Children， as a special group， frequently experience of off-label drug use worldwide. Common reasons for off-label drug use in children include the lack of data on pediatric patients during the clinical trial stage of drug development， delayed updates to drug instructions， and the non-standard professional behavior of some doctors. Off-label drug use in children is a double-edged sword. It could save lives and provide a way to explore additional functions of drugs， while it may also lead to the phenomenon of hyper-indication abuse， increasing the risk of adverse drug events. Regulating off-label drug use in children can safeguard the best treatment rights and interests of children. It is recommended to encourage pharmaceutical enterprises to conduct research and development of pediatric new drugs， simplify the approval process for drug instructions amendments， accumulate evidence-based medical evidence for off-label drug use in children， standardize the process of off-label drug use in children in medical institutions， continuously improve the standardized diagnosis and treatment capabilities of pediatricians， and actively cooperate with the families of pediatric patients in diagnosis and treatment， so as to comprehensively safeguard the rights and interests of both doctors and patients.

The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKO^AST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of d-serine in the mPFC of CKO^AST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKO^AST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKO^AST mice could be reversed through the administration of d-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through d-serine, and may shed light on the treatment of mental disorders.

Objective To investigate the effect of resveratrol(RSV)in the treatment of peri-implantitis in a murine model and its effect on nuclear factor kappa-B(NF-κB)signaling and mitogen-activated protein kinase(MAPKs)signal-ing.Methods This study has been reviewed and approved by the Ethics.After extracting the right maxillary molars of 40 C57BL/6 mice and allowing them to heal naturally for 8 weeks,implants were implanted at the site of the first molar.The mice were randomly divided into a control group,a mouse peri implantitis model group,a low-dose group of 20 mg/kg resveratrol(RSV-L),and a high-dose group of 40 mg/kg resveratrol(RSV-H).After 4 weeks of implant implantation,a silk thread ligation induced peri implantitis model was established in all mice except for the control group.The model group received intervention with physiological saline by gavage,while the drug group received intervention with resvera-trol by gavage for 6 consecutive weeks.After 6-week treatment,observe the swelling of the gums around the implant and measure the bone resorption around the mouse implant using micro CT.Enzyme linked immunosorbent assay(ELISA)was used to detect the levels of tumor necrosis factor alpha(TNF-α)and interleukin-6(IL-6)in gingival crevicular fluid.HE staining was used to observe the infiltration of inflammatory cells in the surrounding tissues of mouse implants.Pro-tein expression level and phosphorylation level of extracellular regulated protein kinases(ERK),p-ERK,c-Jun N-termi-nal kinase(JNK),p-JNK,p38 mitogen activated protein kinase(p38 MAPK),p-p38MAPK,nuclear factor kappa-B(NF-κB),p-NF-κB,nuclear factor-κB inhibitory protein(IκBα),p-IκBα in MAPKs/NF-κB signaling pathway were detected by Western blot(WB).Results Resveratrol group showed reduced tissue edema and decreased alveolar bone resorp-tion.Among them,the high-dose resveratrol group had lighter tissue edema and weaker bone resorption compared to the low-dose group.The micro CT results showed that significant changes in the bone level around the implant were observed in the model group mice at four sites:proximal,distal,buccal,and palatal.High dose resveratrol intervention reduced al-veolar bone resorption(P＜0.05);compared with the low-dose group,the high-dose group showed a decrease in palatal bone resorption(P＜0.05),while there was no significant difference in absorption between the mesial,distal,and buccal sides(P＞0.05).The ELISA results showed that compared with the model group,the levels of TNF-α and IL-6 in the gingival crevicular fluid of mice in the low-dose and high-dose resveratrol groups were lower(P＜0.05).The IL-6 in the gingival crevicular fluid of mice in the high-dose resveratrol group was lower than that in the low-dose group(P＜0.05).However,there was no significant difference in TNF-α levels between the two groups.HE staining showed a decrease in inflammatory cell infiltration in mice after treatment with resveratrol.The WB results showed that compared with the con-trol group,the expression levels of p-Erk,p-JNK,p-p38MAPK,p-IκA,and p-NF-κB phosphorylated proteins in the gingi-val tissue of the model group mice were significantly increased(P＜0.01).The resveratrol treatment group significantly inhibited the phosphorylation of p-Erk,p-JNK,p-p38MAPK,p-IκA,and p-NF-κB proteins.Compared with the low-dose group,the high-dose group inhibited the phosphorylation of MAPKs/NF-κB signaling pathway related proteins more sig-nificantly(P＜0.05).Conclusion Resveratrol protect ligature induced peri-implantitis murine model,which may be re-lated to its inhibition of phosphorylation of MAPKs/NF-κB pathway.

