Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

Factors affecting the accumulation of organotins by wild fish: A case study in the Three Gorges Reservoir, China.

Organotin compounds (OTs) accumulate in fish easily, however, research on their influencing factors is still limited. This study collected 25 species of fish with different diets, habitats, and age from the Three Gorges Reservoir (TGR), the largest deep-water river channel-type reservoir in China, and analyzed the accumulation characteristics of OTs in these fish. The results showed that tributyltin (TBT) and triphenyltin (TPhT) were the dominant OTs in fish from the TGR. The correlation between OTs concentration and age, body length, and body weight varied with fish species. The concentrations of TBT and TPhT in carnivorous fish (mean, 25.78 and 11.69 ng Sn/g dw, respectively) were higher than those in other diet fish (P<0.01), but there was no significant difference in fish at different habitat water layers (P>0.05). In addition, the degradation rates of TBT and TPhT in different fish species were all below 50%. In summary, the accumulation of TBT and TPhT in fish is mainly influenced by diet, and both TBT and TPhT were difficult to degrade in fish. These results reveal the pollution characteristics of OTs in fish from the TGR, and can improve our understanding of the factors influencing TBT and TPhT accumulation in freshwater fish.

Comprehensive analysis of the fates and risks of veterinary antibiotics in a small ecosystem comprising a pig farm and its surroundings in Northeast China.

This study investigated the behavior of veterinary antibiotics (VAs) in a small farm ecosystem. Manure and environmental samples were collected around a large pig farm in northeast China. Thirty-four VAs in six categories were analyzed. Then, a multimedia fugacity model was used to estimate the fates of VAs in the environment. The results showed that VAs were prevalent in manure, soil, water, and sediment, but not in crops. Compared with fresh manure, VA levels were significantly lower in surface manure piles left in the open air for 3-6 months. The main VAs, tetracyclines and quinolones, decreased by 427.12 and 158.45 µg/kg, respectively. VAs from manure piles were transported to the surroundings and migrated vertically into deep soil. The concentrations of ∑VAs detected in agricultural soils were 0.03-4.60 µg/kg; > 94% of the mass inventory of the VAs was retained in soil organic matter (SOM), suggesting that SOM is the main reservoir for antibiotics in soil. Risk assessment and model analysis indicated that the negative impact of mixed antibiotics at low concentrations in farmland on crops may be mediated by indirect effects, rather than direct effects. Our findings highlight the environmental fates and risks of antibiotics from livestock farms.

Hormones other than aldosterone may contribute to hypertension in 3 different subtypes of primary aldosteronism.

Blood pressure (BP) level is similar in patients with 3 subtypes of primary aldosteronism (PA), even though aldosterone levels may vary. Glucocorticoids and adrenomedullary hormones may be influenced and may contribute to hypertension in PA. The authors' objective was to investigate the influence of PA on adrenal gland secretion and the roles of these hormones in hypertension. Patients diagnosed with PA (229 cases) were enrolled and classified into 3 subgroups: aldosterone-producing adenoma (APA), unilateral nodular adrenal hyperplasia (UNAH), and idiopathic hyperaldosteronism (IHA). Patients with essential hypertension served as the control group (100 cases). Concentration of the above hormones was measured and compared between groups. Level of plasma adrenocorticotrophic hormone (ACTH) in patients with APA was significantly lower than that in patients with IHA (P<.001) and UNAH (P<0.5). The 24-hour urinary free cortisol and adrenomedullary hormone levels were highest in patients with IHA, lower in patients with APA, and lowest in patients with UNAH. Systolic BP level was positively correlated with 8 am plasma cortisol level (r=0.142, P=.039) and plasma ACTH level (r=0.383, P=.016). Cortisol and adrenomedullary hormones were different between PA subtypes and they might involve regulation of BP in those patients.

Glyoxalase I and aldose reductase gene polymorphisms and susceptibility to carotid atherosclerosis in type 2 diabetes.

AIMS: To investigate the association of polymorphisms of glyoxalase I (GLO1) A419C, GLO1 C-7T, and aldose reductase C-106T with type 2 diabetes and diabetic carotid atherosclerosis in a Chinese Han population. METHODS: The study population included 362 patients with type 2 diabetes and 301 nondiabetic control subjects. Genetic analyses were performed using either the Taqman polymerase chain reaction or direct sequencing. All patients with diabetes underwent carotid ultrasonography to assess the intima-media thickness and the presence of atherosclerotic plaques. RESULTS: There were no differences between the genotype frequencies of GLO1 A419C, GLO1 C-7T, and aldose reductase C-106T polymorphisms, in the control and diabetic groups. The value of mean carotid intima-media thickness and the prevalence of carotid atherosclerotic plaques were significantly increased in patients with type 2 diabetes with the GLO1-7CC genotype compared with those with the -7CT and TT genotypes (permutation p=0.003 and 0.031, respectively). Multiple regression analysis showed that the GLO1-7CC genotype was an independent determinant of carotid intima-media thickness (ß=0.12, p=0.014), but not an independent risk factor for carotid atherosclerotic plaques (odds ratio [OR]=1.74, 95% CI 0.89-3.42, p=0.10) in patients with type 2 diabetes. CONCLUSIONS: The GLO1 C-7T polymorphism is associated with carotid atherosclerosis in Chinese patients with type 2 diabetes.

[Efficacy and safety of high-dose α-lipoic acid in the treatment of diabetic polyneuropathy].

