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Ji-sheng Wang,1,2,* Xue-feng Gong,3,4,* Jun-long Feng,1,2,* Hai-song Li,2 Xiao Li,5 Sheng Deng,1,2 Pei-zhong Ren,3,4 Jia-mei Wang,3,4 Ming-sheng Lv,3,4 Rui-feng Jin,3,4 Qiu-yi Chen,3,4 Bin Wang,2 Hong-sheng Cui4 1First Clinical Medical College, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Andrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of China; 3The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Pneumology Department, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 5Department of Andrology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin WangAndrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of ChinaEmail dayiwangbln@sina.comHong-sheng CuiPneumology Department, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of ChinaEmail Hshcui@sina.comBackground: Jiawei Shengjiang Powder (JWSJP) is a classical Chinese medicinal formula, which has been widely applied in the treatment of asthma and complications for many years due to its curative effect.Aim: To verify the effect of JWSJP in improving abnormal sperm motility caused by asthma and to explore its potential mechanism.Materials and Methods: The active compounds of JWSJP were obtained from high performance liquid chromatography tandem mass spectrometry and the Traditional Chinese Medicine System Pharmacology. The key active components and targets of JWSJP were predicted based on network pharmacological analysis and bioinformatics research. Rats were randomly divided into normal, model and treatment groups. The rat model of allergic asthma was induced by intraperitoneal injection of ovalbumin solution. The experiment judged improvement of semen quality by evaluating sperm motility, and detected the expression of related proteins in testicular tissue of Sprague-Dawley rats by RT-qPCR and Western blot methods. Hematoxylin and eosin (HE) staining was used to observe the changes in testicular tissue structure in rats.Results: Through the analysis of network pharmacology and bioinformatics, it was found that beta-sitosterol, quercetin, gallic acid, pelargonidin and kaempferol were the key active components of Jiawei Shengjiang Powder. Tumor necrosis factor (TNF), interleukin-6 (IL-6) and insulin (INS) genes are crucial targets of JWSJP in the treatment of spermatogenic dysfunction caused by acute asthma. After 8 weeks of intervention, compared with the model group, the treatment group had significantly improved sperm motility (P < 0.05). There were significant differences in TNF, IL6, and INS proteins in the treatment group, and the HE staining of testicular tissue structure in the treatment group was significantly improved.Conclusion: JWSJP can improve the abnormal sperm motility induced by asthma, and its mechanism may be related to the expression of related proteins and mRNA of TNF, IL6, and INS.Keywords: Jiawei Shengjiang Powder, asthmatic attack, asthenospermia, network pharmacology

Xue-Song Sun,1–3,* Yu-Jing Liang,1–3,* Xiao-Yun Li,1–3,* Sai-Lan Liu,1–3 Qiu-Yan Chen,1–3 Lin-Quan Tang,1–3 Hai-Qiang Mai1–3 1Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, Guangzhou, People’s Republic of China; 2Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China; 3Department of Nasopharyngeal Carcinoma, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lin-Quan Tang;Hai-Qiang MaiDepartment of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of ChinaTel +86 208 734 3643Fax +86 208 734 3392Email maihq@mail.sysu.edu.cn; tanglq@sysucc.org.cnObjective: We aimed to investigate the efficacy and safety of cetuximab (CTX) or nimotuzumab (NTZ) on the addition of palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (NPC).Materials and methods: From 2007 to 2016, 451 eligible patients with de novo metastatic NPC were enrolled in the study. With propensity score matching technique, we created a well-balanced cohort by matching patients who received CTX/NTZ plus PCT (62 patients) with those receiving PCT alone (248 patients) in a ratio of 1:4. The primary endpoint was overall survival (OS). All potential prognostic factors were involved in the multivariate analysis with the Cox regression hazards model. Kaplan–Meier curves were used to compare the survival status, and log-rank test to measure the significance.Results: The median follow-up time was 27.7 months (range, 1–126 months). No significant difference in survival was observed between the CTX/NTZ plus PCT group and PCT group. (3-year OS: 63.0% vs 58.1%; P=0.485). The administration of CTX/NTZ was not found to be an independent prognostic factor in multivariate analysis. With regard to toxicity, the development of a G3-4 skin reaction and mucositis was more common in patients receiving CTX plus PCT. Interaction effects analysis did not show any significant interaction effects on OS between the treatment regimen and prognostic factors (P>0.05).Conclusion: The efficacy of CTX/NTZ and PCT is comparable to single PCT treatment in terms of survival outcomes among de novo metastatic NPC patients. Moreover, the application of CTX exacerbated skin reactions and mucositis.Keywords: targeted drug, chemotherapy, treatment, nasopharyngeal carcinoma and overall survival

