Study on the correlation between the active components of Salviea Miltiorrhizae Radix et Rhizoma screened by high-throughput sequencing and the regulation of lncRNA-mRNA in human lung adenocarcinoma A549 cells / 国际中医中药杂志

Objective:Study on the correlation between the active components of Salviea Miltiorrhizae Radix et Rhizoma screened by high-throughput sequencing and the regulation of lncRNA-mRNA in human lung adenocarcinoma A549 cells.Methods:A549 cells were cultured, and the IC 50 dose of cryptotanshinone and tanshinone ⅡA was confirmed according to the cell proliferation experiment. A549 cells were randomly divided into blank control group, cryptotanshinone group, and tanshinone IIA group using a random number table method. After 24 hours of intervention, the cell cycle was detected by flow cytometry. High-throughput sequencing technique was used to detect the expressions of lncRNA and mRNA in A549 cells in intervention group and non-intervention group. By analyzing the expression profiles of differential genes related to cryptotanshinone and tanshinone ⅡA, the obtained differential genes were analyzed by GO and KEGG. Results:The cell cycle results showed that the proportion of G0/G1 phase cells in cryptotanshinone and Tanshinone ⅡA was increased ( P<0.01), the proportion of S phase cells was decreased ( P<0.01), and the proportion of G2/M phase cells in cryptotanshinone was decreased ( P<0.01). The results of high-throughput screening showed that cryptotanshinone could up-regulate 4 698 lncRNA, down-regulate 1 557 lncRNA, up-regulate 4 810 mRNA and down-regulate 5 644 mRNA. Tanshinone ⅡA could up-regulate 1 348 lncRNA, down-regulate 1 299 lncRNA, up-regulate 4646 mRNA and down-regulate 4 741 mRNA. The function and pathway enrichment analysis of differential lncRNA and mRNA showed that the differentially expressed genes of cryptotanshinone and tanshinone ⅡA were mainly related to cell cycle, autophagy, AMPK signaling pathway, FoxO signaling pathway and EGFR signaling pathway. GAS5 may be one of the targets for the inhibitory effects of cryptotanshinone and tanshinone ⅡA. Conclusion:Cryptotanshinone and tanshinone ⅡA have certain inhibitory effects on A549 cells, and there are differentially expressed genes of lncRNA-mRNA, which are closely related to cell cycle and signal pathway.

Evolution of chemistry and selection technology for DNA-encoded library

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and the non-self-replicating chemical phenotypes, generating a diverse chemical world. In analogy with the biological world, the DEL world can evolve by using a chemical central dogma, wherein DNA replicates using the PCR reactions to amplify the genetic codes, DNA sequencing transcripts the genetic information, and DNA-compatible synthesis translates into chemical phenotypes. Importantly, DNA-compatible synthesis is the key to expanding the DEL chemical space. Besides, the evolution-driven selection system pushes the chemicals to evolve under the selective pressure, i.e., desired selection strategies. In this perspective, we summarized recent advances in expanding DEL synthetic toolbox and panning strategies, which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.

Prevention and Treatment of Radiation-Induced Pulmonary Fibrosis by the Method of Dispelling Stasis to Promote Regeneration / 中医杂志

Blood stasis is an important pathological factor throughout the whole course of radiation-induced pulmonary fibrosis， which could evolve from new into long stagnation， and the methods of dispelling stasis to promote regeneration should throughout the whole disease progress. It is believed that the basis of the radiation-induced pulmonary fibrosis is heat toxin dispersing qi and yin， and deficiency of healthy qi promoting blood stasis. The process of the disease showed latent fire burning pulmonary collaterals， and the binding of phlegm and stasis. The key factors of the disease were the damage of ying-wei （营卫） qi in channels and collaterals， as well as the blood stasis evolving into dried blood. It is suggested that during radiotherapy， we should pay more attention to relieve heat， moisten dryness， supplement qi and yin， nourish and harmonize blood， and remove blood stasis， so as to prevent disease before it arises. If there is radiation pneumonia， we could focus on dissolving phlegm， removing blood stasis， clearing latent fire， and unblocking the collaterals and veins， in order to "control the development of existing disease". If it develops into radiation-induced pulmonary fibrosis， we could relive the center and supplement deficiency， tonify original qi， dispel stasis to promote regeneration， and clear dried blood， for the purpose of slowing the progression of disease. These ideas might provide reference for clinical treatment.

