There is significant inter-individual variation of pharmacokinetics and pharmacody-namics in patients receiving tacrolimus(TAC)for an-ti-rejection therapy,which cause the rejection or toxic action.Based on results of therapeutic drug monitoring and pathophysiological index of trans-plant patients,the individualized dosing regimen can be designed and adjusted by using model in-formed precision dosing(MIPD).The patients'clini-cal outcome can be improved.In the consensus,the different methods of MIPD used for patients re-ceived TAC for anti-rejection therapy were intro-duced,which can be used for the designing and ad-justing doing regimen,predicting adverse drug reac-tion,improving medication adherence and econom-ics during therapy.

There is significant inter-individual variation of pharmacokinetics and pharmacody-namics in patients receiving tacrolimus(TAC)for an-ti-rejection therapy,which cause the rejection or toxic action.Based on results of therapeutic drug monitoring and pathophysiological index of trans-plant patients,the individualized dosing regimen can be designed and adjusted by using model in-formed precision dosing(MIPD).The patients'clini-cal outcome can be improved.In the consensus,the different methods of MIPD used for patients re-ceived TAC for anti-rejection therapy were intro-duced,which can be used for the designing and ad-justing doing regimen,predicting adverse drug reac-tion,improving medication adherence and econom-ics during therapy.

Objective:To investigate the effects of electroacupuncture on neuroinflammation in rats with postherpetic neuralgia (PHN) by regulating advanced glycation end products (AGE) and its receptor (RAGE) signaling pathway.Methods:Ten healthy male SD rats were randomly selected as the control group, and the remaining 30 SD rats were used to induce PHN model by resin toxin (RTX). Thirty SD rats were randomly divided into model group, positive drug group and electroacupuncture group, with 10 rats in each group. Intervention was conducted on the 7th day of modeling. The electroacupuncture group intervened with "Yanglingquan"(GB34) and "Huantiao"(GB30); the positive drug group was intragastrically administered with pregabalin suspension 27 mg/kg, once a day for 1 week; the control group and model group were not treated. The paw retraction threshold (PWMT) and paw retraction latency (PWTL) were measured before modeling and on the 7th, 14th, 21st and 28th days after modeling; histopathological changes of spinal cord were observed by HE staining; the levels of TNF-α, IL-1β and IL-6 in spinal cord tissue were detected by ELISA; the expressions of AGE-RAGE signaling pathway related proteins in spinal cord was detected by Western blot.Results:Compared with the model group, the degree of atrophy and inflammatory infiltration of spinal cord neurons in the positive drug group and electroacupuncture group were reduced. The PWMT value in the positive drug group increased ( P<0.05), and the PWTL value decreased ( P<0.05); compared with the model group, the levels of TNF-α, IL-1β and IL-6 in the spinal cord tissue of the electroacupuncture group and the positive drug group decreased ( P<0.05), and the expressions of AGE, RAGE, p-ERK1/2/ERK1/2, JNK, p-NF-κB/NF-κB and AP-1 decreased ( P<0.05); compared with the positive drug group, the levels of TNF-α, IL-1β and IL-6 in the spinal cord tissue of the electroacupuncture group decreased ( P<0.05), and the protein expressions of AGE, RAGE, p-ERK1/2/ERK1/2, JNK, p-NF-κB/NF-κB and AP-1 decreased ( P<0.05). Conclusion:Electroacupuncture can improve neuroinflammation in PHN rats, the mechanism of which may be related to the regulation of AGE-RAGE mediated pro-inflammatory signaling pathway.