Xiao-Yun Li,1,2,* Xue-Song Sun,1,2,* Sai-Lan Liu,1,2,* Qiu-Yan Chen,1,2 Shan-Shan Guo,1,2 Li-Ting Liu,1,2 Jin-Jie Yan,1,2 Hao-Jun Xie,1,2 Qing-Nan Tang,1,2 Yu-Jing Liang,1,2 Ling Guo,1,2 Lin-Quan Tang,1,2,* Hai-Qiang Mai1,2,*1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 2Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China*These authors contributed equally to this workObjective: This study aimed to establish a nomogram to predict the risk of post-radiation necrosis in nasopharyngeal carcinoma (NPC) patients.Background: This study was performed to identify influencing factors for developing post-radiation necrosis, and to establish an effective nomogram model to predict individual risks in NPC patients.Methods: 7144 NPC patients receiving radical radiotherapy from 2007 to 2012 were involved in the study, and 207 of them developed nasopharyngeal necrosis (NPN). The clinical characteristics and baseline laboratory results were collected and analyzed. Independent predictive factors were selected using the Cox proportional model and incorporated into the nomogram. The receiver operating characteristic curve and the calibration curve were used to verify discrimination and calibration.Results: The experience of re-irradiation contributed most to the occurrence of NPN (HR, 15.56, 95% CI 10.84–22.35, p

Guangda Yang,1 Qianya Chen,1 Jieming Xiao,2 Hailiang Zhang,1 Zhichao Wang,1 Xiangan Lin3 1Department of Cancer Chemotherapy, Zengcheng District People’s Hospital of Guangzhou (BoJi-Affiliated Hospital of Sun Yat-Sen University), Guangzhou, China; 2Department of Emergency, Zengcheng District People’s Hospital of Guangzhou (BoJi-Affiliated Hospital of Sun Yat-Sen University), Guangzhou, China; 3Department of Cancer Chemotherapy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China Background: This study was performed to identify disease-related genes and analyze prognostic values in nonsmoking females with non-small cell lung carcinoma (NSCLC).Materials and methods: Gene expression profile GSE19804 was downloaded from the Gene Expression Omnibus (GEO) database and analyzed by using GEO2R. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for the functional and pathway enrichment analysis. Then, the Search Tool for the Retrieval of Interacting Genes, Cytoscape, and Molecular Complex Detection were used to construct the protein–protein interaction (PPI) network and identify hub genes. Finally, the Kaplan–Meier plotter online tool was used for the overall survival analysis of hub genes.Results: A cohort of 699 differentially expressed genes was screened, and they were mainly enriched in the terms of ECM–receptor interaction, focal adhesion, and cell adhesion molecules. A PPI network was constructed, and 15 hub genes were identified base on the subset of PPI network. Then, two significant modules were detected and several genes were found to be associated with the cell cycle pathway. Finally, nine hub genes’ (UBE2C, DLGAP5, TPX2, CCNB2, BIRC5, KIF20A, TOP2A, GNG11, and ANXA1) expressions were found to be associated with the prognosis of the patients.Conclusion: Overall, we propose that the cell cycle pathway may play an important role in nonsmoking females with NSCLC and the nine hub genes may be further explored as potential targets for NSCLC diagnosis and treatment. Keywords: non-small cell lung carcinoma, NSCLC, nonsmoking females, GEO2R, prognostic biomarkers, Kaplan–Meier plotter

Li X-Y, Sun X-S, Liu S-L, et al. Cancer Manag Res. 2019;11:6253–6263.In Table 2, the authors identified the risk factors of nasopharyngeal necrosis using a logistic regression model, andthe final nomogram model was constructed based on these results. However, the outcome of the univariable analysisand multivariable analysis reported in Table 2 was mistakenly listed as overall survival (HR) and should have been reported as the likelihood of necrosis (OR).Table 2, column 2 heading reads "Univariable analyses HR (95% CI)" should read "Univariable analyses OR (95% CI)". Table 2, column 4 heading reads "Univariable analyses HR (95% CI)" should read "Multivariable analyses OR (95% CI)". The authors wish to apologize for this error.Read the original article

Lu Zhang,1,2 Qiu-Yan Chen,1,2 Huai Liu,1,2 Lin-Quan Tang,1,2 Hai-Qiang Mai1,21State Key Laboratory of Oncology in South China, 2Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of ChinaAbstract: Nasopharyngeal carcinoma is endemic in Asia and is etiologically associated with Epstein–Barr virus. Radiotherapy is the primary treatment modality. The role of systemic therapy has become more prominent. Based on multiple phase III studies and meta-analyses, concurrent cisplatin-based chemoradiotherapy is the current standard of care for locally advanced disease (American Joint Committee on Cancer manual [7th edition] stages II–IVb). The reported failure-free survival rates from phase II trials are encouraging for induction + concurrent chemoradiotherapy. Data from ongoing phase III trials comparing induction + concurrent chemoradiotherapy with concurrent chemoradiotherapy will validate the results of these phase II studies. Intensity-modulated radiotherapy techniques are recommended if the resources are available. Locoregional control exceeding 90% and reduced xerostomia-related toxicities can now be achieved using intensity-modulated radiotherapy, although distant control remains the most pressing research problem. The promising results of targeted therapy and Epstein–Barr virus-specific immunotherapy from early clinical trials should be validated in phase III clinical trials. New technology, more effective and less toxic chemotherapy regimens, and targeted therapy offer new opportunities for treating nasopharyngeal carcinoma.Keywords: nasopharyngeal carcinoma, intensity-modulated radiotherapy, chemoradiotherapy, molecular targeted agents, immunotherapy, prognostic markers

