Traditional Chinese medicine (TCM) exerts integrative effects on complex diseases owing to the characteristics of multiple components with multiple targets. However, the syndrome-based system of diagnosis and treatment in TCM can easily lead to bias because of varying medication preferences among physicians, which has been a major challenge in the global acceptance and application of TCM. Therefore, a standardized TCM prescription system needs to be explored to promote its clinical application. In this study, we first developed a gradient weighted disease-target-herbal ingredient-herb network to aid TCM formulation. We tested its efficacy against intracerebral hemorrhage (ICH). First, the top 100 ICH targets in the GeneCards database were screened according to their relevance scores. Then, SymMap and Traditional Chinese Medicine Systems Pharmacology (TCMSP) databases were applied to find out the target-related ingredients and ingredient-containing herbs, respectively. The relevance of the resulting ingredients and herbs to ICH was determined by adding the relevance scores of the corresponding targets. The top five ICH therapeutic herbs were combined to form a tailored TCM prescriptions. The absorbed components in the serum were detected. In a mouse model of ICH, the new prescription exerted multifaceted effects, including improved neurological function, as well as attenuated neuronal damage, cell apoptosis, vascular leakage, and neuroinflammation. These effects matched well with the core pathological changes in ICH. The multi-targets-directed gradient-weighting strategy presents a promising avenue for tailoring precise, multipronged, unbiased, and standardized TCM prescriptions for complex diseases. This study provides a paradigm for advanced achievements-driven modern innovation in TCM concepts.

Objective:To observe the effect of cross-education combined with electromyography(EMG)biofeedback inter-vention on the wrist dorsal extension function of patients with subacute stroke. Method:Forty-five patients with subacute stroke were randomly divided into cross-education group,EMG bio-feedback group,and combined group,with 15 cases in each group.The patients of three groups received rou-tine rehabilitation training.The cross-education group performed additional cross-education training on this ba-sis,the EMG biofeedback group performed additional EMG biofeedback training,and the combined group per-formed additional cross-education combined with EMG biofeedback.The above treatment lasted for 6 weeks,and before and after treatment,active joint range of motion(AROM),manual muscle test(MMT),simpli-fied Fugl-Meyer motor function score:upper extremity(FMA-UE),modified Barthel index(MBI)were used to assess the patient's wrist extension function,upper limb motor function and activities of daily living. Result:Before treatment,the three groups had no significant difference in FMA-UE score,wrist dorsiflexion AROM,muscle strength score,and MBI score(P＞0.05).After 6 weeks treatment,the FMA-UE score,wrist dorsiflexion AROM,muscle strength score,and MBI score of the three groups were significantly improved compared with those before treatment(P＜0.05).When comparison among the groups,there was no significant difference in MBI score(P＞0.05),and other index score comparisons showed significant differences(P＜0.05),and there was no significant difference in the comparison of the cross-education group and the EMG biofeed-back group(P＞0.05). Conclusion:Cross-education combined with EMG biofeedback is better than single cross-education or EMG biofeedback intervention in improving the wrist extension function,upper limb motor function and activities of daily living in patients with subacute stroke.

OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice ; Animals ; Receptors, Tumor Necrosis Factor/physiology* ; Receptors, OX40 ; Membrane Glycoproteins ; Ligands ; Antibodies, Monoclonal/pharmacology* ; Antineoplastic Agents/pharmacology*

Objective:This study aims to analyze the characteristics and basic principles of emergency surgery risks and anesthesia care of medical support at the landing site for China’s taikonauts of the Shenzhou-12, and to summarize China’s experience in medical support at the landing site for manned spaceflight, and ensure supports in special environments such as an emergency return of manned spaceflight.Methods:This study was carried out through literature research on relevant reports on the emergency surgery risks and aids of domestic and foreign astronauts at the landing sites, and summaries of the experience in medical support for taikonauts of spacecrafts from Shenzhou-5 to Shenzhou-11 at the landing sites. At the same time, according to the characteristics of Shenzhou-12 such as the long on-orbit time, the adjustment in the landing area, the optimization of the mission mode, and new search and rescue power, a series of organization, pre-arranged planning, equipment allocation, and effective anesthesia treatment plan were proposed and inspected in practice.Results:Based on the original anesthesia care plan of medical support, the first-aid carrier was adjusted and modified, the first-aid procedure was optimized, a new generation of supraglottic airway opening tool, video laryngoscope, portable ultrasound, and other devices were added, and the anesthesia care plan at the landing site for manned spaceflight was formulated to provide strong support for the medical care of taikonauts that had stayed in the outer space for a long time.Conclusions:Upon the targeted improvement and process optimization, the anesthesia care plan of medical support for taikonauts of Shenzhen-12 in the landing area fully meets the anesthesia requirement of medical support in special environments such as the emergency return of the taikonauts that have stayed in the outer space for a long time under the new orbital altitude.