Discussion on the Formation and Prevention Strategies of Chemotherapy Resistance of Malignant Tumor Based on “Yin Fire” Theory / 中医杂志

Chemotherapy is currently the main clinical treatment method for malignant tumors， and chemotherapy resistance is the main factor leading to chemotherapy failure and malignant tumor recurrence and metastasis. The cha-racteristics of malignant tumors formation were regarded as similar to the “Yin Fire” theory， manifested that deficiency of original qi as the foundation of malignant tumors， imbalance of original qi and yin fire as the internal cause of malignant tumor progression， and the internal environment of phlegm-blood stasis-toxicity-deficiency caused by yin fire promoted the formation of chemoresistance. In the treatment of chemoresistance of malignant tumors， traditional Chinese medicine should focus on treating disease before its onset by tonifying the spleen and strengthening the middle， nou-rishing the original qi， and reinforcing healthy qi and anti-cancer； during the treatment， the clinicians should regulate the qi and detoxify to clear yin fire， and improve the internal environment. Summarily， the strategies were adjusting the balance of internal environment of original qi and yin fire， and conducting a comprehensive treatment during the whole process， to provide new ideas for the treatment of chemoresistance of malignant tumors with traditional Chinese medicine.

Recommendations for diagnosis and treatment of SARS-CoV-2 infection in children / 西安交通大学学报(医学版)

Children are also at high risk of novel coronavirus infection. However, as children are in the developmental stage and their phylogeny is not yet complete, adult guidelines cannot be directly copied in the diagnosis and treatment of SARS-CoV-2 infection in children. Therefore, The Second Affiliated Hospital of Xi’an Jiaotong University organized relevant professionals of Children’s Hospital. Based on the "Diagnosis and Treatment Plan for SARS-CoV-2 Infection (Trial 10th Edition)" issued by the General Office of the National Health Commission of the State Administration of Traditional Chinese Medicine, the diagnosis and treatment plan suggestions for children with novel coronavirus infection in The Second Affiliated Hospital of Xi’an Jiaotong University were formulated by referring to several instructive diagnosis and treatment plans and combining our hospital’s experience in treating children with SARS-CoV-2 infection. This recommendation makes a concise and practical description from the perspectives of epidemiology, clinical manifestations, clinical typing, treatment and nursing of children infected with SARS-CoV-2, and also makes recommendations for the diagnosis and treatment of high-risk factors and complications for the reference of front-line clinical pediatricians so as to achieve timely and reasonable diagnosis and treatment of children infected with SARS-CoV-2. Early identification and active treatment of high-risk and critically patients can minimize the harm caused by complications.

Efficacy and safety of Omalizumab for the treatment of pediatric allergic asthma: a retrospective multicenter real-world study in China / 中华实用儿科临床杂志