We have measured the superconducting penetration depth Λ(T) in the heavy-fermion/intermediate-valent superconducting alloy series Ce1-xYbxCoIn5 using a transverse-field muon spin relaxation to study the effect of intermediate-valent Yb doping on Fermi-liquid renormalization. From Λ(T) we determine the superfluid density ρs(T) and find that it decreases continuously with increasing nominal Yb concentration x, i.e., with increasing intermediate valence. The temperature-dependent renormalization of the "normal" fluid density ρN(T)=ρs(0)-ρs(T) in both the heavy-fermion and intermediate valence limits is proportional to the temperature-dependent renormalization of the specific heat. This indicates that the temperature-dependent Fermi-liquid Landau parameters of the superconducting quasiparticles entering the two different physical quantities are the same. These results represent an important advance in understanding of both intermediate valence and heavy-fermion phenomena in superconductors.

The Daya Bay Experiment consists of eight identically designed detectors located in three underground experimental halls named as EH1, EH2, EH3, with 250, 265 and 860 meters of water equivalent vertical overburden, respectively. Cosmic muon events have been recorded over a two-year period. The underground muon rate is observed to be positively correlated with the effective atmospheric temperature and to follow a seasonal modulation pattern. The correlation coefficient α, describing how a variation in the muon rate relates to a variation in the effective atmospheric temperature, is found to be αEH1 = 0.362±0.031, αEH2 = 0.433±0.038 and αEH3 = 0.641±0.057 for each experimental hall.

The disappearance of reactor $\bar{\nu}_e$ observed by the Daya Bayexperiment is examined in the framework of a model in which the neutrino isdescribed by a wave packet with a relative intrinsic momentum dispersion$\sigma_\text{rel}$. Three pairs of nuclear reactors and eight antineutrinodetectors, each with good energy resolution, distributed among threeexperimental halls, supply a high-statistics sample of $\bar{\nu}_e$ acquiredat nine different baselines. This provides a unique platform to test theeffects which arise from the wave packet treatment of neutrino oscillation. Themodified survival probability formula was used to fit Daya Bay data, providingthe first experimental limits: $2.38 \cdot 10^{-17} < \sigma_{\rm rel} < 0.23$.Treating the dimensions of the reactor cores and detectors as constraints, thelimits are improved: $10^{-14} \lesssim \sigma_{\rm rel} < 0.23$, and an upperlimit of $\sigma_{\rm rel}

The Daya Bay experiment has observed correlations between reactor core fuel evolution and changes in the reactor antineutrino flux and energy spectrum. Four antineutrino detectors in two experimental halls were used to identify 2.2 million inverse beta decays (IBDs) over 1230 days spanning multiple fuel cycles for each of six 2.9 GW_{th} reactor cores at the Daya Bay and Ling Ao nuclear power plants. Using detector data spanning effective ^{239}Pu fission fractions F_{239} from 0.25 to 0.35, Daya Bay measures an average IBD yield σ[over ¯]_{f} of (5.90±0.13)×10^{-43}  cm^{2}/fission and a fuel-dependent variation in the IBD yield, dσ_{f}/dF_{239}, of (-1.86±0.18)×10^{-43}  cm^{2}/fission. This observation rejects the hypothesis of a constant antineutrino flux as a function of the ^{239}Pu fission fraction at 10 standard deviations. The variation in IBD yield is found to be energy dependent, rejecting the hypothesis of a constant antineutrino energy spectrum at 5.1 standard deviations. While measurements of the evolution in the IBD spectrum show general agreement with predictions from recent reactor models, the measured evolution in total IBD yield disagrees with recent predictions at 3.1σ. This discrepancy indicates that an overall deficit in the measured flux with respect to predictions does not result from equal fractional deficits from the primary fission isotopes ^{235}U, ^{239}Pu, ^{238}U, and ^{241}Pu. Based on measured IBD yield variations, yields of (6.17±0.17) and (4.27±0.26)×10^{-43}  cm^{2}/fission have been determined for the two dominant fission parent isotopes ^{235}U and ^{239}Pu. A 7.8% discrepancy between the observed and predicted ^{235}U yields suggests that this isotope may be the primary contributor to the reactor antineutrino anomaly.

