BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models / 医学前沿

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.

Clinical significance of plasma thrombin-antithrombin complex levels in patients with sepsis-induced cardiomyopathy / 中华检验医学杂志

Objective:To investigate the clinical significance of plasma thrombin-antithrombin complex (TAT) levels in patients with sepsis-induced cardiomyopathy(SIC).Methods:One hundred and seven sepsis patients who were admitted to intensive care units (ICU) of the 908th Hospital of Chinese PLA Logistical Support Force were enrolled in the study. Patients were divided into sepsis group ( n=79) and the sepsis-induced cardiomyopathy group ( n=28) according to whether the cardiac ultrasound examination in 2 hours after admission, and the differences of each indicators between the two groups were compared including acute physiological and chronic health score (APACHEⅡ), lactate, blood routine, liver and kidney function, cardiac troponin I, N-terminal?pro-brain?natriuretic?peptide (NT-pro BNP), conventional coagulation tests and molecular markers of coagulation [tissue plasminogen activator-inhibitor complex (t-PAIC), thrombomodulin (TM), TAT, plasmin-α2-plasmin inhibitor complex (PIC)].Logistical?regression?was?used?to analyze the?risk?factors?for sepsis-induced cardiomyopathy and the receiver operating characteristic (ROC) curve was to analyze their cut-off values. The effect of low-molecular-weight heparin anticoagulation therapy on sepsis patients with TAT>8.26 ng/ml was evaluated by Kaplan-Meier analysis. Results:Compared with the cardiac troponin I[0.02(0.01, 0.09) ng/ml], NT-proBNP [1 118.09 (333.25, 2687.00) pg/ml], lactate[1.35(0.90, 2.60) mmol/L], TAT[6.50(3.94, 12.14) ng/ml], PIC[1.256 (0.668, 2.045) μg/ml] and t-PAIC[10.50 (6.70, 21.30) ng/ml] in sepsis group, the cardiac troponin I [0.75(0.01, 6.02) ng/ml], NT-proBNP[12 125.14(4 185.89, 33 611.62) pg/ml], lactate[2.35(1.43, 4.34) mmol/L], TAT[19.85 (9.08, 45.78) ng/ml], PIC[2.115 (0.878, 4.114) μg/ml] and t-PAIC [22.03(15.61,33.20) ng/ml] levels in the sepsis-induced cardiomyopathy group were significantly increased ( P<0.05). Logistical regression showed that positive NT-pro BNP and elevated TAT levels were independent risk factors for sepsis-induced cardiomyopathy. ROC curve analysis showed that the area under the curve of plasma TAT level for predicting sepsis-induced cardiomyopathy was 0.78. The sensitivity and specificity at the cut-off value of plasma TAT level with 8.26 ng/ml were 0.82 and 0.63, respectively. Conclusions:The elevated TAT level was an independent risk factor for the development of sepsis-induced cardiomyopathy. Low-molecular-weight heparin anticoagulation therapy can improve the 28-day survival rate of sepsis patients with TAT>8.26 ng/ml.

The clinical outcomes of fresh versus frozen embryos transfer in women ≥40 years with poor ovarian response

Objective@#To compare the clinical outcomes of fresh embryo transfers (ETs) and frozen-thawed embryo transfers (FETs) after a freeze-all cycle in women ≥40 years old with poor ovarian response (POR). @*Methods@#We performed a single-center, retrospective, case-control study of patients who underwent in vitro fertilization between January 2014 and June 2019. We included a total of 192 patients aged 40 years or older from whom 3 or fewer oocytes had been retrieved and who were receiving cleavage-stage ET in this study. Of these patients, 101 and 91 patients underwent fresh ET and FET, respectively. The primary outcome was the live birth rate (LBR) after the first ET. Logistic regression analysis was used to compare the IVF outcomes and neonatal characteristics between the fresh ET and FET groups, adjusting for maternal age, body mass index, luteinizing hormone, and the number of good quality embryos transferred. @*Results@#The mean maternal ages and number of oocytes retrieved (43.2 years and 2.3 in both groups, P=0.902 and P=0.927, respectively) were similar in the fresh ET and FET groups. No significant difference was observed between the LBRs of the fresh ET and FET groups (adjusted odds ratio, 1.28; 95% confidence interval, 0.29–5.70). The clinical pregnancy and miscarriage rates, and neonatal characteristics (birth weights and premature infant rates) were similar between the 2 groups. @*Conclusions@#FET after the freeze-all strategy had no beneficial impact on the clinical outcomes of women ≥40 years with POR.