Objective:To assess the clinical effectiveness and safety of Omalizumab for treating pediatric allergic asthma in real world in China.Methods:The clinical data of children aged 6 to 11 years with allergic asthma who received Omalizumab treatment in 17 hospitals in China between July 6, 2018 and September 30, 2020 were retrospectively analyzed.Such information as the demographic characteristics, allergic history, family history, total immunoglobulin E (IgE) levels, specific IgE levels, skin prick test, exhaled nitric oxide (FeNO) levels, eosinophil (EOS) counts, and comorbidities at baseline were collected.Descriptive analysis of the Omalizumab treatment mode was made, and the difference in the first dose, injection frequency and course of treatment between the Omalizumab treatment mode and the mode recommended in the instruction was investigated.Global Evaluation of Treatment Effectiveness (GETE) analysis was made after Omalizumab treatment.The moderate-to-severe asthma exacerbation rate, inhaled corticosteroid (ICS) dose, lung functions were compared before and after Omalizumab treatment.Changes in the Childhood Asthma Control Test (C-ACT) and Pediatric Asthma Quality of Life Questionnaire (PAQLQ) results from baseline to 4, 8, 12, 16, 24, and 52 weeks after Omalizumab treatment were studied.The commodity improvement was assessed.The adverse event (AE) and serious adverse event (SAE) were analyzed for the evaluation of Omalizumab treatment safety.The difference in the annual rate of moderate-to-severe asthma exacerbation and ICS reduction was investigated by using t test.The significance level was set to 0.05.Other parameters were all subject to descriptive analysis.A total of 200 allergic asthma patients were enrolled, including 75.5% ( n=151) males and 24.5% ( n=49) females.The patients aged (8.20±1.81) years. Results:The median total IgE level of the 200 patients was 513.5 (24.4-11 600.0) IU/mL.Their median treatment time with Omalizumab was 112 (1-666) days.Their first dose of Omalizumab was 300 (150-600) mg.Of the 200 cases, 114 cases (57.0%) followed the first Omalizumab dosage recommended in the instruction.After 4-6 months of Omalizumab treatment, 88.5% of the patients enrolled ( n=117) responded to Omalizumab.After 4 weeks of treatment with Omalizumab, asthma was well-controlled, with an increased C-ACT score [from (22.70±3.70) points to (18.90±3.74) points at baseline]. Four-six months after Omalizumab administration, the annual rate of moderate-to-severe asthma exacerbation had a reduction of (2.00±5.68) per patient year( t=4.702 5, P<0.001), the median ICS daily dose was lowered [0 (0-240) μg vs. 160 (50-4 000) μg at baseline] ( P<0.001), the PAQLQ score was improved [(154.90±8.57) points vs. (122.80±27.15) points at baseline], and the forced expiratory volume in one second % predicted (FEV 1%pred) was increased [(92.80±10.50)% vs. (89.70±18.17)% at baseline]. In patients with available evaluations for comorbidities, including allergic rhinitis, atopic dermatitis or eczema, urticaria, allergic conjunctivitis and sinusitis, 92.8%-100.0% showed improved symptoms.A total of 124 AE were reported in 58 (29.0%) of the 200 patients, and the annual incidence was 0(0-15.1) per patient year.In 53 patients who suffered AE, 44 patients (83.0%) and 9 patients (17.0%) reported mild and moderate AE, respectively.No severe AE were observed in patients.The annual incidence of SAE was 0(0-1.9) per patient year.Most common drug-related AE were abdominal pain (2 patients, 1.0%) and fever (2 patients, 1.0%). No patient withdrew Omalizumab due to AE. Conclusions:Omalizumab shows good effectiveness and safety for the treatment of asthma in children.It can reduce the moderate-to-severe asthma exacerbation rate, reduce the ICS dose, improve asthma control levels, and improve lung functions and quality of life of patients.

Effects of pranlinide on cognitive behavior, β amyloid protein 6E10, inflammatory factors and neuronal cell morphology in brain and retina of 5×FAD mice and WT mice / 解剖学报

[Abstract] Objective To study the effects of pranlinide on cognitive behavior, β amyloid(Aβ) protein 6E10, inflammatory factors and neuronal cell morphology in brain and retina of 5×FAD mice and WT mice. Methods Thirty two 5×FAD mice and 16 WT mice were selected. All were female. 5×FAD mice were randomly divided into blank group and treatment group; No treatment was given in WT group. Blank group was intraperitoneally injected with PBS; treatment group was received intraperitoneal injection of pranlinide once a day for 8 weeks. The changes of cognitive ability were measured by Morris water maze test. The expression of Aβ6E10 protein in mice hippocampal cells and retina was detected by immunohistochemistry. Tumor necrosis factor α(NF-α) was determined by enzyme-linked immunosorbent assay. The same method was also used for interleukin-1β(IL-1β) detection (The content of inflammatory factors). The arrangement and morphology of nerve cells in mouse hippocampal tissue were determined by hematoxylin-eosin (HE) staining. Results The latency time of treatment group was shorter than that of 5×FAD group,and the times of crossing the platform and the percentage of target quadrant stay in the treatment group were higher than those in the 5×FAD group, and the differences were statistically significant (P0. 05). Compared with the 5×FAD group, the nerve cells in the treatment group were arramged in order and clear relatively. The distribution of glial cells was concentrated; The surrounding clearance was small. Conclusion Pranlinide can improve the cognitive ability of mice. The arrangement of nerve cells is regular, the shape is regular and the boundary is clear; The distribution of glial cells is concentrated; surrounding of clearance decrease. Aβ6E10 is synchronized in brain and retina.