A measurement of electron antineutrino oscillation by the Daya Bay Reactor Neutrino Experiment is described in detail. Six 2.9-GWth nuclear power reactors of the Daya Bay and Ling Ao nuclear power facilities served as intense sources of νe's. Comparison of the νe rate and energy spectrum measured by antineutrino detectors far from the nuclear reactors (∼1500-1950 m) relative to detectors near the reactors (∼350-600 m) allowed a precise measurement of νe disappearance. More than 2.5 million νe inverse beta-decay interactions were observed, based on the combination of 217 days of operation of six antineutrino detectors (December, 2011-July, 2012) with a subsequent 1013 days using the complete configuration of eight detectors (October, 2012-July, 2015). The νe rate observed at the far detectors relative to the near detectors showed a significant deficit, R=0.949±0.002(stat)±0.002(syst). The energy dependence of νe disappearance showed the distinct variation predicted by neutrino oscillation. Analysis using an approximation for the three-flavor oscillation probability yielded the flavor-mixing angle sin22θ13=0.0841±0.0027(stat)±0.0019(syst) and the effective neutrino mass-squared difference of |Δmee2|=(2.50±0.06(stat)±0.06(syst))×10-3 eV2. Analysis using the exact three-flavor probability found Δm322=(2.45±0.06(stat)±0.06(syst))×10-3 eV2 assuming the normal neutrino mass hierarchy and Δm322=(-2.56±0.06(stat)±0.06(syst))×10-3 eV2 for the inverted hierarchy.

A new measurement of the reactor antineutrino flux and energy spectrum by the Daya Bay reactor neutrino experiment is reported. The antineutrinos were generated by six 2.9 GWth nuclear reactors and detected by eight antineutrino detectors deployed in two near (560 m and 600 m flux-weighted baselines) and one far (1640 m flux-weighted baseline) underground experimental halls. With 621 days of data, more than 1.2 million inverse beta decay (IBD) candidates were detected. The IBD yield in the eight detectors was measured, and the ratio of measured to predicted flux was found to be 0.946±0.020 (0.992±0.021) for the Huber+Mueller (ILL+Vogel) model. A 2.9σ deviation was found in the measured IBD positron energy spectrum compared to the predictions. In particular, an excess of events in the region of 4-6 MeV was found in the measured spectrum, with a local significance of 4.4σ. A reactor antineutrino spectrum weighted by the IBD cross section is extracted for model-independent predictions.

This Letter reports an improved search for light sterile neutrino mixing in the electron antineutrino disappearance channel with the full configuration of the Daya Bay Reactor Neutrino Experiment. With an additional 404 days of data collected in eight antineutrino detectors, this search benefits from 3.6 times the statistics available to the previous publication, as well as from improvements in energy calibration and background reduction. A relative comparison of the rate and energy spectrum of reactor antineutrinos in the three experimental halls yields no evidence of sterile neutrino mixing in the 2×10^{-4}≲|Δm_{41}^{2}|≲0.3  eV^{2} mass range. The resulting limits on sin^{2}2θ_{14} are improved by approx imately a factor of 2 over previous results and constitute the most stringent constraints to date in the |Δm_{41}^{2}|≲0.2  eV^{2} region.

Searches for a light sterile neutrino have been performed independently by the MINOS and the Daya Bay experiments using the muon (anti)neutrino and electron antineutrino disappearance channels, respectively. In this Letter, results from both experiments are combined with those from the Bugey-3 reactor neutrino experiment to constrain oscillations into light sterile neutrinos. The three experiments are sensitive to complementary regions of parameter space, enabling the combined analysis to probe regions allowed by the Liquid Scintillator Neutrino Detector (LSND) and MiniBooNE experiments in a minimally extended four-neutrino flavor framework. Stringent limits on sin^{2}2θ_{μe} are set over 6 orders of magnitude in the sterile mass-squared splitting Δm_{41}^{2}. The sterile-neutrino mixing phase space allowed by the LSND and MiniBooNE experiments is excluded for Δm_{41}^{2}

This article reports an improved independent measurement of neutrino mixing angle θ13 at the Daya Bay Reactor Neutrino Experiment. Electron antineutrinos were identified by inverse β-decays with the emitted neutron captured by hydrogen, yielding a data set with principally distinct uncertainties from that with neutrons captured by gadolinium. With the final two of eight antineutrino detectors installed, this study used 621 days of data including the previously reported 217-day data set with six detectors. The dominant statistical uncertainty was reduced by 49%. Intensive studies of the cosmogenic muon-induced Li9 and fast neutron backgrounds and the neutron-capture energy selection efficiency, resulted in a reduction of the systematic uncertainty by 26%. The deficit in the detected number of antineutrinos at the far detectors relative to the expected number based on the near detectors yielded sin22θ13=0.071±0.011 in the three-neutrino-oscillation framework. The combination of this result with the gadolinium-capture result is also reported.

The Daya Bay experiment was the first to report simultaneous measurements of reactor antineutrinos at multiple baselines leading to the discovery of ν¯e oscillations over km-baselines. Subsequent data has provided the world's most precise measurement of sin22θ13 and the effective mass splitting Δmee2. The experiment is located in Daya Bay, China where the cluster of six nuclear reactors is among the world's most prolific sources of electron antineutrinos. Multiple antineutrino detectors are deployed in three underground water pools at different distances from the reactor cores to search for deviations in the antineutrino rate and energy spectrum due to neutrino mixing. Instrumented with photomultiplier tubes, the water pools serve as shielding against natural radioactivity from the surrounding rock and provide efficient muon tagging. Arrays of resistive plate chambers over the top of each pool provide additional muon detection. The antineutrino detectors were specifically designed for measurements of the antineutrino flux with minimal systematic uncertainty. Relative detector efficiencies between the near and far detectors are known to better than 0.2%. With the unblinding of the final two detectors' baselines and target masses, a complete description and comparison of the eight antineutrino detectors can now be presented. This paper describes the Daya Bay detector systems, consisting of eight antineutrino detectors in three instrumented water pools in three underground halls, and their operation through the first year of eight detector data-taking.