The clinical outcomes of fresh versus frozen embryos transfer in women ≥40 years with poor ovarian response

Objective@#To compare the clinical outcomes of fresh embryo transfers (ETs) and frozen-thawed embryo transfers (FETs) after a freeze-all cycle in women ≥40 years old with poor ovarian response (POR). @*Methods@#We performed a single-center, retrospective, case-control study of patients who underwent in vitro fertilization between January 2014 and June 2019. We included a total of 192 patients aged 40 years or older from whom 3 or fewer oocytes had been retrieved and who were receiving cleavage-stage ET in this study. Of these patients, 101 and 91 patients underwent fresh ET and FET, respectively. The primary outcome was the live birth rate (LBR) after the first ET. Logistic regression analysis was used to compare the IVF outcomes and neonatal characteristics between the fresh ET and FET groups, adjusting for maternal age, body mass index, luteinizing hormone, and the number of good quality embryos transferred. @*Results@#The mean maternal ages and number of oocytes retrieved (43.2 years and 2.3 in both groups, P=0.902 and P=0.927, respectively) were similar in the fresh ET and FET groups. No significant difference was observed between the LBRs of the fresh ET and FET groups (adjusted odds ratio, 1.28; 95% confidence interval, 0.29–5.70). The clinical pregnancy and miscarriage rates, and neonatal characteristics (birth weights and premature infant rates) were similar between the 2 groups. @*Conclusions@#FET after the freeze-all strategy had no beneficial impact on the clinical outcomes of women ≥40 years with POR.

On the status quo and influencing factors on the knowledge, attitude and practice of innovation and entrepreneurship activities in a medical university / 中华医学教育探索杂志

Objective To understand the situation of college students' knowledge, attitude and practice (KAP) of innovation and entrepreneurship activities and analyze their influencing factors, in order to provide a scientific basis for further promotion of innovation and entrepreneurship activities. Methods A self-administered questionnaire survey using cluster sampling method was conducted among 850 undergraduates in a medical university in May, 2018. The demographic characteristics and questions pertaining to the KAP of innovation and entrepreneurship activities were collected, The weighted scores of KAP were calculated using the Delphi method. Chi-square test, multivariate logistic regression and linear regression analysis were used to analyze the data. Results A total of 850 questionnaires were sent out and 800 valid questionnaires were collected. The average scores and pass rates for the knowledge, attitude and practice of the 800 college students were (0.54 ±0.14), 38.1％; (0.56 ±0.23), 51.5％; and (0.37 ±0.19), 12.6％, respectively. Knowledge: the pass rate for the concepts related to innovation and entrepreneurship was 70.5％, and the pass rate for the policies related to innovation and entrepreneurship was 17.2％. The pass rate of senior students and excellent students were higher than those of junior students and students of lower academic competence (P=0.000, P=0.004). Attitudes: the pass rate for attitude towards the relationship between innovation and entrepreneurship and personal development was 63.6％, the pass rate for attitudes towards participation in innovation and entrepreneurship was 49.8％, and the pass rate for attitudes towards the school continuing to carry out innovation and entrepreneurship related activities was 23.8％. Practice:the pass rates for participation in scientific research and academic activities and social practice , voluntary cultivation of innovation ability and self-employment were 8.5％, 62.9％, 11.9％and 27.3％, respectively. The pass rate of senior grades was higher than that of junior grades (P=0.001). Scores for knowledge and those of attitude are positively correlated. Scores for practice and those of knowledge and attitude are positively correlated. Conclusion The higher pass rates for medical college students' attitude toward innovation and entrepreneurship activities as compared to those for knowledge and practice indicates high eagerness toward participation in innovation and entrepreneurship activities; a high rate knowledge is conducive to the cultivation of attitudes and the improvement of participation in activities . Therefore , it is necessary to strengthen the efforts in carrying out innovation and entrepreneurship activities , improve publicity and education, and promote the awareness-raising of innovation and entrepreneurship.

