Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but ...the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence.
Circularly polarized organic light‐emitting diodes (CP‐OLEDs) are particularly favorable for the direct generation of CP light, and they demonstrate a promising application in 3D display. However, up ...to now, such CP devices have suffered from low brightness, insufficient efficiency, and serious efficiency roll‐off. In this study, a pair of octahydro‐binaphthol (OBN)‐based chiral emitting enantiomers, (R/S)‐OBN‐Cz, are developed by ingeniously merging a chiral source and a luminophore skeleton. These chirality–acceptor–donor (C–A–D)‐type and rod‐like compounds concurrently generate thermally activated delayed fluorescence with a small ΔEST of 0.037 eV, as well as a high photoluminescence quantum yield of 92% and intense circularly polarized photoluminescence with dissymmetry factors (|gPL|) of ≈2.0 × 10−3 in thin films. The CP‐OLEDs based on (R/S)‐OBN‐Cz enantiomers not only display obvious circularly polarized electroluminescence signals with a |gEL| of ≈2.0 × 10−3, but also exhibit superior efficiencies with maximum external quantum efficiency (EQEmax) up to 32.6% and extremely low efficiency roll‐off with an EQE of 30.6% at 5000 cd m−2, which are the best performances among the reported CP devices to date.
Octahydrobinaphthol‐compound‐based circularly polarized delayed fluorescence enantiomers, (R/S)‐OBN‐Cz are developed by merging a chiral source and a luminophore skeleton. The circularly polarized organic light‐emitting diodes based on (R/S)‐OBN‐Cz display intense CP‐electroluminescence signals with a |gEL| of ≈2.0 × 10−3, and achieve superior efficiencies with external quantum efficiency (EQE) up to 32.6% and extremely low efficiency roll‐off with an EQE of 30.6% at 5000 cd m−2.
Background
The prognosis of patients who have Epstein‐Barr virus (EBV)‐related nasopharyngeal carcinoma (NPC) in which the tumor tissues harbor EBV have a better prognosis than those without ...EBV‐related NPC. Therefore, the eighth edition of the TNM staging system could be modified for EBV‐related NPC by incorporating the measurement of plasma EBV DNA.
Methods
In total, 979 patients with NPC who received intensity‐modulated radiotherapy (IMRT) were retrospectively reviewed. Recursive partitioning analysis was conducted based on tumor (T) classification, lymph node (N) classification, and EBV DNA measurement to derive objectively the proposed stage groupings. The validity of the proposed stage groupings was confirmed in a prospective cohort of 550 consecutive patients who also received with IMRT.
Results
The pretreatment plasma EBV DNA level was identified as a significant, negative prognostic factor for progression‐free survival and overall survival in univariate analysis (all P < .001) and multivariate analysis (all P < .05). Recursive partitioning analysis of the primary cohort to incorporate EBV DNA generated the following proposed stage groupings: stage RI (T1N0), RIIA (T2‐T3N0 or T1‐T3N1, EBV DNA ≤2000 copies/mL), stage RIIB (T2‐T3N0 or T1‐T3N1, EBV DNA >2000 copies/mL; T1‐T3N2, EBV DNA ≤2000 copies/mL), stage RIII (T1‐T3N2, EBV DNA >2000 copies/mL; T4N0‐N2), and stage RIVA (any T and N3). In the validation cohort, the 5‐year progression‐free survival rate was 100%, 87.9%, 76.7%, 68.7%, and 50.4% for proposed stage RI, RIIA, RIIB, RIII, and RIV NPC, respectively (P < .001). Compared with the eighth edition TNM stage groupings, the proposed stage groupings incorporating EBV DNA provided better hazard consistency, hazard discrimination, outcome prediction, and sample size balance.
Conclusions
The proposed stage groupings have better prognostic performance than the eighth edition of the TNM staging system. EBV DNA titers should be included in the TNM staging system to assess patients who have EBV‐related NPC.
