Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities.

Clinical application of PD-1 and PD-L1 monoclonal antibodies (mAbs) is hindered by their relatively low response rates and the occurrence of drug resistance. Co-expression of B7-H3 with PD-L1 has been found in various solid tumors, and combination therapies that target both PD-1/PD-L1 and B7-H3 pathways may provide  additional therapeutic benefits. Up to today, however, no bispecific antibodies targeting both PD-1 and B7-H3 have reached the clinical development stage. In this study, we generated a stable B7-H3×PD-L1 bispecific antibody (BsAb) in IgG1-VHH format by coupling a humanized IgG1 mAb against PD-L1 with a humanized camelus variable domain of the heavy-chain of heavy-chain antibody (VHH) against human B7-H3. The BsAb exhibited favorable thermostability, efficient T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC). In a PBMC humanized A375 xenogeneic tumor model, treatment with BsAb (10 mg/kg, i.p., twice a week for 6 weeks) showed enhanced antitumor activities compared to monotherapies and, to some degree, combination therapies. Our results suggest that targeting both PD-1 and B7-H3 with BsAbs increases their specificities to B7-H3 and PD-L1 double-positive tumors and induces a synergetic effect. We conclude that B7-H3×PD-L1 BsAb is favored over mAbs and possibly combination therapies in treating B7-H3 and PD-L1 double-positive tumors.

Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain.

Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor-associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement-dependent cytotoxicity (CDC). We hypothesized that modifying ch14.18 using antibody engineering techniques, such as humanization, affinity maturation, and Fc engineering, may enable the development of next-generation GD2-specific antibodies with reduced neuropathic pain and enhanced antitumor activity. In this study we developed the H3-16 IgG1m4 antibody from ch14.18 IgG1. H3-16 IgG1m4 exhibited enhanced binding activity to GD2 molecules and GD2-positive cell lines as revealed by ELISA, and its cross-binding activity to other gangliosides was not altered. The CDC activity of H3-16 IgG1m4 was decreased, and the antibody-dependent cellular cytotoxicity (ADCC) activity was enhanced. The pain response after H3-16 IgG1m4 antibody administration was also reduced, as demonstrated using the von Frey test in Sprague-Dawley (SD) rats. In summary, H3-16 IgG1m4 may have potential as a monoclonal antibody with reduced side effects.

[Clinical significance of intermittent sinusoidal fetal heart rate at third trimester].

OBJECTIVE: To investigate clinical significance of intermittent sinusoidal fetal heart rate at third trimester. METHODS: From Jan 2002 to Dec 2010, 48 pregnant women at 33 to 41 gestational weeks undergoing electronic fetal heart rate (FHR) monitoring presented with intermittent sinusoidal FHR in Department of Obstetrics and Gynecology, Second School of Clinical Medicine, Jinan University were enrolled in this retrospective study. Twenty-one cases were categorized into continuous group (i.e. with sinusoidal feature and a constant duration ≥ 10 minutes), while the other 27 cases were categorized into intermittent group (i.e. with a duration < 10 minutes). In the mean time, 76 normal cases were chosen randomly matched as control group. Blood gas and hemoglobin were measured in umbilical artery after fetal head delivery. General neurological system examination were performed in those fetus in hospitalization. The outcome of those fetuses was compared. RESULTS: (1) Neonatal complications: the rate of asphyxia, meconium-stained amniotic fluid and fetal anemia were 63% (17/27), 33% (9/27) and 63% (17/27) in group of intermittent sinusoidal FHR, which were significantly higher than 1% (1/76), 4% (3/76), 3% (2/76) in control group (P < 0.05). When compared with 67% (14/21), 52% (11/21), 76% (16/21) in group of continuous sinusoidal, the statistical difference were not observed (P > 0.05). (2) Blood gas in neonate: the rates of pH less than 7 were 18% (5/27) in intermittent group, 52% (11/21) in continuous group and 0 in control group, which all reached statistical difference among those three groups (P < 0.05). (3) Brain damage and death: the rates of brain damage and death were 48% (13/27) and 11% (3/27) in intermittent group, 81% (17/21) and 43% (9/21) in continuous group, and 0 in control group, which all showed significant difference between them (P < 0.05). CONCLUSION: Intermittent and continuous sinusoidal FHR are typical graphics of severe fetal anemia at third trimester. Intermittent sinusoidal FHR is indicative of serious fetal hypoxia.

Co-production of acetoin and succinic acid by metabolically engineered Enterobacter cloacae.