This Letter reports a measurement of the flux and energy spectrum of electron antineutrinos from six 2.9 GWth nuclear reactors with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls in the Daya Bay experiment. Using 217 days of data, 296 721 and 41 589 inverse β decay (IBD) candidates were detected in the near and far halls, respectively. The measured IBD yield is (1.55±0.04) ×10(-18)  cm(2) GW(-1) day(-1) or (5.92±0.14) ×10(-43)  cm(2) fission(-1). This flux measurement is consistent with previous short-baseline reactor antineutrino experiments and is 0.946±0.022 (0.991±0.023) relative to the flux predicted with the Huber-Mueller (ILL-Vogel) fissile antineutrino model. The measured IBD positron energy spectrum deviates from both spectral predictions by more than 2σ over the full energy range with a local significance of up to ∼4σ between 4-6 MeV. A reactor antineutrino spectrum of IBD reactions is extracted from the measured positron energy spectrum for model-independent predictions.

We report a new measurement of electron antineutrino disappearance using the fully constructed Daya Bay Reactor Neutrino Experiment. The final two of eight antineutrino detectors were installed in the summer of 2012. Including the 404 days of data collected from October 2012 to November 2013 resulted in a total exposure of 6.9×10^{5} GW_{th}  ton days, a 3.6 times increase over our previous results. Improvements in energy calibration limited variations between detectors to 0.2%. Removal of six ^{241}Am-^{13}C radioactive calibration sources reduced the background by a factor of 2 for the detectors in the experimental hall furthest from the reactors. Direct prediction of the antineutrino signal in the far detectors based on the measurements in the near detectors explicitly minimized the dependence of the measurement on models of reactor antineutrino emission. The uncertainties in our estimates of sin^{2}2θ_{13} and |Δm_{ee}^{2}| were halved as a result of these improvements. An analysis of the relative antineutrino rates and energy spectra between detectors gave sin^{2}2θ_{13}=0.084±0.005 and |Δm_{ee}^{2}|=(2.42±0.11)×10^{-3}  eV^{2} in the three-neutrino framework.

The Daya Bay experiment consists of functionally identical antineutrino detectors immersed in pools of ultrapure water in three well-separated underground experimental halls near two nuclear reactor complexes. These pools serve both as shields against natural, low-energy radiation, and as water Cherenkov detectors that efficiently detect cosmic muons using arrays of photomultiplier tubes. Each pool is covered by a plane of resistive plate chambers as an additional means of detecting muons. Design, construction, operation, and performance of these muon detectors are described.

A new measurement of the $\theta_{13}$ mixing angle has been obtained at theDaya Bay Reactor Neutrino Experiment via the detection of inverse beta decaystagged by neutron capture on hydrogen. The antineutrino events for hydrogencapture are distinct from those for gadolinium capture with largely differentsystematic uncertainties, allowing a determination independent of thegadolinium-capture result and an improvement on the precision of $\theta_{13}$measurement. With a 217-day antineutrino data set obtained with sixantineutrino detectors and from six 2.9 GW$_{th}$ reactors, the rate deficitobserved at the far hall is interpreted as $\sin^22\theta_{13}=0.083\pm0.018$in the three-flavor oscillation model. When combined with thegadolinium-capture result from Daya Bay, we obtain$\sin^22\theta_{13}=0.089\pm0.008$ as the final result for thesix-antineutrino-detector configuration of the Daya Bay experiment.

A new measurement of the $\theta_{13}$ mixing angle has been obtained at theDaya Bay Reactor Neutrino Experiment via the detection of inverse beta decaystagged by neutron capture on hydrogen. The antineutrino events for hydrogencapture are distinct from those for gadolinium capture with largely differentsystematic uncertainties, allowing a determination independent of thegadolinium-capture result and an improvement on the precision of $\theta_{13}$measurement. With a 217-day antineutrino data set obtained with sixantineutrino detectors and from six 2.9 GW$_{th}$ reactors, the rate deficitobserved at the far hall is interpreted as $\sin^22\theta_{13}=0.083\pm0.018$in the three-flavor oscillation model. When combined with thegadolinium-capture result from Daya Bay, we obtain$\sin^22\theta_{13}=0.089\pm0.008$ as the final result for thesix-antineutrino-detector configuration of the Daya Bay experiment.

