The TET (ten-eleven translocation) family of α-ketoglutarate (α-KG)-dependent dioxygenases catalyzes the sequential oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), ...5-formylcytosine and 5-carboxylcytosine, leading to eventual DNA demethylation. The TET2 gene is a bona fide tumor suppressor frequently mutated in leukemia, and TET enzyme activity is inhibited in IDH1/2-mutated tumors by the oncometabolite 2-hydroxyglutarate, an antagonist of α-KG, linking 5mC oxidation to cancer development. We report here that the levels of 5hmC are dramatically reduced in human breast, liver, lung, pancreatic and prostate cancers when compared with the matched surrounding normal tissues. Associated with the 5hmC decrease is the substantial reduction of the expression of all three TET genes, revealing a possible mechanism for the reduced 5hmC in cancer cells. The decrease of 5hmC was also observed during tumor development in different genetically engineered mouse models. Together, our results identify 5hmC as a biomarker whose decrease is broadly and tightly associated with tumor development.
Purpose
To assess the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) in liver cancer patients with different times of previous conventional transarterial ...chemoembolization (cTACE) treatments.
Methods
367 liver cancer patients about to receive DEB-TACE treatment were enrolled in this prospective cohort study. All patients were divided into no previous cTACE group (NPC group), 1–2 times previous cTACE group (PC group) and triple or above previous cTACE group (TPC group) according to the times of previous cTACE treatments.
Results
There was no difference in complete response (CR) (
P
= 0.671) and objective response rate (ORR) (
P
= 0.062) among three groups. Additionally, no difference in overall survival (OS) among groups (
P
= 0.899) was found. As to liver function, most liver function indexes were deteriorative at 1 week after DEB-TACE operation, but returned to baseline at 1–3 months after DEB-TACE operation in all three groups, while percentage of abnormal total bile acid (TBA) patients was higher in TPC group than NPC and PC groups at 1–3 month post-DEB-TACE (
P
= 0.018). As for safety profiles, the incidence of pain during DEB-TACE operation was lower in TPC group compared to NPC and PC groups (
P
= 0.005), while no difference of other adverse events was found during and 1 month post-DEB-TACE treatment among three groups.
Conclusion
DEB-TACE treatment was equally efficient and tolerated in liver cancer patients with different times of previous cTACE treatments.
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and ...neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.
Abstract
Current approaches of using neural networks in lane departure warning systems are expensive. And it is difficult for neural networks to process 2K and 4K images. In this paper, we use a ...series of image preprocessing techniques such as perspective transformation, threshold processing and mask operation to process high-resolution images and the optimized sliding window method to fit the lane lines. Compared with neural network method, we can not only reduce hardware cost, but also quickly process high-resolution images. In addition, compared with the traditional lane line detection algorithm, we extract the region of interest through perspective transformation, which not only greatly reduces computation, but also converts images into an aerial view for subsequent processing. Especially, we carry out threshold operation and mask operation after perspective transformation, which greatly improves the performance of our algorithm in a strongly interfering environment. As can be seen from the experimental results, our method has good detection effect and can be applied to various road sections in different environments.
Genetic polymorphisms of CYP2C9 significantly influence the pharmacokinetics and pharmacodynamics of some drugs, which might result in adverse drug effects and therapeutic failure. Several studies ...have been performed on CYP2C9 genetic polymorphisms in Han Chinese populations. However, these studies only focused on two commonly investigated alleles, *2 and *3, in relatively small sample sizes. To scale up the gene-scanning region and determine relatively precise data on the genetic distribution pattern in Chinese populations, unrelated healthy Han Chinese volunteers from Zhejiang Province (n=1127) and Hebei (n=1000) Province were recruited as subjects for the direct sequencing of all exons of CYP2C9. As a result, 14 previously reported alleles were detected in this work, and 8 of these alleles (*14, *16, *19, *23, *27, *29, *33 and *34) were described for the first time in Chinese populations. In addition, 37 novel mutations were also detected, of which 22 variants were non-synonymous, and 21 new alleles, *36-*56, were designated by the Human CYP Allele Nomenclature Committee. In vitro functional analysis of these 22 novel CYP2C9 variants revealed that 17 mutations had a significant influence on the protein's catalytic activity. Our study provides the most accurate data on CYP2C9 polymorphisms in Han Chinese populations and detects the largest number of novel allelic variants existing to date. These new alleles will greatly enrich the current knowledge of naturally occurring CYP2C9 variants in Chinese populations.
