Background: Sorafenib is a multikinase-tyrosine kinase inhibitor commonly used in a variety of cancers. There are concerns about the increased risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib. We performed an up-to-date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs. Patients and methods: We carried out a systematic search of electronic databases for studies published from inception to February 2016 without any restrictions. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with nontargeted chemotherapy (Sorafenib arm) versus placebo or nontargeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs). Results: Of 471 studies identified, a total of 12 phase 3 RCTs involving 6797 solid cancer patients comparing sorafenib with control met the eligibility criteria and were included. The overall incidence of SAEs and FAEs with sorafenib were 26.4% (95% CI, 18.0-36.9%) and 1.3% (95% CI: 0.8-2.2%), respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs (RR: 1.49, 95% CI: 1.18-1.89, P = 0.001) and FAEs (RR: 1.82, 95% CI: 1.05-3.14, P = 0.033). This association varied significantly with cancer types (P < 0.001) and approval status (P = 0.012) for SAEs but no evidence of heterogeneity was found for FAEs. Conclusions: This meta-analysis of phase 3 RCTs demonstrates an increased risk of both SAEs and FAEs with sorafenib use in adult patients with solid cancers. This quantification of increased risks of SAEs and FAEs will be important in considering the trade-off of sorafenib treatment during shared decision-making.
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Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias/mortalidade , Niacinamida/efeitos adversos , Modelos de Riscos Proporcionais , Risco , SorafenibeRESUMO
The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still unknown in Japan. We collected a broad cohort of 33 unrelated patients with predominant sensory and/or autonomic dysfunctions, who were referred to our genetic laboratory. A gene panel sequencing targeting 18 HSAN-related genes was performed using a next-generation sequencing system. A recurrent frame shift mutation in the WNK1/HSN2 gene, c.3237_3238insT (p.Asp1080*), was detected in 5 patients. This mutation was homozygous in 4 cases and of a compound heterozygous genotype in 1 case. Geographic and haplotype analysis of all 5 patients suggested a founder event. In addition, a novel heterozygous nonsense variant, c.2615C>G (p.Ser872*), was identified. All the 5 patients presented with severe sensory and autonomic dysfunctions at birth or during adolescence. In 2 patients, an uncommon phenotype of acute pathological pain presented at ~50 years of age. Here, we present the first founder mutation of WNK1/HSN2, in addition to French Canadian, which accounts for ~15.2% of Japanese patients with HSAN in our cohort. We have also reviewed all previously described mutations in WNK1/HSN2 and reconciled their nomenclature strategy on the basis of the current longest transcript.
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Códon sem Sentido , Efeito Fundador , Mutação da Fase de Leitura , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Adulto , Idade de Início , Idoso , Povo Asiático , Estudos de Coortes , Feminino , Expressão Gênica , Haplótipos , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Neuropatias Hereditárias Sensoriais e Autônomas/etnologia , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan. MATERIALS AND METHODS: From April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing. RESULTS: We identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy. CONCLUSION: We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.
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Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Efeito Fundador , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Proteínas da Mielina/genética , Linhagem , Reprodutibilidade dos Testes , Sequenciamento do Exoma , Adulto JovemRESUMO
Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino-terminal domain (46-290) for memory suppression whereas carboxyl domain (598-854) and the amino-terminal residues (1-45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion/mutation constructs reveal that protein domains 598-854 and 349-402 are both required for the suppression of axonal branching, while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403-596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403-596 and 349-402 for synaptic suppression, while amino-terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.
Assuntos
Memória/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Animais , Animais Geneticamente Modificados/genética , Axônios/metabolismo , Encéfalo/metabolismo , Dendritos/metabolismo , Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Disbindina , Proteínas Associadas à Distrofina/metabolismo , Humanos , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Neurônios/metabolismo , Domínios Proteicos/genética , Sinapses/genética , Sinapses/metabolismoRESUMO
BACKGROUND AND PURPOSE: The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of Charcot-Marie-Tooth disease (CMT) type 2Z in 2016. We aimed to describe the clinical and mutational spectrum of patients with CMT harboring MORC2 mutations in Japan. METHODS: We analyzed samples from 781 unrelated patients clinically diagnosed with CMT using deoxyribonucleic acid microarray or targeted resequencing by next-generation sequencing, and samples from 434 mutation-negative patients were subjected to whole-exome sequencing. We extracted MORC2 variants from these whole-exome sequencing data and classified them according to American College of Medical Genetics standards and guidelines. RESULTS: We identified MORC2 variants in 13 patients. As the second most common causative gene of CMT type 2 after MFN2, MORC2 variants were detected in 2.7% of patients with CMT type 2. The mean age of onset was 10.3 ± 8.7 years, and the inheritance pattern was mostly sporadic (11/13 patients, 84.6%). The clinical phenotype was typically length-dependent polyneuropathy, and electrophysiological studies revealed sensory-dominant axonal neuropathy. Mental retardation was identified in 4/13 patients (30.8%). p.Arg190Trp, as a mutational hotspot, was observed in eight unrelated families. We also identified two novel probably pathogenic variants, p.Cys345Tyr and p.Ala369Val, and one novel uncertain significance variant, p.Tyr332Cys. CONCLUSIONS: Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Mutação , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Japão , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
This study aimed to validate quantitative light-induced fluorescence (QLF) as a diagnostic tool for mild and moderate enamel fluorosis in permanent teeth, comparing it to visual diagnosis and histological assessment completed using polarized light microscopy (PLM). The buccal surfaces of 139 teeth were visually classified using the Thylstrup and Fejerskov Index (TFI) into sound (TFI 0; n = 17), mild (TFI 1-2; n = 69), and moderate (TFI 3-4; n = 43) fluorosis. Fluorosis was then assessed with QLF (variables ΔF, A, and ΔQ at 5-, 15-, and 30-radiance thresholds) using as reference areas the entire surface and a region of interest (ROI), identified as the most representative region of a fluorosis lesion. PLM images of longitudinal thin sections including the ROI were assessed for histological changes. Correlations among TFI, PLM, and QLF were determined. A receiver-operating characteristic curve was conducted to determine QLF's diagnostic accuracy when compared to the TFI and PLM assessments. This was used to assess the probability that the images were correctly ranked according to severity as determined by PLM and TFI. A positive correlation was found between QLF and PLM, and between QLF and TFI. QLF showed the highest sensitivity and specificity for the diagnosis of mild fluorosis. There was also a strong agreement between TFI and PLM. The selection of a ROI resulted in a stronger correlation with TFI and PLM than when the entire surface was used. The study results indicate that defining an ROI for QLF assessments is a valid method for the diagnosis of mild and moderate enamel fluorosis.