Exome sequencing of a single individual for a clinical indication may result in the identification of incidental deleterious variants unrelated to the indication for testing (secondary findings). ...Given the recent availability of clinical exome testing, there is a limited knowledge regarding the disclosure preferences and impact of secondary findings in a clinical diagnostic setting. In this article, we provide preliminary data regarding the preferences for secondary findings results disclosure based on the first 200 families referred to Ambry Genetics for diagnostic exome sequencing.
Secondary findings were categorized into four groups in the diagnostic exome sequencing consent: carrier status of recessive disorders, predisposition to later-onset disease, predisposition to increased cancer risk, and early-onset disease. In this study, we performed a retrospective analysis of patient responses regarding the preferences for secondary findings disclosure.
The majority of patients (187/200; 93.5%) chose to receive secondary results for one or more available categories. Adult probands were more likely than children to opt for blinding of secondary data (16 vs. 4%, respectively). Among responses for blinding, preferences were evenly scattered among categories.
These data represent the unprecedented results of a large reference laboratory providing clinical exome sequencing. We report, for the first time, the preferences of patients and families for the receipt of secondary findings based on clinical genome sequencing. Overwhelmingly, families undergoing exome sequencing opt for the disclosure of secondary findings. The data may have implications regarding the development of guidelines for secondary findings reporting among patients with severe and/or life-threatening disease undergoing clinical genomic sequencing.
...we propose that it is possible to identify drugs potentially regulative for BCa, based on a newly established algorithm predicting the infiltration level of immune and stromal cells in the tumor ...microenvironment. ...these results enhance the idea that HIF-1α may be a potential target of immunotherapy for BCa. Caspase-8 plays an essential role by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. ...caspase-8 is an important regulator of immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment. ...the current study identified six potentially regulative drugs (FG-2216, Emricasan, ENMD-1198, Carvedilol, PX-478, and 2-Methoxyestradiol) and a potential immunotherapy target (EFNB2) of BCa based on the concept of the tumor microenvironment.
The last Monday in February is the ＂Rare Disease Day＂ every year. This year the theme of it is ＂Join us in making the voice of rare diseases heard＂, proposed by World Health Organization ...（http：//www.rarediseaseday.org）. Rare diseases are a group of serious chronic diseases, with a high morbidity and mortality rates.
•Our study confirms that abnormal deposition of iron in the SNc and SNr is an obvious characteristic in PD patients.•Our data showed that PDAR patients have higher iron content in the GP than PDTD ...patients.•Our study indicates that abnormal iron deposition in the GP is related to the phenotype of Akinetic/Rigid in PD patients.
The loss of dopaminergic cells and excessive iron deposition in some deep brain nuclei are associated with the pathophysiology of PD, and different clinical subtypes may indicate different pathological processes. This study was designed to investigate the relationships between regional iron in the cardinal subcortical nuclei and different clinical subtypes.
Nine Arkinetic/Rigid-dominant Parkinson’s disease (PDAR) patients, eight Tremor-dominant (PDTD)patients and 10 matched healthy controls were recruited for this study. The iron content in 8 cardinal subcortical nuclei was measured through SWI sequence scanning (3.0 T), and different patterns of iron deposition were analyzed not only between the PD patients and HC groups but also between the different clinical subtypes.
Compared with the healthy controls, the iron content in the substantia nigra pars compacta(SNc), substantia nigra pars reticulata(SNr) from both the severe and milder side in PD groups were significantly increased (P < 0.01 and P < 0.02 for SNc; both P < 0.01 for SNr), and the iron content in the GP of both the severe and milder side of the PDAR patients was significantly increased compared with the PDTD patients (P < 0.01 and P = 0.02, respectively)
SWI is a very good technique for the in vivo assessment of subcortical nucleus iron content, and abnormal deposition of iron in the SNc and SNr is an obvious characteristic in PD patients. Furthermore, our data indicates that PDAR patients have higher iron content in the GP than PDTD patients and HCs, indicating that abnormal iron deposition in GP is related to the phenotype of Akinetic/Rigid in PD patients.