We report on 22 yr of radio timing observations of the millisecond pulsar J1024−0719 by the telescopes participating in the European Pulsar Timing Array (EPTA). These observations reveal a ...significant second derivative of the pulsar spin frequency and confirm the discrepancy between the parallax and Shklovskii distances that has been reported earlier. We also present optical astrometry, photometry and spectroscopy of 2MASS J10243869−0719190. We find that it is a low-metallicity main-sequence star (K7V spectral type, M/H = −1.0, T
eff = 4050 ± 50 K) and that its position, proper motion and distance are consistent with those of PSR J1024−0719. We conclude that PSR J1024−0719 and 2MASS J10243869−0719190 form a common proper motion pair and are gravitationally bound. The gravitational interaction between the main-sequence star and the pulsar accounts for the spin frequency derivatives, which in turn resolves the distance discrepancy. Our observations suggest that the pulsar and main-sequence star are in an extremely wide (P
b > 200 yr) orbit. Combining the radial velocity of the companion and proper motion of the pulsar, we find that the binary system has a high spatial velocity of 384 ± 45 km s−1 with respect to the local standard of rest and has a Galactic orbit consistent with halo objects. Since the observed main-sequence companion star cannot have recycled the pulsar to millisecond spin periods, an exotic formation scenario is required. We demonstrate that this extremely wide-orbit binary could have evolved from a triple system that underwent an asymmetric supernova explosion, though find that significant fine-tuning during the explosion is required. Finally, we discuss the implications of the long period orbit on the timing stability of PSR J1024−0719 in light of its inclusion in pulsar timing arrays.
There are limited data comparing the prognosis and fertility outcomes of the patients with early cervical cancer treated by trans-vaginal radical trachelectomy (VRT) or abdominal radical ...trachelectomy (ART).The objective of this study was to compare the surgical and pathologic characteristics, the prognosis and fertility outcomes of the patients treated by VRT or ART.
Matched-case study based on a prospectively maintained database of patients underwent radical trachelectomy in 10 centres of China was designed to compare the prognosis and fertility outcomes of the patients treated by VRT or ART.
Totally 150 cases, 77 in the VRT and 73 in the ART group, were included. VRT and ART provide similar surgical and pathological outcomes except larger specimens obtained by ART. In the ART group, no patient developed recurrent diseases, but, in the VRT group, 7 (9.8%) patients developed recurrent diseases and 2 (1.6%) patients died of the tumours (P=0.035). The rate of pregnancy in the VRT group was significantly higher than those of ART (39.5% vs 8.8%; P=0.003). The patients with tumour size >2 cm showed significant higher recurrent rate (11.6% vs 2.4%, P<0.05) and lower pregnant rate (12.5% vs 32.1%, P=0.094) compared with the patients with tumour size <2 cm.
Patients treated by ART obtained better oncology results, but their fertility outcomes were unfavourable compared with VRT. Tumour size <2 cm should be emphasised as an indication for radical trachelectomy for improving the outcome of fertility and prognosis.
Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus ...2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies.
Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients).
A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality.
Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies.
NCT04354701
•Among 4966 patients with COVID-19 and a history of or active cancer, 58% were hospitalized and 14% died within 30 days.•Older age, male sex, obesity, comorbidities, non-Hispanic black race, and Hispanic ethnicity were associated with higher COVID-19 severity.•Worse performance status, hematologic malignancy, and recent cytotoxic chemotherapy were associated with more severe COVID-19.•Low or high absolute lymphocyte count, high absolute neutrophil count, low platelets, abnormal creatinine, troponin, lactate dehydrogenase, or C-reactive protein were associated with more severe COVID-19.•Specific anticancer therapies were associated with high 30-day all-cause mortality.
To validate the feasibility of Actiwatch 2 (AW2) to measure sleep quality in thermal comfort researches, five parameters drawn from AW2 and the subjective evaluation of sleep quality, sleep quality ...vote (SQV) were collected. Furthermore, to explore the effect of thermal environment and IAQ on sleep quality with AW2, the standard effective temperature (SET) was induced to evaluate the integrated effect of the sleeping thermal environment and CO2 was to indicate the freshness of air quality. Ambient temperature, relative humidity, mean radiant temperature, air velocity and CO2 concentration were monitored in 6 bedroom of different type, including natural-ventilated rooms and air-conditioned rooms, during the hot season in Beijing for nearly one month. The occupant bedding system, posture habit and thermal sensation vote before sleep (BTSV) and after sleep (ATSV) of 3 female and 3 male subjects were recorded with questionnaire. The results showed that some of the sleep quality parameters measured by AW2 accorded with the subjective evaluation; Thermal environment had an effect on sleep quality according to the significant correlations between SET and the sleep quality parameters measured by AW2; The thermoneutral range of SET in sleeping condition was between 29.1–29.7°C, based on which the thermal insulation of bedding system (Icl) was recommended to be 0.96–1.08clo.
Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in ...the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-beta-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.
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