Expression and Prognostic Impact of HK2 in Bone Marrow of Patients with Newly Diagnosed Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To detect the expression level of HK2 gene in the bone marrow of newly diagnosed patients with acute myeloid leukemia (AML) and investigate its influence on the clinical characteristics and prognosis.@*METHODS@#The expression level of HK2 gene in the bone marrow of 90 newly diagnosed patients with AML that accompanying clinical characteristics and survival status were detected by RT-qPCR, and compared with 18 allogeneic hematopoietic stem cell transplantation (allo-HSCT) donors. The Chi-square test, Kaplan-Meier survival analysis, and Cox proportional hazards regression model were used to analyze the correlation of HK2 expression level with clinical characteristics and prognosis.@*RESULTS@#Compared with allo-HSCT donors, the HK2 expression was significantly increased in newly diagnosed AML patients (P <0.01). Compared with patients with total response (OR, complete response + complete response with incomplete hematologic recovery) after 2 courses of induction chemotherapy, the expression of HK2 in patients without OR was significantly increased (P <0.05). There was a significant difference in the relative expression of HK2 between patients with and without OR after 2 courses of induction therapy (P <0.001). The median survival time of patients with high expression of HK2 was significantly shorter than that of patients with low expression of HK2 (P <0.05). The multivariate Cox proportional hazards regression analysis showed that prognostic stratification, the expression level of HK2, and whether two courses of induction therapy achieved OR were independent factors affecting the prognosis of AML patients (P <0.05).@*CONCLUSIONS@#Compared with allo-HSCT donors, the expression level of HK2 gene is increased in the bone marrow of newly diagnosed AML patients. The prognosis of patients with high expression of HK2 is poor. The expression level of HK2 is an independent factor affecting the prognosis of AML patients.

Establishing a noninvasive canine model of lumbar intervertebral disc degeneration through cumulative axial load and compound motion / 中华骨科杂志