OBJECTIVE: To evaluate the efficacy and safety of high-dose α-lipoic acid in the treatment of diabetic polyneuropathy with regards to sensory symptoms and nerve conduction velocity. METHODS: A total of 236 diabetics with symptomatic polyneuropathy were enrolled into this 5-center, randomized, double-blind and placebo-controlled study of α-lipoic acid 1800 mg daily (n = 117) or matching placebo (n = 119) for 12 weeks. The primary outcome was total symptom score (TSS). Secondary end points included nerve conduction velocity, individual symptom score, HbA1c and safety parameters. The above parameters were reviewed and recorded at zero point and after treatment for 2, 4, 8, 12 weeks separately. RESULTS: 73.27% patients with symptomatic polyneuropathy improved after treatment with α-lipoic acid for 12 weeks versus 18.27% with placebo. TSS declined by 2.6 ± 2.3 with α-lipoic acid. And it was more than 0.7 ± 1.4 versus placebo (P < 0.05). TSS decreased quickly after treatment with α-lipoic acid for 2 weeks (P < 0.05). And it was better than placebo. Individual symptom scores of pain, extremity numbness, burning sensation or resting abnormal sensations were significantly diminished as compared to those before treatment and placebo group (all P < 0.05). Nerve conduction velocity had no change. HbA1c further decreased at the end of trial after α-lipoic acid treatment (P < 0.05). The incidence rates of adverse effects were 25.4% vs 11.8% in the treatment and control groups. The major manifestation was burning sensation from throat to stomach (12.7%). CONCLUSION: Oral treatment with high-dose α-lipoic acid for 12 weeks may improve symptoms in patients with diabetic polyneuropathy. Dose of 600 mg thrice daily for 2 weeks has marked effects with a reasonable safety.

[Risk factors for cardiovascular autonomic neuropathy and their prognostic implications in type 2 diabetes mellitus].

OBJECTIVE: Risk factors for diabetic cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes were analyzed to establish a regression model for evaluating the diagnosis of CAN. METHODS: 325 patients with type 2 diabetes were divided into four groups according to the results of four standard function tests. Every patient was required to offer detailed disease history and accept physical examination, serum and urine tests and examinations including ECG, nerve conduction velocity, retinoscope and Doppler of carotid and lower limb arteries. RESULTS: 64.0% of the patients had abnormal autonomic function and 30.2% definite CAN. There was significant difference among groups about age, average glycosylated forms of hemoglobin (HbA1c), systolic blood pressure, corrected 24 h albumin excretion and heart rate at rest (P < 0.001). The incidence of diabetic complications and accompanying diseases increased with deterioration of CAN (P < 0.05). The regression model showed that age, average HbA1c, hypertension, peripheral neuropathy, retinopathy, tachycardia at rest and duration of peripheral neuropathy were significant related factors for CAN. With these factors, a mathematic formula was established which could be used for evaluating the diagnosis of CAN. CONCLUSION: Except for age and hypertension, risk factors were all induced by hyperglycemia. It is suggested that control of hyperglycemia is of primary importance in preventing diabetic complications.

[Clinical characteristics and surgery outcomes of unilateral nodular adrenal hyperplasia in primary aldosteronism: study of 145 cases].

OBJECTIVE: To investigate the clinical characteristics, differential diagnosis, and surgery outcome of unilateral nodular adrenal hyperplasia (UNAH). METHODS: The clinical data of 145 patients with primary aldosteronism, 67 males and 78 females, aged 37.9 (19-60), including 78 cases of aldosterone-producing adenoma (APA), 14 cases of UNAH, and 55 cases of idiopathic bilateral adrenal hyperplasia (BAH), were collected. Radioimmunoassay was used to examine the blood and urine aldosterone and plasma rennin activity. Automatic biochemical apparatus was used to examine the blood and urine electrolytes, renal functions, and urine microalbumin. Twelve-lead electrocardiography, echocardiography, and plain scanning of enhanced CT scanning of the bilateral adrenals were conducted. Adrenal venous sampling (AVS) was conducted in 62 patients to collect blood samples from vena cava and bilateral suprarenal veins to detect the levels of aldosterone and cortisol. All UNAH patients and 3 BAH patients underwent unilateral adrenalectomy and three APA patients underwent unilateral adrenalectomy or adenoma resection. Then the patients were followed up for 39.2 months. RESULTS: The incidence of UNAH is 9.7% in the primary aldosteronism patients. There were no significant differences in age, gender, duration of hypertension, blood pressure (SBP, DBP), and indexes indicating damages in target organs of hypertension (left ventricular hypertrophy rate, blood creatinine, urine microalbumin, etc) among these three groups. The level of serum potassium of the APA group was significantly lower than that of the BAH group (P < 0.01), and the levels of plasma and urine aldosterone of the APA group were significantly higher than those of the BAH group (P < 0.05 and P < 0.01). The serum potassium of the UNAH group was higher than that of the APA group and lower than that of the BAH group, and the levels of plasma and urine aldosterone of the UNAH group were both higher than those of the APA group and lower than those of the BAH group, however all not significantly (all P > 0.05). The coincidence rate of CT was 50% (7/14) in the UNAH group. The accuracy of AVS for diagnosis of UNAH was 85.7% (12/14). After operation, the serum potassium and plasma aldosterone concentrations returned normal in all the UNAH patients. Blood pressure returned to normal in 50% (7/14) of the UNAH patients, and was improved in the other 50% (7/14) patients. CONCLUSION: UNAH can be cured by adrenal surgery. The diagnostic values of clinical examination and adrenal CT are limited. AVS is essential in diagnosing UNAH patients.