Abstract It has been reported that some single-nucleotide polymorphisms (SNPs) are associated with the risk of Parkinson's disease (PD), but whether a combination of these SNPs would have a stronger ...association with PD than any individual SNP is unknown. Sixteen SNPs located in the 8 genes and/or loci ( SNCA , LRRK2 , MAPT , GBA , HLA-DR , BST1 , PARK16 , and PARK17 ) were analyzed in a Chinese cohort consisting of 1061 well-characterized PD patients and 1066 control subjects from Central South of Mainland China. We found that Rep1, rs356165, and rs11931074 in SNCA gene; G2385R in LRRK2 gene; rs4698412 in BST1 gene; rs1564282 in PARK17 ; and L444P in GBA gene were associated with PD with adjustment of sex and age ( p < 0.05) in the analysis of 16 variants. PD risk increased when Rep1 and rs11931074, G2385R, rs1564282, rs4698412; rs11931074 and G2385R, rs1564282, rs4698412; G2385R and rs1564282, rs4698412; and rs1564282 and rs4698412 were combined for the association analysis. In addition, PD risk increased cumulatively with the increasing number of variants (odds ratio for carrying 3 variants, 3.494). In summary, we confirmed that Rep1, rs356165, and rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17 , and L444P in GBA gene have an independent and combined significant association with PD. SNPs in these 4 genes have a cumulative effect with PD.
ObjectivesCarcinosarcoma (CS) is a rare and biphasic malignancy characterised by a highly invasive biological nature and poor prognosis. This study explored the epidemiology, site-specific ...characteristics and survival outcome of CS.DesignWe conducted a retrospective study in the Surveillance, Epidemiology and End Results (SEER) database (1975–2018) for primary CS.Setting and participantsSEER database includes publicly available information from regional and state cancer registries in the US centres. A total of 5042 CS patients were identified. We selected the top five anatomic CS (uterus, double adnexa, lung, bladder and breast) patients for further analysis.Primary outcome measuresIncidence was estimated by geographical region, age, sex, race, stage and primary site. Trends were calculated using joinpoint regression. The cancer-specific survival (CSS) rate and initial treatment were summarised.ResultsNearly 80% of CS occurred in the uterus and double adnexa, followed by lung, bladder and breast. The elderly and black population presented the highest age-adjusted rate of CS. The rates of distant metastasis in CS progressively increased from 1989 to 2018. Atlanta was the area with the highest incidence at 0.7 per 100 000. Pulmonary and bladder CS more frequently occurred in men and were diagnosed with regional stage. Distant metastasis was mostly found in ovary/fallopian tube CS. Radiotherapy was more commonly applied in uterine CS, while adnexa CS cases were more likely to receive chemotherapy. Multiple treatments were more used in breast CS. Pulmonary CS seemed to suffer worse CSS (median: 9.92 months), for which radiotherapy might not provide survival benefits (HR 0.60, 95% CI 0.42 to 0.86). Compared with the common histological types in each site, CS had the shortest survival.ConclusionsCS has unique clinical features in each primary site. Substantial prognosis variances exist based on tumour locations. The aggressive course is the common feature in CS at all sites.
Summary
Background
In addition to their original applications for lowering cholesterol, statins display multiple neuroprotective effects. Inflammatory reactions and the PI3K/AKT/caspase 3 pathway are ...strongly implicated in dopaminergic neuronal death in Parkinson's disease (PD). This study aims to investigate how simvastatin affects 6‐hydroxydopamine‐lesioned PC12 via regulating PI3K/AKT/caspase 3 and modulating inflammatory mediators.
Methods
6‐hydroxydopamine‐treated PC12 cells were used to investigate the neuroprotection of simvastatin, its association with the PI3K/AKT/caspase 3 pathway, and antiinflammatory responses. Dopamine transporters (DAT) and tyrosine hydroxylase (TH) were examined in 6‐hydroxydopamine‐treated PC12 after simvastatin treatment.
Results
Simvastatin‐mediated neuroprotection was associated with a robust reduction in the upregulation induced by 6‐OHDA of inflammatory mediators including IL‐6, COX2, and TNF‐α. The downregulated DAT and TH levels in 6‐OHDA‐lesioned PC12 were restored after simvastatin treatment. Simvastatin reversed 6‐OHDA‐induced downregulation of PI3K/Akt phosphorylation and attenuated 6‐OHDA‐induced upregulation of caspase 3 in PC12. Furthermore, the PI3K inhibitor LY294002 pronouncedly abolished the simvastatin‐mediated attenuation in caspase 3.