Objective:To investigate the feasibility of establishing a canine model of lumbar intervertebral disc degeneration through the application of cumulative axial load and a six-phase combined motion on the vertical sitting dog's lumbar spine.Methods:Twenty adult female grass dogs, each weighing 10.0±0.5 kg, were randomly divided into two groups, with 10 dogs in each group. In the model group, dogs were secured to an exercise machine in a vertical position, and six phases of lumbar spine movement (flexion and extension, left and right lateral flexion, left and right rotation, 45° each) were combined with a specific number of cycles under continuous axial load (245 N). In the control group, dogs were secured to the exercise machine in a vertical position without any intervention. Radiographic examinations were performed before and after 20,000, 50,000, 100,000, and 150,000 compound exercises in the model group. The disc height index (DHI) was measured through lateral X-ray, and MRI T2-mapping was used for quantitative analysis of intervertebral disc degeneration. When intervertebral disc degeneration was evident on MRI T2-weighted imaging (modified Pfirrmann system > Grade V), the combined motion was halted. Micro-CT quantitative analysis of bone mineral density (BMD) in the upper and lower endplates, trabecular bone structure, and histological staining (HE staining, "O" staining, Sirius red staining) were employed to verify and assess the degree of intervertebral disc degeneration.Results:After 50,000 compound exercises, mild degeneration of the intervertebral discs at L 6-7 and L 7S 1 was observed on T2-weighted imaging. With the accumulation of exercise load, the degree of degeneration progressively increased, reaching a moderate degree of degeneration after 100,000 composite exercises, and DHI began to decrease. Mild degeneration was also observed in the upper L 5-6 intervertebral disc. When the cumulative exercise volume reached 150,000 repetitions, the height of intervertebral spaces in the L 5-6, L 6-7, and L 7S 1 segments further decreased, and the intervertebral discs exhibited severe degeneration (improved Pfirrmann grading system Grades IV-VI). The upper L 4-5 intervertebral discs also displayed mild degeneration. Histological scores were as follows: L 5-6 (8.2±0.8), L 6-7 (9.5±0.7), and L 7S 1 (10.3±0.5), indicating a degree of degeneration in the order of L 5-6<L 6-7<L 7S 1. HE and safranine "O" staining confirmed the significant collapse of the intervertebral spaces in the L 5-6, L 6-7, and L 7S 1 segments, characterized by severe shrinkage of the nucleus pulposus tissue, a disordered internal structure, and nearly absent vacuolar-like nucleus pulposus cells. Sirius red staining revealed pronounced folds, disordered arrangement, and multiple fractures in the fibers of the anterior and posterior rings of the intervertebral disc. The posterior ring of the disc exhibited more pronounced changes than the anterior ring, and the thickness of the bone endplate and bone trabecular density became thinner and less dense. Micro-CT quantitative analysis further confirmed that the BMD and number of trabeculae in the upper and lower endplates of the L 5-6, L 6-7, and L 7S 1 segments were significantly lower than those in the control group and other segments of the model group, while the trabecular separation was significantly higher than that in the control group and other segments of the model group. Conclusion:The utilization of the "Lumbar Composite Exercise Machine" can effectively replicate the biomechanical and kinematic characteristics of human lumbar intervertebral discs. Cumulative axial load and six-phase composite exercise can induce varying degrees of chronic degeneration in canine lumbar intervertebral discs, which is related to the exercise load, particularly in the L 5-6, L 6-7, and L 7S 1 segments.

Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells.

Anthraquinone-based intercalating compounds, namely doxorubicin and mitoxantrone, have been used clinically based on their capacity to bind DNA and induce DNA damage. However, their applications have been limited by side effects and drug resistance. New-generation anthraquinone derivatives fused with different heterocycles have been chemically synthesized and screened for higher anticancer potency. Among the compounds reported in our previous study, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated 2c) was found to be apoptotic, but the direct cellular target responsible for the cytotoxicity remained unknown. Here, we report the synthesis and anticancer properties of two other derivatives, 4,11-bis(2-(2-chloroacetamidine)ethylamino)naphtho[2,3-f]indole-5,10-dione dihydrochloride (2a) and 4,11-bis(2-(2-chloroacetamidine)ethylamino)-2-methylanthra[2,3-b]furan-5,10-dione dihydrochloride (2b). We sought to identify and validate the protein target(s) of these derivatives in oral cancer cells, using molecular docking simulations and cellular thermal shift assays (CETSA). Our CETSA results illustrate that these derivatives targeted the tumor-associated NADH oxidase (tNOX, ENOX2), and their direct binding downregulated tNOX in p53-functional SAS and p53-mutated HSC-3 cells. Interestingly, the compounds targeted and downregulated tNOX to reduce SIRT1 deacetylase activity and increase Ku70 acetylation, which triggers c-Flip ubiquitination and induces apoptosis in oral cancer cells. Together, our data highlight the potential value of these heteroarene-fused anthraquinones in managing cancer by targeting tNOX and augmenting apoptosis.