BACKGROUND: Renewable chemicals have attracted attention due to increasing interest in environmental concerns and resource utilization. Biobased production of industrial compounds from nonfood biomass has become increasingly important as a sustainable replacement for traditional petroleum-based production processes depending on fossil resources. Therefore, we engineered an Enterobacter cloacae budC and ldhA double-deletion strain (namely, EC∆budC∆ldhA) to redirect carbon fluxes and optimized the culture conditions to co-produce succinic acid and acetoin. RESULTS: In this work, E. cloacae was metabolically engineered to enhance its combined succinic acid and acetoin production during fermentation. Strain EC∆budC∆ldhA was constructed by deleting 2,3-butanediol dehydrogenase (budC), which is involved in 2,3-butanediol production, and lactate dehydrogenase (ldhA), which is involved in lactic acid production, from the E. cloacae genome. After redirecting and fine-tuning the E. cloacae metabolic flux, succinic acid and acetoin production was enhanced, and the combined production titers of acetoin and succinic acid from glucose were 17.75 and 2.75 g L-1, respectively. Moreover, to further improve acetoin and succinic acid production, glucose and NaHCO3 modes and times of feeding were optimized during fermentation of the EC∆budC∆ldhA strain. The maximum titers of acetoin and succinic acid were 39.5 and 20.3 g L-1 at 72 h, respectively. CONCLUSIONS: The engineered strain EC∆budC∆ldhA is useful for the co-production of acetoin and succinic acid and for reducing microbial fermentation costs by combining processes into a single step.

[Effects of cultivation patterns on the radiation use and grain yield of winter wheat].

Taking winter wheat cultivar 'Tainong 18' as test material, this paper set three treatments, local farmer's traditional cultivation pattern (FP), super high yield pattern (SH) and high yield high efficiency pattern ( HH) to investigate the effects of cultivation patterns on the intercepted photosynthetically active radiation (IPAR), PAR use efficiency (RUE), dry matter (DM) accumulation, harvest index (HI), grain yield and fertilizers' partial factor productivity (PFP) in 2012-2013. The results showed that IPAR, RUE and DM accumulation of the total growth stage and grain yield under SH pattern were significantly higher than those under FP pattern. IPAR of the total growth stage under HH pattern was lower than that under FP pattern, but RUE, DM accumulation and HI were significantly higher than that under FP pattern, so grain yield was higher than that under FP pattern. The grain yields under HH pattern were respectively decreased by 3.8% and 2.8% under high and low fertility levels compared that under SH pattern, while the PFP of N, P and K under HH pattern were averagely 26.4%, 68.5% and 92.6% higher than those under SH pattern, respectively. In conclusion, HH pattern, with the characteristics of 'reducing fertilizer', 'increasing planting density' and 'delaying sowing date', was the recommended cultivation pattern under the condition similar to this experiment balancing the grain yield, radiation use and fertilizer use.

Grafting of ß-cyclodextrin to magnetic graphene oxide via ethylenediamine and application for Cr(VI) removal.

A novel ß-cyclodextrin (ß-CD) polymer adsorbent named ß-cyclodextrin/ethylenediamine/magnetic graphene oxide (CD-E-MGO) was synthesized for decontamination of Cr(VI) from aqueous solution. The sorption kinetics, isotherms and thermodynamics, as well as the effects of pH, aniline and ionic strength on the sorption process were investigated. The results indicated that CD-E-MGO could effectively remove Cr(VI) from aqueous solution and the sorption data could be well described by pseudo-second-order and Langmuir models. The intraparticle diffusion study indicated that intraparticle diffusion was not the only rate-limiting step. Thermodynamic parameters revealed that the sorption reaction was an endothermic and spontaneous process. The decontamination of Cr(VI) was influenced by solution pH and ionic strength. In the system with aniline, the Cr(VI) sorption was improved at low pH values but reduced at high pH values. These results are important for estimating and optimizing the removal of metal ions by CD-E-MGO composite.

Etiology and antimicrobial resistance of community-acquired pneumonia in adult patients in China.

BACKGROUND: Appropriate antimicrobial therapy of community-acquired pneumonia (CAP) is mainly based on the distribution of etiology and antimicrobial resistance of major pathogens. We performed a prospective observational study of adult with CAP in 36 hospitals in China. METHODS: Etiological pathogens were isolated in each of the centers, and all of the isolated pathogens were sent to Zhongshan Hospital for antimicrobial susceptibility tests using agar dilution. RESULTS: A total of 593 patients were enrolled in this study, and 242 strains of bacteria were isolated from 225 patients. Streptococcus pneumoniae (79/242, 32.6%) was the most frequently isolated pathogen, followed by Haemophilus influenzae (55/242, 22.7%) and Klebsiella pneumoniae (25/242, 10.3%). Totally 527 patients underwent serological tests for atypical pathogens; Mycoplasma pneumoniae and Chlamydia pneumoniae infections were identified in 205 (38.9%) and 60 (11.4%) patients respectively. Legionella pneumophila infections were identified in 4.0% (13/324) of patients. The non-susceptibility rate of isolated Streptococcus pneumoniae to erythromycin and penicillin was 63.2% and 19.1% respectively. Six patients died from the disease, the 30-day mortality rate was 1.1% (6/533). CONCLUSIONS: The top three bacteria responsible for CAP in Chinese adults were Streptococcus pneumonia, Haemophilus influenza and Klebsiella pneumonia. There was also a high prevalence of atypical pathogens and mixed pathogens. The resistance rates of the major isolated pathogens were relatively low except for the high prevalence of macrolide resistance in Streptococcus pneumoniae.