The proposed stage groupings incorporating Epstein‐Barr virus DNA by Recursive partitioning analysis have better prognostic performance than the eighth edition American Joint Committee on Cancer/Union for International Cancer Control TNM staging system. Compared with the eighth edition, the proposed stage groupings incorporating Epstein‐Barr virus DNA provide better hazard consistency, hazard discrimination, outcome prediction, and sample size balance
Pure organic materials with intrinsic room‐temperature phosphorescence typically rely on heavy atoms or heteroatoms. Two different strategies towards constructing organic room‐temperature ...phosphorescence (RTP) species based upon the through‐space charge transfer (TSCT) unit of 2.2paracyclophane (PCP) were demonstrated. Materials with bromine atoms, PCP‐BrCz and PPCP‐BrCz, exhibit RTP lifetime of around 100 ms. Modulating the PCP core with non‐halogen‐containing electron‐withdrawing units, PCP‐TNTCz and PCP‐PyCNCz, successfully elongate the RTP lifetime to 313.59 and 528.00 ms, respectively, the afterglow of which is visible for several seconds under ambient conditions. The PCP‐TNTCz and PCP‐PyCNCz enantiomers display excellent circular polarized luminescence with dissymmetry factors as high as −1.2×10−2 in toluene solutions, and decent RTP lifetime of around 300 ms for PCP‐TNTCz enantiomers in crystalline state.
A series of organic phosphors based on paracyclophanes (PCPs) exhibit both strong room‐temperature phosphorescence (RTP) and excellent circularly polarized luminescence. Modulating the PCP core with non‐halogen‐containing electron‐withdrawing units elongates the RTP lifetime to 313.59 and 528.00 ms. The afterglow is visible for several seconds under ambient conditions.
Six novel benzimidazole‐based D‐π‐A compounds 4 a–4 f were concisely synthesized by attaching different donor/acceptor units to the skeleton of 1,3‐bis(1H‐benzimidazol‐2‐yl)benzene on its 5‐position ...through an ethynyl link. Due to the twisted conformation and effective conjugation structure, these dual‐state emission (DSE) molecules show intense and multifarious photoluminescence, and their fluorescence quantum yields in solution and solid state can be up to 96.16 and 69.82 %, respectively. Especially, for excellent photostability, obvious solvatofluorochromic and extraordinary wide range of solvent compatibility, DSE molecule 4 a is a multifunctional fluorescent probe for the visual detection of nitroaromatic compounds (NACs) with the limit of detection as low as 10−7 M. The quenching mechanism has been proved as the results of photoinduced electron transfer and fluorescence resonance energy transfer processes. Importantly, probe 4 a can sensitively detect NACs not only in real water samples, but also on 4 a‐coated strips and 4 a@PBAT thin films.
Novel benzimidazole‐based D‐π‐A fluorophores are rationally designed and concisely synthesized. Six compounds 4 a–4 f, as dual‐state emission (DSE) materials, exhibit excellent photostability, solvatofluorochromic and extraordinary wide range of solvent compatibility. Among them, the DSE material 4 a is not only reasonably developed as a multifunctional fluorescent probe for sensitive detection of nitroaromatic compounds (NACs) in aqueous system, but also processed into test strips and thin films for visual detection of NACs.
Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving ...standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options.
This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18–65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III–IVA, excluding T3–4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12–16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111.
Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33–42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% 95% CI 80·4–90·6) than in the standard therapy group (75·7% 69·9–81·9), with a stratified hazard ratio of 0·50 (95% CI 0·32–0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 9% patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group.
The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma.
The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation.
For the Chinese translation of the abstract see Supplementary Materials section.
Chiral materials with circularly polarized luminescence (CPL) are potentially applicable for 3D displays. In this study, by decorating the pyridinyl‐helicene ligands with ‐CF3 and ‐F groups, the ...platinahelicene enantiomers featured superior configurational stability, as well as high sublimation yield (>90 %) and clear CPPL properties, with dissymmetry factors (|gPL|) of approximately 3.7×10−3 in solution and about 4.1×10−3 in doped film. The evaporated circularly polarized phosphorescent organic light‐emitting diodes (CP‐PhOLEDs) with two enantiomers as emitters exhibited symmetric CPEL signals with |gEL| of (1.1–1.6)×10−3 and decent device performances, achieving a maximum brightness of 11 590 cd m−2, a maximum external quantum efficiency up to 18.81 %, which are the highest values among the reported devices based on chiral phosphorescent PtII complexes. To suppress the effect of reverse CPEL signal from the cathode reflection, the further implementation of semitransparent aluminum/silver cathode successfully boosts up the |gEL| by over three times to 5.1×10−3.
Two platinahelicene enantiomers with configurational stability and good CPPL property were used as emitters in efficient evaporated circularly polarized phosphorescent organic light‐emitting diodes (CP‐PhOLEDs). A maximum brightness of 11 590 cd m−2, a maximum external quantum efficiency up to 18.81 %, and symmetric CPEL signals with |gEL| of (1.1–1.6)×10−3 were achieved. Further implementation of semitransparent silver/aluminum cathode successfully boosted up the |gEL| by over three times to 5.1×10−3.