ObjectiveTo observe the clinical efficacy of acupuncture combined with bloodletting and cupping in the treatment of chronic spontaneous urticaria（CSU） and to explore its potential mechanisms of action. MethodsSeventy CSU patients were randomly divided into loratadine group and acupuncture + bloodletting group， with 35 patients in each group. The loratadine group received oral loratadine tablets， 10 mg once daily in the evening. The acupuncture + bloodletting group received acupuncture at Zhongwan （CV 12）， Guanyuan （CV 4）， Tianshu （ST 25）， Zusanli （ST 36）， Sanyinjiao （SP 6）， Xuehai （SP 10）， Quchi （LI 11）， Hegu （LI 4）， Taichong （LR 3）， Baihui （GV 20）， and Shenting （GV 24）， once daily，along with bloodletting and cupping at Dazhui （GV 14） and Geshu （BL 17）， every other day. Both groups were treated for 4 weeks. The 7-day urticaria activity score（UAS7） was assessed before and after the treatment， and levels of serum immunoglobulin E （IgE）， interleukin-4 （IL-4）， interleukin-5 （IL-5）， eosinophil cationic protein （ECP）， plasma tissue factor （TF）， activated factor Ⅶ （FⅦa）， prothrombin fragment 1+2 （F1+2）， D-dimer （D-D） and complement component 5a （C5a） were detected. ResultsA total of 65 patients were included in the final analysis， 32 in the loratadine group and 33 in the acupuncture + bloodletting group. Before treatment， there was no significant difference in UAS7 score， serum IgE， IL-4， IL-5， ECP levels， or plasma TF， FⅦa， F1+2， D-D， C5a levels between groups （P＞ 0.05）. After treatment， both groups showed significant reductions in UAS7 score， serum IgE， IL-4， IL-5， and plasma TF， FⅦa， F1+2， D-D， and C5a levels compared to those before treatment （P＜0.01）. However， after treatment， there was no significant difference in UAS7 score and serum ECP， IgE， IL-4， IL-5 levels between groups （P＞0.05）. The acupuncture + bloodletting group showed lower plasma TF， FⅦa， F1+2， D-D and C5a levels compared to the loratadine group （P＜0.05 or P＜0.01）. ConclusionAcupuncture combined with bloodletting and cupping can effectively improve the skin symptoms of CSU patients and reduce the levels of inflammatory factors. The potential mechanism of action may involve the regulation of the coagulation-complement-mast cell activation axis， thereby inhibiting mast cell degranulation.

OBJECTIVE: To observe the effects of acupuncture combined with bloodletting on the expression of inflammatory factors in serum, the morphology of sensitized skin tissue and the mast cell degranulation in urticaria rats, and to explore the potential mechanism of this therapy for urticaria. METHODS: Among 42 SD rats of SPF grade, 6 rats were randomly collected for the preparation of sensitized antiserum; and the rest 36 rats were randomized into a blank group, a model group, a positive drug group, an acupuncture group, a bloodletting group and a combined treatment group (acupuncture + bloodletting), 6 rats in each one. The rat model of urticaria was established by passive cutaneous anaphylaxis. In the positive drug group, loratadine (1 mg•kg^-1) by gavage was administered once a day. In the acupuncture group, 1 h after gavage with 0.9% NaCl (1 mL), acupuncture was delivered at "Baihui" (GV 20), "Zhongwan" (CV 12), and bilateral "Quchi" (LI 11) and "Xuehai" (SP 10) for 15 min, once daily . In the bloodletting group, 1 h after gavage with 0.9% NaCl (1 mL), bloodletting was operated at "Dazhui" (GV 14) and bilateral "Geshu" (BL 17), around 0.1 mL of bleeding volume at each point, once daily. In the combined treatment group, 1 h after gavage with 0.9% NaCl (1 mL), the interventions as the acupuncture group and the bloodletting group were adopted, once daily. All the interventions started on day 6 of modeling, lasting 2 weeks. After intervention completion, antigenic stimulation was performed in the rats of each group. Using ELISA, the levels of serum immunoglobulin E (IgE), tryptase (TPS), interleukin-4 (IL-4), interleukin-5 (IL-5), tumor necrosis factor-α (TNF-α) were detected. The diameter of the blue spots of the sensitized skin on the back was measured with ruler in each rat. The morphology of sensitized skin tissue was observed using HE staining, and the degranulation of mast cells was observed using Toluidine blue staining. RESULTS: Compared with the blank group, in the model group, the levels of serum IgE, TPS, IL-4, IL-5 and TNF-α increased (P<0.01), the diameter of blue spot on the sensitized part of the rat back was larger (P<0.01), the degranulation rate of mast cells was elevated (P<0.01), and there were obvious inflammatory cell infiltration and edema in the dermis of sensitized skin tissue on the rat back. Compared with the model group, the serum levels of IgE, TPS, IL-4, IL-5 and TNF-α were reduced in the positive drug group, the acupuncture group, the bloodletting group and the combined treatment group (P<0.01, P<0.05); skin blue spot diameter was smaller in the positive drug group and the combined treatment group (P<0.05); the degranulation rate of mast cells decreased in the positive drug group, the acupuncture group, the bloodletting group and the combined treatment group (P<0.01); and the dermal edema, inflammatory infiltration were attenuated in the positive drug group, the acupuncture group, the bloodletting group and the combined treatment group. Compared with the acupuncture group and the bloodletting group, the serum levels of IgE, TPS, IL-4, IL-5 and TNF-α, as well as the degranulation rate of mast cells in the sensitized tissue were lower in the positive drug group and the combined treatment group (P<0.05). CONCLUSION Acupuncture combined with bloodletting effectively suppress mast cell degranulation in the sensitized skin tissue on the back of urticaria rats, and ameliorate the histopathological morphology. Its effect mechanism may be related to inhibiting the differentiation and proliferation of helper T cells 2 and regulating the humoral immune response.
Animals ; Rats ; Mast Cells/immunology* ; Acupuncture Therapy ; Rats, Sprague-Dawley ; Male ; Cell Degranulation ; Humans ; Bloodletting ; Urticaria/immunology* ; Female ; Acupuncture Points ; Tumor Necrosis Factor-alpha/blood* ; Interleukin-4/blood* ; Interleukin-5/blood* ; Combined Modality Therapy ; Immunoglobulin E/blood* ; Disease Models, Animal