Value of thromboelastography in evaluating prognosis of polytrauma patients / 中华创伤杂志

Objective To investigate the value of thromboelastography ( TEG) in evaluating the prognosis of polytrauma patients. Methods A retrospective case control study was conducted to analyze the clinical data of 155 polytrauma patients admitted to 94th Hospital of People's Liberation Army from September 2015 to December 2017. There were 118 males and 37 females, aged 18-88 years [(49. 0 ± 1. 3)years]. Injury severity score (ISS) was (26. 4 ± 11. 0)points. According to the prognosis of patients 90 days after injury, the patients were divided into survival group ( 143 patients ) and death group (12 patients). The ISS on admission, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ), Glasgow coma score ( GCS ) , systolic blood pressure ( SBP ) , respiratory rate ( RR ) and outcome of 90 days after injury were collected. Red blood cells( RBC) , hemoglobin( Hb) , plasma prothrombin time ( PT) , activated partial thromboplastin time ( APTT) , fibrinogen ( FIB) , international normalized ratio ( INR) , thrombin time ( TT) , platelet count ( PLT) and TEG-related indicators within 2 hours after ICU admission were collected. TEG-related indicators including TCG clotting reaction time ( R ) , clot formation rate (K), clot formation kinetics (α angle), maximum amplitude (MA), coagulation index (CI), blood clotting strength (G), elasticity constant (E) and clot lysis time (CLT) were collected within 2 hours after admission to ICU. The changes of TEG-related indicators were compared between the two groups, and logistic regression analysis and receiver operating characteristic ( ROC) curve analysis were performed. Results Compared with the survival group, ISS and APACHE II scores in the death group were significantly higher, while GCS, SBP, RR, RBC and Hb were significantly lower (P<0. 05). Compared with the survival group, death group showed significantly prolonged PT [(21. 1 ± 9. 1) s vs. (16. 5 ± 4. 3)s] as well as reduced FIB [(1. 7 ± 1. 5)g/L vs. (2. 7 ± 1. 7)g/L] (P<0. 05). Compared with the survival group, the K value in the death group was significantly prolonged [5. 2(1. 8,8. 0)min vs. 2. 9(2. 1,4. 2)min] (P<0. 05). Compared with the survival group, death group showed significant decrease in G value (3762. 4 ± 3346. 7 vs. 6366. 5 ± 3886. 1), E value (75. 3 ± 67. 0 vs. 127. 3 ± 77.7),αangle[(38.4±19.7)°vs. (49.4±16.6)°],MA[(37.4±17.5)mmvs.(52.0±13.3)mm], CI [-6. 8(-9. 5, 1. 5) vs. -2. 9 ( -5. 9, -0. 7)] and CLT [39. 2 (32. 5, 46. 9) min vs. 46. 4 (32. 7, 60.8) min] (P<0. 05). There were no significant differences in APTT, TT, INR, PLT and R between the two groups (P>0. 05). Logistic regression analysis showed that MA was significantly associated with the prognosis of polytrauma patients (OR=1. 15, 95％ CI 1. 04-1. 28, P<0. 05). The area under the ROC curve of MA was 0. 756 (P <0. 05). When the MA threshold was 43. 1 mm, the sensitivity, specificity, positive predictive value and negative predictive value of predicted survival were 77. 5％, 76. 9％, 76. 1％ and 97. 3％, respectively. Conclusion TEG index MA can determine the prognosis of polytrauma patients, and the mortality rate is significantly increased at MA<43. 1 mm.

Regulatory effect of emodin on platelet function in mice with late sepsis / 医学研究生学报

Objective Secretion and aggregation dysfunction of platelets are closely related with uncontrollable septic inflammation and abnormal blood coagulation.This study was to investigate the effect of emodin on platelet aggregation (PA) and secretion in mice with late sepsis.Methods We randomly divided 111 healthy SPF male C57BL/6 mice into a sham operation (SO) group, a cecal ligation (CL) group, and an emodin (Em) group and treated those of the Em group intragastrically with emodin after cecal ligation.At 72 hours after operation, we recorded the survival rate of the mice, measured the platelet count and the levels of serum alanine aminotransferase (ALT) and creatinine (Cr), and detected the PA rate by aggregometry, the P-selectin level by flow cytometry, the serum 5-HT concentration by ELISA, and the expressions of Rab27 mRNA and protein by RT-PCR and Western blot, respectively.Results At 72 hours after cecal ligation, the survival rates in the SO, CL and Em groups were 100%, 60% and 66.7%, respectively.The platelet count was significantly decreased in the CL group as compared with that in the SO group ([461.00±64.77] vs [775.00±65.89]×109/L, P0.05).The Rab27b protein expression was markedly lower in the CL and Em groups than in the SO group (0.093±0.015 and 0.140±0.026 vs 10.380±0.036, P0.05).Conclusion Emodin can improve platelet count and aggregation, down-regulate the expression of P-selectin, protect the liver and kidney function, and reduce mortality from late sepsis.