To analyze how the handover were effected by the conditions of manned spaceflight medical support mission through the practice of medical equipment and drugs in Shenzhou-12 and Shenzhou-13 manned spaceflight medical rescue support missions, this article discussed the preparation, organization and implementation in the handover of medical equipment and drugs in the changing of medical rescue teams, summarized the notices in the work of handover, and provided experience for the smooth handover of different manned spaceflight medical rescue teams in the future.

Objective To detect the changes in vertebral marrow fat fraction (MFF) using T2 *-corrected water-fat MRI and to analyze the relationships between MFF with bone biomarkers of non-dialysis chronic kidney disease (CKD).Methods 78 CKD patients were divided into five groups according to the eGFR and underwent water/fat MRI to obtain MFF.The reliability of MFF measurements by two radiologists was assessed with intra-class correlation coefficient (ICC).Serum calcium,phosphorus,alkaline phosphatase,osteocalcin,intact parathyroid hormone and 25(OH)D3 were determined.Results Mean CV for MFF measurements reproducibility was 2.37％.The inter-observer agreement for MFF was excellent (ICC=0.901).The ICC for each intra-observer agreement was excellent (ICC=0.959 and 0.948,respectively).There were statistical differences in MFF among five groups of CKD.Changes of MFF were earlier than those of serum calcium,phosphorus,parathyroid hormone,alkaline phosphatase and osteocalcin.MFF was positively correlated with serum phosphorus (r =3.011,P =0.003),parathyroid hormone (r=3.852,P＜0.001),and negatively associated with calcium (r=-2.767,P=0.017),25(OH)D3 (r=6.032,P＜0.001),eGFR (r=-5.104,P＜0.001),respectively.Multivariable regression analysis showed MFF was negatively correlated with 25(OH)D3(Sβ=-0.343)and eGFR(S(S=-0.284,P＜0.001).Conclusion CKD patients had higher marrow fat.T2 *-corrected water fat MRI could serve as a useful tool to quantify marrow fat content for CKD patients.

Objective: To investigate the clinicopathological features of mammary analogue secretory carcinoma (MASC) of salivary glands, and its diagnosis, differential diagnosis, immunohistochemistry and molecular pathology. Methods: Seventeen cases of MASC were enrolled, with 9 cases of salivary acinar cell carcinoma and 18 cases of adenoid cystic carcinoma as control groups from Nanjing General Hospital from 1997 to 2014 were included in this retrospective study, combined with immunohistochemistry and molecular detection of ETV6-NTRK3 gene fusion. All cases were histologically reviewed with immunohistochemical staining (EnVision) for S-100 protein, SOX10, GATA3, CD117 expression in each group. Fluorescence in situ hybridization (FISH) was used to detect the ETV6-NTRK3 gene fusion. Results: The age of MASC patients ranged from 27 to 74 years with mean age of 47 and ratio of male and female was 4∶3. All cases showed infiltrative growth and diverse cytology and histology, including lobular (8 cases), cystic papillary (3 cases), cribriform mixed with papillary and glandular structures (6 cases) at various proportions. Some tumors of MASC also exhibited solid growth areas with occasional microcystic honeycombed pattern composed of small cysts merged into larger cysts resembling thyroid follicles. S-100 protein and SOX10 were strongly positive in all MASC cases (17/17). In addition, there was insignificant positivity for GATA3 (3/17) and CD117 (4/17). ETV6 gene fusion detection was informative in 12 MASC cases by FISH with 10 positive cases and 2 negative cases. Conclusions Combined immunohistochemical positivity of S-100 protein, CD117 and SOX10 are useful in the diagnosis and differential diagnosis of MASC. FISH detection of ETV6-NTRK3 fusion offers an additional molecular diagnostic marker for the diagnosis.