Accurate identification of compound-protein interactions (CPIs) in silico may deepen our understanding of the underlying mechanisms of drug action and thus remarkably facilitate drug discovery and development. Conventional similarity-or docking-based computational methods for predicting CPIs rarely exploit latent features from currently available large-scale unlabeled com-pound and protein data and often limit their usage to relatively small-scale datasets. In the present study, we propose DeepCPI, a novel general and scalable computational framework that combines effective feature embedding (a technique of representation learning) with powerful deep learning methods to accurately predict CPIs at a large scale. DeepCPI automatically learns the implicit yet expressive low-dimensional features of compounds and proteins from a massive amount of unla-beled data. Evaluations of the measured CPIs in large-scale databases, such as ChEMBL and Bind-ingDB, as well as of the known drug-target interactions from DrugBank, demonstrated the superior predictive performance of DeepCPI. Furthermore, several interactions among small-molecule compounds and three G protein-coupled receptor targets (glucagon-like peptide-1 recep-tor, glucagon receptor, and vasoactive intestinal peptide receptor) predicted using DeepCPI were experimentally validated. The present study suggests that DeepCPI is a useful and powerful tool for drug discovery and repositioning. The source code of DeepCPI can be downloaded from https://github.com/FangpingWan/DeepCPI.

Objective This study aims to explore the characteristics of gender and age in six different suicide methods in urban area of China. Methods We collected 548 suicides from Shanghai, Jinhua, Wuhan, Loudi and Duyun, and then analyzed the age and gender characteristics in each suicide method. Results In the age characteristics, the mean age for jumping and hanging was oldest (about 55 years old), followed by drowning and hanging (about 49 years old), oral intake poisoning was much younger (about 49 years old), while carbon monoxide poisoning was youngest (about 37 years old). In the gender differences, male were more than females in suicides by sharp object (52:24), hanging (67:33) and jumping (55:45), while females were more than males in suicides by drowning (58:42). Conclusion The age and gender difference was eminent in different suicide methods. Carbon monoxide poisoning was the youngest age group in suicides and males involved more than females in suicides by mechanical methods.

Objective To explore the effect of preoperative neutrophil lymphocyte ratio (NLR) on the prognosis of patients with laryngeal carcinoma.Methods Clinical data of 202 patients with laryngeal carcinoma treated from January 2004 to October 2009 were retrospective analyzed to determine the optimal critical value of NLR.To study whether NLR is an independent factor affecting the recurrence and 5-year survival rate of patients with laryngeal cancer after surgery,single factor and multivariate analyses were performed.The factors included age,gender,T stage,pathological differentiation,lymph node metastasis,primary tumor site and NLR value.The relationship between NLR and cervical lymph node metastasis was analyzed.Results The optimal critical value of NLR was 2.85,by which cases were divided into high NLR group (NLR≥2.85) and low NLR group (NLR ＜ 2.85).Single factor and multivariate analyses indicated that T staging,lymph node metastasis,primary tumor location,and NLR were the independent factors affecting the recurrence of laryngeal carcinoma.T stage and lymph node metastasis were the independent factors affecting 5-year survival rate of laryngeal carcinoma.The increase of NLR value increased the rate of cervical lymph node metastasis.Conclusion Preoperative NLR level influences the recurrence and cervical lymph node metastasis of laryngeal carcinoma and can be considered a prognosis factor of laryngeal cancer.

OBJECTIVETo analyze the clinical features and treatment of skull base osteosarcoma.

METHODSThe clinical data of 18 patients with skull base osteosarcoma, who were admitted to the CAMS Cancer Hospital from January 2005 to November 2013, were retrospectively analyzed. The patients were followed up by telephone, outpatient review and other means. Fifteen patients were followed up, 4 cases received surgery only, and 11 cases received surgery with adjuvant chemotherapy and/or radiotherapy. Kaplan-Meier survival curve analysis was used to analyze the clinical data and Log rank method was used for verification.

RESULTSNine patients died among the 15 patients who were followed up for 3-103 months (mean 25.0 months): seven patients died of local recurrence, and two patients died of distant metastasis, and six patients were still alive. Four patients received surgery only, with a median survival time of 25.0 months, and 11 patients received comprehensive treatment, with a median survival time of 47.0 months (P = 0.02). Five patients received sub-total resection, with a mean survival time of 47.0 months, and 10 patients received total resection, with a mean survival time of 45.0 months (P = 0.37). The 1- and 2-year recurrence rates were 46.6% and 68.9%, respectively. The overall 1-, 2-, 3- and 5-year survival rates were 82.4%, 61.8%, 36.0% and 36.0%, respectively, with a median survival time of 30.0 months.

CONCLUSIONSTo compare the long bone and head and neck osteosarcoma with skull base osteosarcoma, the skull base osteosarcoma has a lower total resection rate, a higher recurrence rate, and a poorer prognosis. Radical surgery and comprehensive treatment are appropriate for skull base osteosarcoma.