Effects of HMG supplementation in the middle and late follicle phases on the outcome of in vitro fertilization-embryo transfer / 重庆医学

Objective To explore the effects of human menopausal gonadotropopin(HMG) supplementation on the outcome of women underwent in vitro fertilization-embryo transfer(IVF-ET) .Methods The data of 406 IVF-ET cycles in Reproductive Medi-cine Center of the 105th Hospital of PLA were analyzed retrospectively .All cases underwent long down regulation protocol with gonadotropin releasing hormone agonist(GnRH-a) in the mid-luteal phase and controlled ovarian stimulation(COS) was carried out with follicle stimulation hormone(r-FSH) on the days 3 -5 of the menstrual cycle .Then 75 -150 U HMG was administrated in group A(257 cycles) when a dominant follicle reached a diameter of 14 mm ,while the remaining cases(149 cycles) underwent HCG still with r-FSH were served as group B .Based on the LH levels on the day of HMG administration ,the cases in group A were sub-divided into :group A1(99 cycles) ,LH2 U/L .Clinical outcomes of all groups were analyzed and compared .Results The durations and doses of gonadotropin(Gn) ,the rates of fertilization and pregnancy were higher and the abortion rate was lower in group A than that in group B (P0 .05) .There was significant difference in serum LH levels on the day of HMG supplementation among group A1 ,A2 and A3(P0 .05) .Conclusion HMG supplementation in the middle and late follicle phases in stand-ard long down-regulation protocol during IVF could obtain higher pregnancy rate and lower abortion rate ,especially when their ser-um LH level was between 1 U/L and 2 U/L without obvious increase of LH .

Effect of two different hemostatic regimens on pelvic fracture combined with hemorrhagic shock / 中华创伤杂志

Objective To compare the clinical effect of two hemostatic methods for patients with pelvic fracture combined with hemorrhagic shock in the early stage.Methods A retrospective analysis was done on clinical data of 90 patients with unstable pelvic fracture combined with hemorrhagic shock managed by damage control resuscitation from January 2008 to December 2012.Unstable blood pressure and abdominal distension were noted postoperatively.Forty patients in Group A received laparotomy and bilateral internal iliac artery ligation from January 2008 to January 2010.Fifty patients in Group B underwent internal iliac artery embolization from February 2010 to December 2012.Comparative measurement was made on parameters of mortality,24-hour blood transfusion volume,24-hour lactic acid value,postoperative systolic blood pressure,postoperative body temperature,and postoperative prothrombin time (PT).Results Following parameters differed significantly between Groups A and B (P ＜ 0.05):mortality rate (53％ vs 12％),24-hour blood transfusion volume[(3 865.5 ±451.3)ml vs (2 108.8 ±336.4)ml],24-hour lactic acid value[(13.0 ± 2.0)mmol/L vs (5.4 ± 1.2)mmol/L],postoperative systolic blood pressure [(80.50 ± 22.73) mmHg vs (113.23 ± 20.89) mmHg],postoperative body temperature [(32.4 ± 0.2)℃ vs (36.1 ±0.3)℃],postoperative PT [(24.5 ±3.6)s vs (18.4±2.1)s].Conclusion For pelvic fracture combined with hemorrhagic shock,if the indications of abdominal viscera rupture are unclear,the interventional embolization can gain advantage over laparotomy in improving treatment success rate and reducing mortality and complications.

New insights into the regulation of Axin function in canonical Wnt signaling pathway

The Wnt signaling pathway plays crucial roles during embryonic development, whose aberration is implicated in a variety of human cancers. Axin, a key component of canonical Wnt pathway, plays dual roles in modulating Wnt signaling: on one hand, Axin scaffolds the "β-catenin destruction complex" to promote β-catenin degradation and therefore inhibits the Wnt signal transduction; on the other hand, Axin interacts with LRP5/6 and facilitates the recruitment of GSK3 to the plasma membrane to promote LRP5/6 phosphorylation and Wnt signaling. The differential assemblies of Axin with these two distinct complexes have to be tightly controlled for appropriate transduction of the "on" or "off" Wnt signal. So far, there are multiple mechanisms revealed in the regulation of Axin activity, such as post-transcriptional modulation, homo/hetero-polymerization and auto-inhibition. These mechanisms may work cooperatively to modulate the function of Axin, thereby playing an important role in controlling the canonical Wnt signaling. In this review, we will focus on the recent progresses regarding the regulation of Axin function in canonical Wnt signaling.