OBJECTIVETo study the clinicopathologic characteristics of primary renal hemangioblastoma.

METHODSThe morphologic features, immunophenotype and molecular findings of 3 cases of primary renal hemangioblastoma were studied, with review of literature.

RESULTSThe age of patients ranged from 43 to 57 years. There were 2 women and a man. The patients often presented with renal mass. Histologically, the tumors were surrounded by thick fibrous capsule and composed of epithelioid or spindle cells. Two cases had a prominent stromal component and the other one was rich in capillary network. Lipid vacuoles were observed in all cases. Features of hemorrhage were demonstrated in 2 cases. Capsular invasion and necrosis were seen in 1 case. Immunohistochemical study showed that the stromal cells were positive for alpha-inhibin (3/3), S-100 protein (3/3), EGFR (2/2), PAX-2 (2/2), PAX-8 (2/2) and CA9 (2/2) but negative for CKpan (2/2) and HMB45 (2/2). Focal membranous staining for CD10 (3/3) was noted. No VHL gene mutations or chromosome 3p deletion were detected in the 2 cases studied.

CONCLUSIONSRenal hemangioblastoma shows distinctive morphologic appearance with a wide range of variation. The unexpected positive staining for PAX-2, PAX-8 and CD10 in renal hemangioblastoma needs to be aware. Immunohistochemical study may be helpful in differential diagnosis of these renal tumors.

Objective To study the clinicopathologic characteristics of primary renal hemangioblastoma.Methods The morphologic features, immunophenotype and molecular findings of 3 cases of primary renal hemangioblastoma were studied, with review of literature.Results The age of patients ranged from 43 to 57 years.There were 2 women and a man.The patients often presented with renal mass.Histologically, the tumors were surrounded by thick fibrous capsule and composed of epithelioid or spindle cells.Two cases had a prominent stromal component and the other one was rich in capillary network. Lipid vacuoles were observed in all cases.Features of hemorrhage were demonstrated in 2 cases.Capsular invasion and necrosis were seen in 1 case.Immunohistochemical study showed that the stromal cells were positive for alpha-inhibin (3/3), S-100 protein (3/3), EGFR (2/2), PAX-2 (2/2), PAX-8 (2/2) and CA9 (2/2) but negative for CKpan (2/2) and HMB45 (2/2).Focal membranous staining for CD10 (3/3) was noted.No VHL gene mutations or chromosome 3p deletion were detected in the 2 cases studied. Conclusions Renal hemangioblastoma shows distinctive morphologic appearance with a wide range of variation.The unexpected positive staining for PAX-2, PAX-8 and CD10 in renal hemangioblastoma needs to be aware.Immunohistochemical study may be helpful in differential diagnosis of these renal tumors.

Objective To investigate the clinical value of joint detection of procalcitoninl (PCT ) ,C-reactive protein (CRP) ,and myocardial enzymes in patients with neonatal hyperbilirubinemia .Methods 30 cases of each cause were included in the study ,which were neonatal hyperbilirubinemia caused by sepsis ,pneumonia ,ABO hemolytic and breast milk jaundice .20 cases of each cause were selected including neonatal hyperbilirubinemia caused by neonatal hepatitis and low birth weight infants .All the cases involved in the study were diagnosed .30 healthy full-term newborns in the same period were recruited as control group .PCT ,CRP and myocar-dial enzymes (AST ,CK ,CK-MB ,and LDH) concentration in serum were determined .Results Compared with the control group , CRP and PCT concentration increased significantly in bacterial infected group (P< 0 .05) .Myocardial enzyme concentration in-creased significantly both in infected group and non-infected group(P<0 .05) .Among myocardial enzymes ,CK-MB concentration increased significantly in bacterial infected group ,low birth weight infants group and ABO hemolytic group(P<0 .01) and increased significantly in breast milk jaundice group and hepatitis group (P<0 .05) .AST and LDH concentration increased very significantly in hepatitis group(P<0 .01) .The specificity of PCT in bacterial infected group was significantly higher than that of CRP (P<0 .05) ,while its sensitivity was significantly lower than that of CRP in pneumonia group (P<0 .01) .Conclusion Changes of PCT , CRP and myocardial enzymes concentration are related to the occurrence and development of neonatal hyperbilirubinemia ,determi-nation of these indicators can be complementary .