Straw return is an important management tool for tackling and promoting soil nutrient conservation and improving crop yield in Huang-Huai-Hai Plain, China. Although the incorporation of maize straw ...with deep plowing and rotary tillage practices are widespread in the region, only few studies have focused on rotation tillage. To determine the effects of maize straw return on the nitrogen （N） efficiency and grain yield of winter wheat （Triticum aestivum L.）, we conducted experiments in this region for 3 years. Five treatments were tested： （i） rotary tillage without straw return （RT）; （ii） deep plowing tillage without straw return （DT）; （iii） rotary tillage with total straw return （RS）; （iv） deep plowing tillage with total straw return （DS）; （v） rotary tillage of 2 years and deep plowing tillage in the 3rd year with total straw return （TS）. Treatments with straw return increased kernels no. ear-1, thousand-kernel weight （TKW）, grain yields, ratio of dry matter accumulation post-anthesis, and nitrogen （N） efficiency whereas reduced the ears no. ha-1 in the 2011-2012 and 2012-2013 growing seasons. Compared with the rotary tillage, deep plowing tillage significantly increased the grain yield, yield components, total dry matter accumulation, and N efficiency in 2013-2014. RS had significantly higher straw N distribution, soil inorganic nitrogen content, and soil enzymes activities in the 0-10 cm soil layer compared with the DS and TS. However, significantly lower values were ob- served in the 10-20 and 20-30 cm soil layers. TS obtained approximately equal grain yield as DS, and it also reduced the resource costs. Therefore, we conclude that TS is the most economical method for increasing grain yield and N efficiency of winter wheat in Huang-Huai-Hai Plain.
Prostate cancer remains one of the most lethal cancers for men in the United States. The study aims to detect fusion transcripts in the blood samples of prostate cancer patients. We analyzed nine ...fusion transcripts including MAN2A1-FER, SLC45A2-AMACR, TRMT11-GRIK2, CCNH-C5orf30, mTOR-TP53BP1, KDM4-AC011523.2, TMEM135-CCDC67, LRRC59-FLJ60017 and Pten-NOLC1147 in the blood samples from 147 prostate cancer patients and 14 healthy individuals, using Taqman RT-PCR and Sanger's sequencing. Similar analyses were also performed on 25 matched prostate cancer samples for matched-sample evaluation. Eighty-two percent blood samples from the prostate cancer patients were positive for MAN2A1-FER transcript, while 41.5% and 38.8% blood samples from the prostate cancer patients were positive for SLC45A2-AMACR and Pten-NOLC1, respectively. CCNH-c5orf30 and mTOR-TP53BP1 had low detection rates, positive in only 5.4% and 4% of the blood samples from the prostate cancer patients. Only 2 blood samples were positive for KDM4B-AC011523.2 transcript. Overall, 89.8% patients were positive for at least one fusion transcript in their blood samples. The statistical analysis showed varied sensitivity of fusion transcript detection in the blood based on the types of fusions. In contrast, the blood samples from all healthy individuals were negative for the fusion transcripts. Detection of fusion transcripts in the blood samples of the prostate cancer patients may be a fast and cost-effective way to detect prostate cancer.
During cancer therapy, phagocytic clearance of dead cells plays a vital role in immune homeostasis. The nonapoptotic form of cell death, ferroptosis, exhibits extraordinary potential in tumor ...treatment. However, the phagocytosis mechanism that regulates the engulfment of ferroptotic cells remains unclear. Here, we establish a novel pathway for phagocytic clearance of ferroptotic cells that is different from canonical mechanisms by using diverse ferroptosis models evoked by GPX4 dysfunction/deficiency. We identified the oxidized phospholipid, 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH), as a key eat-me signal on the ferroptotic cell surface. Enriching the plasma membrane with SAPE-OOH increased the efficiency of phagocytosis of ferroptotic cells by macrophage, a process that was suppressed by lipoprotein-associated phospholipase A
. Ligand fishing, lipid blotting, and cellular thermal shift assay screened and identified TLR2 as a membrane receptor that directly recognized SAPE-OOH, which was further confirmed by TLR2 inhibitors and gene silencing studies. A mouse mammary tumor model of ferroptosis verified SAPE-OOH and TLR2 as critical players in the clearance of ferroptotic cells in vivo. Taken together, this work demonstrates that SAPE-OOH on ferroptotic cell surface acts as an eat-me signal and navigates phagocytosis by targeting TLR2 on macrophages.
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