Safety and immunogenicity of a broad-spectrum mosaic vaccine as a booster dose against SARS-CoV-2 Omicron and other circulating variants

BACKGROUNDThe rising breakthrough infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, especially Omicron and its sub-lineages, have raised an urgent need to develop broad-spectrum vaccines against coronavirus disease 2019 (COVID-19). We have developed a mosaic-type recombinant vaccine candidate, named NVSI-06-09, having immune potentials against a broad range of SARS-CoV-2 variants. METHODSAn ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of NVSI-06-09 as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had completed two or three doses of BBIBP-CorV vaccinations at least 6 months prior to the enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against SARS-CoV-2 Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. RESULTSA total of 516 participants received booster vaccination. Interim results showed a similar safety profile between NVSI-06-09 and BBIBP-CorV booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 after the booster vaccination, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline level elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those boosted by BBIBP-CorV. CONCLUSIONSA booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against SARS-CoV-2 prototype strain and immune-evasive variants, including Omicron and its sub-lineages. The immunogenicity of NVSI-06-09 as a booster vaccine was superior to that of BBIBP-CorV. (Funded by LIBP and BIBP of Sinopharm; ClinicalTrials.gov number, NCT05293548).

Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients: a randomized controlled phase 2 trial

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with immune escape ability raises the urgent need for developing cross-neutralizing vaccines against the virus. NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluated the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in adults previously vaccinated with the inactivated vaccine BBIBP-CorV in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who had administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, were vaccinated with either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The primary outcome was immunogenicity and safety of booster vaccinations. The exploratory outcome was cross-reactive immunogenicity against multiple SARS-CoV-2 variants of concerns (VOCs). The incidence of adverse reactions was low in both booster vaccinations, and the overall safety profile of heterologous boost was quite similar to that of homologous boost. Heterologous NVSI-06-08 booster was immunogenically superior to homologous booster of BBIBP-CorV. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster were significantly higher than by the booster of BBIBP-CorV against not only SARS-CoV-2 prototype strain but also multiple VOCs. Especially, the neutralizing activity induced by NVSI-06-08 booster against the immune-evasive Beta variant was no less than that against the prototype strain, and a considerable level of neutralizing antibodies against Omicron (GMT: 367.67; 95%CI, 295.50-457.47) was induced by heterologous booster, which was substantially higher than that boosted by BBIBP-CorV (GMT: 45.03; 95%CI, 36.37-55.74). Our findings showed that NVSI-06-08 was safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which was immunogenically superior to homologous boost with another dose of BBIBP-CorV. Our study also indicated that the design of hybrid antigen may provide an effective strategy for broad-spectrum vaccine developments.

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the inactivated vaccine BBIBP-CorV. Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

Evaluating dose distributions of normal organs for patients undergoing VMAT therapy of nasopharyngeal carcinoma using Rando phantom and TLD-100H.

BACKGROUND: The routine radiation therapy treatment planning does not include secondary radiation and peripheral doses resulting from radiotherapy exposure in patients with nasopharyngeal carcinoma (NPC) undergoing Volumetric Modulated Arc Therapy (VMAT) using an linear accelerator (linac) of Axesse (Elekta 2538). OBJECTIVE: VMAT has a better dose conformity of the tumor and is also operated by adjusting the shapes of mulileaf collimator. However, such treatment is potentially important to improve the accuracy of estimated health risks. METHODS: This study aimed to evaluate the equivalent dose of organ or tissue (DT) and effective dose (E) for normal organs using the Alderson Rando phantom as an equivalent of the human body. Thermoluminescent dosimeters (TLD-100H) were calibrated by 6 MV X-ray originated by the linac. A total of 252 TLDs were used. These TLDs were inserted into phantom organ or tissue which closely approximated to these places. RESULTS: The thyroid dose (D𝑡ℎ𝑦) had the highest dose, 1840 ± 202 mSv/treatment. The E of the Rando was 7.11 ± 0.61 mSv/treatment, as estimated using ICRP 103. The skin doses (D𝑠𝑘𝑖𝑛) varied significantly outside the treatment field and decreased as the distance from the treatment field increased. CONCLUSIONS: This study can be referred to practical guidance regarding radiation protections of the public.