A search for light sterile neutrino mixing was performed with the first 217 days of data from the Daya Bay Reactor Antineutrino Experiment. The experiment's unique configuration of multiple baselines from six 2.9 GW(th) nuclear reactors to six antineutrino detectors deployed in two near (effective baselines 512 m and 561 m) and one far (1579 m) underground experimental halls makes it possible to test for oscillations to a fourth (sterile) neutrino in the 10(-3) eV(2)

Objective: To evaluate the feasibility and therapeutic effect of treating sternoclavicular joint dislocation by K-wire and tension band wire fixation, and to improve the safety and stability of this technique.Methods: This study consisted of 9 cases, 6 males and 3 females with the mean age of 25 years (range, 9-62 years). The causes were traffic accident in 7 cases, falling in 1 case and fight in 1 case. The duration from injury to operation was 2 hours to 7 days. There were 5 left dislocations and 4 right dislocations; 8 anterior dislocations and 1 posterior dislocation, including one combined with left scapular fracture and one with left olecranon fracture. Open reduction and internal fixation using K-wires and tension band wires were performed to treat dislocations.Results: All patients were followed up for 6 to 24 months, 10 months on average. According to Rockwood's rating scale on postoperative sternoclavicular joint, 8 cases achieved excellent outcomes with an average score of 13.88, and the rest case achieved a good outcome with the score of 12. Anatomical reduction was obtained in all cases. There were no such postoperative complications as severe infection, injury to blood vessel and nerve, failure of fixation, etc. Patients were all satisfied with the anatomical reduction and functional recovery.Conclusions: The technique of K-wire and tension band wire fixation is safe, simple, effective, less invasive and has been successfully used in orthopedic surgery. It is effective in treating sternoclavicular joint dislocation though it has some disadvantages. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the preliminary clinical outcomes of coccygectomy in patients with coccydynia after a failure of conservative treatment.Methods: From May 2002 to January 2010, 31 patients with coccydynia were treated by coccygectomy in our department after conservative measures had failed to produce significant relief. A questionnaire, which included the extent of relief in the painful area, improvement in quality of life, intensity of pain in the sitting position, and pain score during daily activities, was used to evaluate the results.Results: All patients were followed up for 1 to 6 years (mean 3.3 years). The results were excellent in 20 patients (64.5%), good in 7 patients (22.6%), moderate in 3 patients (9.7%) and poor in 1 patient (3.2%). The excellent and good rates amounted to 87.1%. All patients except one had complete resolution of their symptoms and were subjectively highly satisfied with the outcomes of the surgery. Only 2 cases of superficial infection were observed postoperatively.Conclusion: Coccygectomy is a feasible management option for patients with coccygodynia that has no response to conservative treatments. [ABSTRACT FROM AUTHOR]

BACKGROUND: The TAS1R1 and TAS1R3 G protein-coupled receptors are believed to function in combination as a heteromeric glutamate taste receptor in humans. OBJECTIVE: We hypothesized that variations in the umami perception of glutamate would correlate with variations in the sequence of these 2 genes, if they contribute directly to umami taste. DESIGN: In this study, we first characterized the general sensitivity to glutamate in a sample population of 242 subjects. We performed these experiments by sequencing the coding regions of the genomic TAS1R1 and TAS1R3 genes in a separate set of 87 individuals who were tested repeatedly with monopotassium glutamate (MPG) solutions. Last, we tested the role of the candidate umami taste receptor hTAS1R1-hTAS1R3 in a functional expression assay. RESULTS: A subset of subjects displays extremes of sensitivity, and a battery of different psychophysical tests validated this observation. Statistical analysis showed that the rare T allele of single nucleotide polymorphism (SNP) R757C in TAS1R3 led to a doubling of umami ratings of 25 mmol MPG/L. Other suggestive SNPs of TAS1R3 include the A allele of A5T and the A allele of R247H, which both resulted in an approximate doubling of umami ratings of 200 mmol MPG/L. We confirmed the potential role of the human TAS1R1-TAS1R3 heteromer receptor in umami taste by recording responses, specifically to l-glutamate and inosine 5'-monophosphate (IMP) mixtures in a heterologous expression assay in HEK (human embryonic kidney) T cells. CONCLUSIONS: There is a reliable and valid variation in human umami taste of l-glutamate. Variations in perception of umami taste correlated with variations in the human TAS1R3 gene. The putative human taste receptor TAS1R1-TAS1R3 responds specifically to l-glutamate mixed with the ribonucleotide IMP. Thus, this receptor likely contributes to human umami taste perception. Copyright © 2009 American Society for Nutrition [ABSTRACT FROM AUTHOR]

An efficient protocol was reported for the synthesis of 2-trifluoromethyl indoles through visible-light-promoted intermolecular cyclization of sulfoxonium ylides with azides, without the need for external photocatalysts, transition metals, or bases. The formation of 2-trifluoromethyl indoles involves an intriguing cascade process including azide rearrangement, intermolecular nucleophilic addition, and visible-light-promoted cyclization of a key intermediate. The protocol features high efficiency, mild conditions, excellent substrate compatibility and good regioselectivity. The practicality of this approach is demonstrated through scale-up reactions and further modifications of the synthesized indoles.

The pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment is distinguished by a high degree of fibrosis and inflammation, known as desmoplasia. Desmoplasia increases the stromal deposition and extracellular matrix (ECM) stiffness observed in the tumor microenvironment, contributing to the dampened penetration of pharmacological agents. The molecular and biophysical composition of the ECM during the earliest cellular changes in the development of PDAC, i.e. acinar ductal metaplasia (ADM), has not been extensively explored. We report that the mRNA expression of key protein components of the ECM increases during ADM in p48 Cre/+ ;LSL-Kras G12D (KC) mouse acinar organoids cultured in Matrigel. Treatment of the organoids with small molecular weight epigenetic modulating compounds that inhibit or reverse ADM (largazole, FK228 and chaetocin) dramatically reduced the tissue mRNA expression of collagens, hyaluronan synthase, laminin and fibronectin. The storage moduli, determined by video tracking of fluorescent nanoparticles embedded into the Matrigel, increased during ADM and was reduced following treatment with the epigenetic modulating compounds. We report that the ECM of mouse organoids stiffens during ADM and is further enhanced by the presence of mutant Kras. Moreover, select HDAC and HMT inhibitors reduced the mRNA expression of ECM components and ECM stiffness during inhibition and reversal of ADM, suggesting that these compounds may be useful as adjuvants to enhance the tumor penetration of agents used to treat PDAC., Competing Interests: Declaration of competing interest HL is co-founder of Oceanyx Pharmaceuticals, Inc., which has optioned and is negotiating licenses for patent applications related to largazole., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Covering 2010-April 2024There have been tremendous new discoveries and developments since 2010 in anticancer research based on marine cyanobacteria. Marine cyanobacteria are prolific sources of anticancer natural products, including the tubulin agents dolastatins 10 and 15 which were originally isolated from a mollusk that feeds on cyanobacteria. Decades of research have culminated in the approval of six antibody-drug conjugates (ADCs) and many ongoing clinical trials. Antibody conjugation has been enabling for several natural products, particularly cyanobacterial cytotoxins. Targeting tubulin dynamics has been a major strategy, leading to the discovery of the gatorbulin scaffold, acting on a new pharmacological site. Cyanobacterial compounds with different mechanisms of action (MOA), targeting novel or validated targets in a range of organelles, also show promise as anticancer agents. Important advances include the development of compounds with novel MOA, including apratoxin and coibamide A analogues, modulating cotranslational translocation at the level of Sec61 in the endoplasmic reticulum, largazole and santacruzamate A targeting class I histone deacetylases, and proteasome inhibitors based on carmaphycins, resembling the approved drug carfilzomib. The pipeline extends with SERCA inhibitors, mitochondrial cytotoxins and membrane-targeting agents, which have not yet advanced clinically since the biology is less understood and selectivity concerns remain to be addressed. In addition, efforts have also focused on the identification of chemosensitizing and antimetastatic agents. The review covers the state of current knowledge of marine cyanobacteria as anticancer agents with a focus on the mechanism, target identification and potential for drug development. We highlight the importance of solving the supply problem through chemical synthesis as well as illuminating the biological activity and in-depth mechanistic studies to increase the value of cyanobacterial natural products to catalyze their development.