Conclusions
Our results demonstrate that simvastatin provides robust neuroprotection against dopaminergic neurodegeneration, partially via antiinflammatory mechanisms and the PI3K/Akt/caspase 3 pathway. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD and might elucidate the molecular mechanisms of simvastatin effects in PD.
Parkinson’s disease (PD) is a progressive neurodegenerative disease primarily characterized by the hallmarks of motor symptoms, such as tremor, bradykinesia, rigidity, and postural instability. ...However, through clinical investigations in patients and experimental findings in animal models of Parkinson’s disease for years, it is now well recognized that Parkinson’s disease is more than just a motor-deficit disorder. The majority of Parkinson’s disease patients suffer from nonmotor disabilities, for instance, cognitive impairment, autonomic dysfunction, sensory dysfunction, and sleep disorder. So far, anti-PD prescriptions and surgical treatments have been mainly focusing on motor dysfunctions, leaving cognitive impairment a marginal clinical field. Within the nonmotor symptoms, cognitive impairment is one of the most common and significant aspects of Parkinson’s disease, and cognitive deficits such as dysexecutive syndrome and visuospatial disturbances could seriously affect the quality of life, reduce life expectancy, prolong the duration of hospitalization, and therefore increase burdens of caregiver and medical costs. In this review, we have done a retrospective study of the recent related researches on epidemiology, clinical manifestation and diagnosis, genetics, and potential treatment of cognitive deficits in Parkinson’s disease, aiming to provide a summary of cognitive impairment in Parkinson’s disease and make it easy for clinicians to tackle this challenging issue in their future practice.
Brassinosteroids (BRs) play important roles in plant growth and development. Although BR receptors have been intensively studied in Arabidopsis, those in foxtail millet remain largely unknown. Here, ...we show that the BR signaling function of BRASSINOSTEROID INSENSITIVE 1 (BRI1) is conserved between Arabidopsis and foxtail millet, a new model species for C4 and Panicoideae grasses. We identified four putative BR receptor genes in the foxtail millet genome: SiBRI1, SiBRI1-LIKE RECEPTOR KINASE 1 (SiBRL1), SiBRL2 and SiBRL3. Phylogenetic analysis was used to classify the BR receptors in dicots and monocots into three branches. Analysis of their expression patterns by quantitative real-time PCR (qRT-PCR) showed that these receptors were ubiquitously expressed in leaves, stems, dark-grown seedlings, roots and non-flowering spikelets. GFP fusion experiments verified that SiBRI1 localized to the cell membrane. We also explored the SiBRI1 function in Arabidopsis through complementation experiments. Ectopic overexpression of SiBRI1 in an Arabidopsis BR receptor loss-of-function mutant, bri1-116, mostly reversed the developmental defects of the mutant. When SiBRI1 was overexpressed in foxtail millet, the plants showed a drooping leaf phenotype and root development inhibition, lateral root initiation inhibition, and the expression of BR synthesis genes was inhibited. We further identified BRI1-interacting proteins by immunoprecipitation (IP)-mass spectrometry (MS). Our results not only demonstrate that SiBRI1 plays a conserved role in BR signaling in foxtail millet but also provide insight into the molecular mechanism of SiBRI1.
Populus euphratica is native to semi-arid regions of the Xinjiang Uyghur Autonomous Region of China, and studying its drought responses will greatly increase the understanding of how trees acclimate ...to drought. Water was withheld for seven weeks in four different drought stress treatments, with regime 1 being the least drought stressed and regime 4 being the most, and the poplar's transcriptional profiles examined with Affymetrix Poplar GeneChip microarrays. The number of significantly up or down transcriptional changes increased with the severity of drought stress, with regime 1, 2, 3 and 4 showing 952, 1354, 2138 and 2360 altered transcripts, respectively. Only 277 of these were found in common across all four regimes, while 1938 transcripts were found to be unique to the individual treatments. Genes with altered transcript abundance included members of the transcription factor families AP2/EREPB, bZIP, NAC, NF-Y, WRKY, MYB and Homeobox, as well as genes for the small HSP, HSP70 and HSP90 heat shock protein families. Analysis of the transcript data from these experiments indicated that P. euphratica activates specific regulatory pathways according to the degree of drought stress it receives. These results provide important insights into the molecular mechanisms underpinning the drought stress responses of poplar, as well as providing candidates for future experimentation.
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