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor (iPDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation, macrophage polarization and DC maturation. The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

Objective:To describe the characteristics, etiology and patterns of outpatients and inpatients patients with moderate or severe valvular heart disease (VHD).Methods:This is a cross-sectional study. Outpatients and inpatients with moderate or severe VHD who underwent transthoracic echocardiography for first examination from 1 st January 2001 to 1 st January 2020 in Southwest Hospital, Army Medical University were enrolled. Data were collected from medical records and big data platform of Southwest Hospital. Characteristics of age and gender, etiology and types of VHD were descriptively analysed. Results:A total of 68 354 patients with moderate or severe VHD were enrolled. The age was 63 (50, 72) years. And 35 706 (52.24%) patients were female. (1) Age characteristics: There was similar age trend between male and female patients with moderate or severe VHD. The number of patients increased firstly and then decreased and reached its peak in the age group of 65-69 years old. The peak age of mitral stenosis patients was 45-49 years, which was earlier than that of whole patients with moderate or severe VHD. The median age of patients with bicuspid aortic valve was 42 years. (2) Gender characteristics: The proportion of tricuspid regurgitation, pulmonary regurgitation, mitral regurgitation, mitral stenosis and valve surgery in female patients with moderate or severe VHD were higher than those in male patients. The proportion of aortic regurgitation, aortic stenosis and bicuspid aortic valve in male patients with moderate or severe VHD were significantly higher than those in female patients (all P<0.05). (3) Etiology: The proportion of rheumatic VHD was 13.07% (8 934/68 354), which was higher than that of degenerative VHD (0.67% (458/68 354)). (4) Types of VHD: Tricuspid regurgitation made contribution to the largest proportion with 60.72% (41 503/68 354), followed by mitral regurgitation, aortic regurgitation, mitral stenosis, pulmonary regurgitation and aortic stenosis. Conclusions:There are certain regional characteristics in the prevalence of moderate or severe VHD in southwest China, suggesting different attention should be paid on the whole process of refined management of moderate or severe VHD.

Allergic rhinitis is a common allergic disease in children.Its pathogenesis is complex and it is difficult to achieve radi-cal cure or effective and stable long-term treatment goals.Chinese medicine has obvious advantages in preventing and treating allergic rhinitis in children due to its wide range of targets,long-lasting effects and few adverse reactions.This paper proposes that the onset of allergic rhinitis is mostly caused by the dysfunction of the lung,spleen and kidney,the external wind triggering the latent wind,and the combination of the two winds.A staged prevention and treatment strategy of Chinese medicine should be adopted,which includes dispersing external wind,suppressing latent wind,and promoting lung-qi and clearing nasal orifice during the attack period to treat its symptoms,and preventing external wind,calming down latent wind,and regulating and tonifying the lung,spleen,and kidney during the remission period to treat its root cause;meanwhile,attention should be paid to avoiding the adverse effects of congenital endowment factors and the induction of acquired environmental factors,strengthening the body's health to protect against the evil wind,preventing the transformation of existing diseases and the recurrence of allergic rhinitis in children at all stages.

Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood‒brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d,l-lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d,l-lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.

Model informed precision dosing for warfarin is to provide individualized dosing by integrating information related to patient characteristics, disease status and pharmacokinetics /pharmacodynamics of warfarin, through mathematical modeling and simulation techniques based on the quantitative pharmacology. Compared with empirical dosing, it can improve the safety, effectiveness, economy, and adherence of pharmacotherapy of warfarin. This consensus report describes the commonly used modeling and simulation techniques for warfarin, their application in developing and adjusting dosing regimens, medication adherence and economy. Moreover, this consensus also elaborates the detailed procedures for the implementation in the warfarin pharmacy service pathway to facilitate the development and application of model informed precision dosing for warfarin.