Recent progress of targeted small molecular CDK9 degraders based on PROTAC technology / 药学学报

CDKs proteins are a kind of cell cycle protein-dependent kinases, which serve as important roles in controlling cell division and transcriptional stages. Among them, CDK9, as a key regulator responsible for the transcriptional elongation of cells, drives the development of various malignant cells and is considered as an important target in the field of anti-tumor drug development. However, the CDK family proteins feature high conservativeness and similarity in structure, leading to the poor selectivity and severe side effects for traditional small-molecular CDK9 inhibitors, which has limited their clinical applications. In view of this, there is an urgent need to investigate CDK9 targets through a novel strategy. The PROTAC is an emerging drug discovery strategy that the degrader could specifically recognize the target protein through indirect linkage with ubiquitin ligases and ultimately eliminate the target protein through the ubiquitination degradation system. This paper provides a brief overview of the structure and function of CDK9 protein, its relationship with the poor prognosis of clinical diseases, as well as the currently reported small molecular inhibitors. The latest research progress on the targeted degradation of CDK9 protein based on PROTAC technology is highlighted. Finally, the development prospects of this target protein in this novel technology field are summarized and prospected, aiming to provide a reference for the development of antitumor drugs in this direction.

Mechanism and Application of α7 nAChR in Cholinergic Antiinflammatory Pathway / 中国生物化学与分子生物学报

Cholinergic anti-inflammatory pathway in which acetylcholine released as the neurotransmitter, plays an important role in nerve-immune regulation. In this pathway, with the vagus nerve in the central nervous system as a starting point, the alpha 7 nicotinic acetylcholine receptor (α7 nAChR) on the surface of immune cell membrane is the key functional part. The interaction between electrical and chemical signals regulates the inflammation in the body via modulation of the JAK-STAT3, PI3K-Akt and other signaling pathways and the nuclear translocation of NF-κB, leading to inhibition of the release of pro-inflammatory factors and promotion of the release of anti-inflammatory factors. However, the detailed mechanism is far from clear. Studies have shown that the cholinergic anti-inflammatory pathway can be activated by drug targeting α7 nAChR and electrical stimulation of vagus nerve. Activation of α7 nAChR has the advantages of simple operation, less damage and significant effect. The commonly used drugs are selective agonists such as PNU282987 and GTS-21, and non-selective agonists such as nicotine. And this method has been found to play a role in the treatment of peripheral organ inflammatory diseases such as sepsis, ischemia-reperfusion injury, gastroenteritis, osteoarthritis and autoimmune diseases. As a key factor in the cholinergic anti-inflammatory pathways, α7 nAChR has become a potential therapeutic target for many inflammatory diseases. This paper reviewed the anti-inflammatory mechanism and activation mode of α7 nAChR involved in cholinergic anti-inflammatory pathway, as well as its application in inflammatory diseases in recent years, which may provide a reference for future research on its detailed mechanism of action and potential application as a new therapeutic target.

Interpretation of the 2022 edition guidelines for hepatolenticular degeneration diagnosis and treatment / 中华肝脏病杂志

In order to help liver disease-related clinicians make rational decisions, the Inherited and Metabolic Liver Disease Cooperative Group of Hepatology Branch of Chinese Medical Association released the 2022 edition guidelines for hepatolenticular degeneration diagnosis and treatment. This article introduces the ten highlights of this guideline from the aspects of epidemiology, pathogenesis, clinical characteristics, laboratory tests, diagnosis, treatment, monitoring, and so forth, with practicality and operability as prominent features.

Structure and computation-guided design of a mutation-integrated trimeric RBD candidate vaccine with broad neutralization against SARS-CoV-2

The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 is an attractive target for COVID-19 vaccine developments, which naturally exists in a trimeric form. Here, guided by structural and computational analyses, we present a mutation-integrated trimeric form of RBD (mutI tri-RBD) as a broadly protective vaccine candidate, in which three RBDs were individually grafted from three different circulating SARS-CoV-2 strains including the prototype, Beta (B.1.351) and Kappa (B.1.617). The three RBDs were then connected end-to-end and co-assembled to possibly mimic the native trimeric arrangements in the natural S protein trimer. The recombinant expression of the mutI tri-RBD, as well as the homo-tri-RBD where the three RBDs were all truncated from the prototype strain, by mammalian cell exhibited correct folding, strong bio-activities, and high stability. The immunization of both the mutI tri-RBD and homo-tri-RBD plus aluminum adjuvant induced high levels of specific IgG and neutralizing antibodies against the SARS-CoV-2 prototype strain in mice. Notably, regarding to the "immune-escape" Beta (B.1.351) variant, mutI tri-RBD elicited significantly higher neutralizing antibody titers than homo-tri-RBD. Furthermore, due to harboring the immune-resistant mutations as well as the evolutionarily convergent hotspots, the designed mutI tri-RBD also induced strong broadly neutralizing activities against various SARS-CoV-2 variants, especially the variants partially resistant to homo-tri-RBD. Homo-tri-RBD has been approved by the China National Medical Products Administration to enter clinical trial (No. NCT04869592), and the superior broad neutralization performances against SARS-CoV-2 support the mutI tri-RBD as a more promising vaccine candidate for further clinical developments.