Background: Patients with locoregionally advanced nasopharyngeal carcinoma with a high pretreatment plasma concentration of Epstein-Barr virus (EBV) DNA remain at high risk for recurrence after concurrent chemoradiotherapy. This study aimed to compare the efficacy and safety of neoadjuvant-adjuvant treatment with the PD-1 inhibitor toripalimab and concurrent chemoradiotherapy versus placebo and concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma., Methods: This randomised, single-centre, double-blind, placebo-controlled, phase 2 trial was conducted at Sun Yat-sen University Cancer Centre in Guangzhou, China. Adult patients (aged 18-65 years) with newly diagnosed high-risk stage III-IVa locoregionally advanced nasopharyngeal carcinoma, with a pretreatment plasma EBV DNA concentration of at least 1500 copies per mL and an Eastern Cooperative Oncology Group performance score of 0-1, were eligible. Patients were randomly assigned (2:1) using an interactive web response system (block size of six), stratified by TNM stage (III vs IVa), to neoadjuvant toripalimab (240 mg intravenously) or placebo once every 2 weeks for two cycles, followed by concurrent cisplatin (100 mg/m 2 intravenously) on days 1, 22, and 43 during intensity-modulated radiotherapy and adjuvant toripalimab (240 mg intravenously) or placebo once every 3 weeks for up to eight cycles. The primary endpoint was 2-year progression-free survival in the intention-to-treat population. This study was registered with ClinicalTrials.gov, NCT03925090, and is closed to enrolment; follow-up is ongoing., Findings: Between Dec 6, 2019, and Dec 9, 2021, 150 patients were enrolled and randomly assigned to the toripalimab group (n=100) or placebo group (n=50). 115 (77%) patients were male and 35 (23%) were female. As of data cutoff (May 31, 2024), median follow-up for progression-free survival was 37·8 months (IQR 34·2-46·5) for the intention-to-treat population analyses. 2-year progression-free survival was higher in the toripalimab group (92·0% [95% CI 86·7-97·3]) than in the placebo group (74·0% [61·8-86·2]; stratified hazard ratio 0·40 [95% CI 0·18-0·89]; log-rank p=0·019). The most common grade 3 or worse acute adverse events (occurring within 1 year of randomisation) were leukopenia (40 [40%] of 99 patients in the toripalimab group vs 22 [44%] of 50 patients in the placebo group), mucositis (28 [28%] vs ten [20%]), neutropenia (17 [17%] vs nine [18%]), anaemia (16 [16%] vs five [10%]), and weight loss (12 [12%] vs six [12%]). The most common grade 3 or worse late adverse events (occurring >1 year after randomisation) was auditory or hearing loss (eight [8%] vs four [8%]). Immune-mediated adverse events of grade 3 or worse occurred in ten (10%) patients only in the toripalimab group. One (2%) of 50 patients in the placebo group died due to septic shock caused by bacteraemia considered not treatment related. There were no treatment-related deaths in the toripalimab group., Interpretation: Our findings suggested that a so-called sandwich approach involving toripalimab (in the neoadjuvant and adjuvant phases) combined with concurrent chemoradiotherapy could be a highly promising therapy for the treatment of locoregionally advanced nasopharyngeal carcinoma. Phase 3 non-inferiority trials are warranted comparing neoadjuvant and adjuvant toripalimab versus cisplatin plus gemcitabine neoadjuvant chemotherapy combined with concurrent chemoradiotherapy., Funding: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Science and Technology Program of Guangzhou, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Postdoctoral Innovative Talent Support Program, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, and Fundamental Research Funds for the Central Universities., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Elderly patients with advanced gastric cancer have poor prognoses. This study aims to develop a prediction model for long-term survival after radical surgery and to identify patients who may benefit from chemotherapy., Methods: Data from 555 elderly patients with advanced gastric cancer admitted to two medical centers from 2009 to 2018 were retrospectively analyzed. Sarcopenia was combined with the Controlling Nutritional Status (CONUT) score to create a modified nutritional index (mCONUT). Cox regression analyses were used to develop a novel nomogram prediction model (mCNS) that combined mCONUT, pN, and tumor size, and its performance was further verified both internally and externally., Results: Multivariate Cox analysis revealed that tumor size, pN, and mCONUT were independent prognostic risk factors for overall survival (OS). The mCNS model showed good fit and high predictive value (AUC: training set 0.711; validation set 0.707), outperforming the pTNM model (p < 0.05). To further investigate the association between the model and adjuvant chemotherapy, we categorized the model into two risk groups: a high-risk group and a low-risk group. Further analysis revealed that, in the low-risk group, the OS and recurrence-free survival(RFS) for patients receiving adjuvant chemotherapy was significantly better than that of those who did not receive chemotherapy (p = 0.047,p = 0.019). In the high-risk group, this result was not observed (p = 0.120, p = 0.053)., Conclusion: The mCNS model has high predictive value in predicting long-term survival of elderly patients with advanced gastric cancer. Patients with mCNS-L were able to benefit from chemotherapy after laparoscopic radical gastrectomy., Competing Interests: Declaration of competing interest None reported., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The impact of postoperative sarcopenia on the Textbook Oncological Outcome (TOO) in locally advanced gastric cancer (LAGC) remains uncertain. This study investigates the relationship between sarcopenia and TOO, explores its long-term prognostic value, and develops a prognostic model incorporating sarcopenia and TOO for survival prediction., Methods: We performed a retrospective analysis of clinical and pathological data from patients with LAGC who underwent radical surgery at two Chinese tertiary referral hospitals. Sarcopenia was defined as an SMI < 36.4 cm 2 /m 2 in males and < 28.4 cm 2 /m 2 in females. TOO was defined as the addition of perioperative chemotherapy to the textbook outcomes (TO). A nomogram was developed to predict postoperative overall survival (OS) and recurrence-free survival (RFS) in LAGC patients., Results: The study included 972 patients with LAGC. The overall TOO achievement rate was 67.1%. The TOO achievement rate was significantly higher in patients non-sarcopenia compared to those with sarcopenia (68.9% vs. 61.1%, P = 0.031). Logistic regression revealed that age ≥ 65, high ASA score, and sarcopenia were independent risk factors for TOO failure. Cox regression analysis identified TOO, sarcopenia, tumor size, differentiation, vascular invasion, pT stage, and pN stage as independent predictors of OS and RFS. Nomogram models based on sarcopenia and TOO accurately predicted the 3-year and 5-year OS and RFS., Conclusion: Preoperative sarcopenia was an independent predictor of TOO implementation. A prognostic prediction model that integrates preoperative sarcopenia and TOO, which outperforms the current staging system, can aid clinicians in effectively assessing the prognosis of patients with LAGC., Competing Interests: Declarations Disclosures Qing Zhong, Zi-Fang Zheng, Dong Wu, Zhi-Xin Shang-Guan, Zhi-Yu Liu, Yi-Ming Jiang, Jian-Xian Lin, Jia-Bin Wang, Qi-Yue Chen, Jian-Wei Xie, Wei Lin, Chao-Hui Zheng, Chang-Ming Huang, and Ping Li have no conflicts of interest or financial ties to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)