Bone Neoplasms ; diagnosis ; pathology ; therapy ; Chemotherapy, Adjuvant ; Combined Modality Therapy ; Humans ; Kaplan-Meier Estimate ; Neoplasm Recurrence, Local ; Osteosarcoma ; diagnosis ; pathology ; therapy ; Retrospective Studies ; Skull Base ; pathology ; Survival Rate

Objective To analyze the clinical features and treatment of skull base osteosarcoma. Methods The clinical data of 18 patients with skull base osteosarcoma, who were admitted to the CAMS Cancer Hospital from January 2005 to November 2013, were retrospectively analyzed.The patients were followed up by telephone, outpatient review and other means.Fifteen patients were followed up, 4 cases received surgery only, and 11 cases received surgery with adjuvant chemotherapy and/or radiotherapy. Kaplan-Meier survival curve analysis was used to analyze the clinical data and Log rank method was used for verification.Results Nine patients died among the 15 patients who were followed up for 3-103 months ( mean 25.0 months):seven patients died of local recurrence, and two patients died of distant metastasis, and six patients were still alive.Four patients received surgery only, with a median survival time of 25.0 months, and 11 patients received comprehensive treatment, with a median survival time of 47.0 months ( P=0.02) .Five patients received sub-total resection, with a mean survival time of 47.0 months, and 10 patients received total resection, with a mean survival time of 45.0 months ( P=0.37) .The 1-and 2-year recurrence rates were 46.6%and 68.9%, respectively.The overall 1-, 2-, 3-and 5-year survival rates were 82.4%, 61.8%, 36.0%and 36.0%, respectively, with a median survival time of 30.0 months.Conclusions To compare the long bone and head and neck osteosarcoma with skull base osteosarcoma, the skull base osteosarcoma has a lower total resection rate, a higher recurrence rate, and a poorer prognosis. Radical surgery and comprehensive treatment are appropriate for skull base osteosarcoma.

Background and objectiveIt has been proven that tumor necrosis factor receptor-associated factor 6 (TARF6) was a commonly ampliifed oncogene in lung cancer. However, the precise role of TARF6 protein in lung cancer has not been extensively investigated. hTis study analyzed the effects of TARF6 on the proliferation, apoptosis, cell cycle, migration, and invasion capability of lung cancer cell lines, as well as the potential molecular mechanisms involved.MethodsTo address the expression of TARF6 in lung cancer cells, four lung cancer cell lines (A549, H1650, SPC-A-1 and Calu-3) were assayed to determine the expression of TARF6 protein by Western blot and TARF6 mRNA via qRT-PCR. Moreover, siRNA targeting TARF6 was introduced into SPC-A-1 and Calu-3 cells. Nuclear factor-?B (NF-?B) DNA-binding activity, apoptosis rates, cell proliferation, cell cycle, migration, and invasion were determined by electrophoretic mobility shitf assay, lfow cytometry, MTS assay, lfow cytometry, scratch test, and transwell chamber assay, respectively. Western blot analysis was also performed to evalu-ate the expression of the following proteins through K63-ubiquitination: P65, CD24 and CXCR4. Whole-genome sequencing analysis was conducted using a second-generation sequencer in SPC-A-1 cells.Results TARF6 was highly up-expressed in SPC-A-1 and Calu-3 cell lines than the other two cells, which also showed K63-ubiquitinization in TARF6. However, consti-tutive activation of NF-?B was observed only in SPC-A-1 lung cancer cells. Downregulation of TARF6 suppressed the NF-κB activation, cell migration, and invasion but promoted the cell apoptosis of SPC-A-1 cells. Markedly decreased expression of CD24 and CXCR4 was observed in SPC-A-1 cells transfected by TARF6 siRNA. Nevertheless, TARF6 downregulation did not affect the proliferation and cell cycle of SPC-A-1 cells. Additionally, TARF6 regulation did not affect the proliferation, apoptosis, cell cycle, migration, and invasion of Calu-3 cells. No mutations and no changes in gene copy numbers of TARF6 were found by whole-exome sequencing of SPC-A-1 cells.ConclusionTARF6 may be involved in cell migration, invasion, and apoptosis of SPC-A-1 cells, possibly through regulating the NF-?B-CD24/CXCR4 pathway.

Objective To analyze the clinical features and treatment of skull base osteosarcoma. Methods The clinical data of 18 patients with skull base osteosarcoma, who were admitted to the CAMS Cancer Hospital from January 2005 to November 2013, were retrospectively analyzed.The patients were followed up by telephone, outpatient review and other means.Fifteen patients were followed up, 4 cases received surgery only, and 11 cases received surgery with adjuvant chemotherapy and/or radiotherapy. Kaplan-Meier survival curve analysis was used to analyze the clinical data and Log rank method was used for verification.Results Nine patients died among the 15 patients who were followed up for 3-103 months ( mean 25.0 months):seven patients died of local recurrence, and two patients died of distant metastasis, and six patients were still alive.Four patients received surgery only, with a median survival time of 25.0 months, and 11 patients received comprehensive treatment, with a median survival time of 47.0 months ( P=0.02) .Five patients received sub-total resection, with a mean survival time of 47.0 months, and 10 patients received total resection, with a mean survival time of 45.0 months ( P=0.37) .The 1-and 2-year recurrence rates were 46.6%and 68.9%, respectively.The overall 1-, 2-, 3-and 5-year survival rates were 82.4%, 61.8%, 36.0%and 36.0%, respectively, with a median survival time of 30.0 months.Conclusions To compare the long bone and head and neck osteosarcoma with skull base osteosarcoma, the skull base osteosarcoma has a lower total resection rate, a higher recurrence rate, and a poorer prognosis. Radical surgery and comprehensive treatment are appropriate for skull base osteosarcoma.