Determination of Three Types of New Psychoactive Tryptamines in Blood by QuEChERS Combined with UPLC-MS/MS / 法医学杂志

Objective To establish a method combining QuEChERS and ultra-high liquid chromatography-tandem mass spectrometry （UPLC-MS/MS） for rapid screening and testing of three types of new psychoactive tryptamines in human blood： 5-MeO-DALT, 5-MeO-MiPT and 5-MeO-DiPT. Methods The effects of the type of extractant, the type and dosage of salting-out agent, and the dosage of adsorbent on the test results of the three tryptamines were investigated. Blood samples were processed by QuEChERS method and then determined by UPLC-MS/MS. Results The linear relationships of 5-MeO-DALT, 5-MeO-MiPT and 5-MeO-DiPT in human blood were good in the range of 0.5-100, 0.5-100 and 0.2-100 ng/mL, respectively, with their coefficients higher than 0.99. The limits of detection （LODs） were 0.1-0.2 ng/mg. The recoveries ranged from 84.86% to 94.57%. Intra-day and inter-day precisions were good. Conclusion The method is simple, rapid, easy to operate and has a high recovery. It is suitable for the qualitative and quantitative study of tryptamines in blood and can provide the reference for public security organs to deal with related cases.

Analysis of clinical trials of dermatological drugs in China, 2020 / 中华皮肤科杂志

Objective:To deliver understanding of the latest research progress on clinical trials and approval of dermatological drugs in China in 2020.Methods:A registration and information disclosure platform for drug clinical studies and a query system for domestic and imported drugs in the National Medical Products Administration of China were searched for registered clinical trials and approved dermatological drugs, respectively. The number and stages of clinical trials, indications and classification of involved products, and listed dermatological drugs in 2020 were summarized and depicted.Results:There were 157 dermatological drug trials registered in China in 2020, accounting for 6.16% of all the 2 548 clinical drug trials, including 127 (80.9%) initiated by Chinese pharmaceutical enterprises and 25 (15.9%) international multicenter trials. Among the 127 drug trials initiated by Chinese pharmaceutical enterprises, bioequivalence trials were mostly common, accounting for 55.9% (71/127) . Compared with global pharmaceutical enterprises, domestic pharmaceutical companies initiated significantly decreased proportions of international multicenter trials (1.9% [3/157] vs. 14.0% [22/157], P < 0.001) , but significantly increased proportions of phaseⅠclinical trials and bioequivalence trials (24.4% [31/127] vs. 10.0% [3/30], 55.9% [71/127] vs. 0, respectively, both P < 0.001) . Totally, 90 kinds of dermatological drug were involved in all the trials, psoriasis, atopic dermatitis and melanoma were the most common indications, and innovative drugs accounted for 53.3% (48/90) ; the proportion of innovative drugs was significantly lower in domestic pharmaceutical companies than in global pharmaceutical companies (43.2% [32/74] vs. 16/16, P < 0.001) . In addition, 28 dermatological drugs developed by 22 pharmaceutical companies were approved in China in 2020, of which 21 drugs were developed by domestic pharmaceutical companies. Conclusion:Clinical drug trials carried out by domestic pharmaceutical companies mostly focus on generic drugs, and it is still necessary for domestic pharmaceutical companies to further improve the innovation ability.