Site-Selective Tyrosine Reaction for Antibody-Cell Conjugation and Targeted Immunotherapy.

Targeted immunotherapies capitalize on the exceptional binding capabilities of antibodies to stimulate a host response that effectuates long-lived tumor destruction. One example is the conjugation of immunoglobulins (IgGs) to immune effector cells, which equips the cells with the ability to recognize and accurately kill malignant cells through a process called antibody-dependent cellular cytotoxicity (ADCC). In this study, a chemoenzymatic reaction is developed that specifically functionalizes a single tyrosine (Tyr, Y) residue, Y296, in the Fc domain of therapeutic IgGs. A one-pot reaction that combines the tyrosinase-catalyzed oxidation of tyrosine to o-quinone with a subsequent [3+2] photoaddition with vinyl ether is employed. This reaction installs fluorescent molecules or bioorthogonal groups at Y296 of IgGs or the C-terminal Y-tag of an engineered nanobody. The Tyr-specific reaction is utilized in constructing monofunctionalized antibody-drug conjugates (ADCs) and antibody/nanobody-conjugated effector cells, such as natural killer cells or macrophages. These results demonstrate the potential of site-selective antibody reactions for enhancing targeted cancer immunotherapy.

Trialkylphosphonium oxoborates as C(sp3)-H oxyanion holes and their application in catalytic chemoselective acetalization.

The use of trialkylphosphonium oxoborates (TOB) as catalysts is reported. The site-isolated borate counter anion in a TOB catalyst increases the availability of C(sp3)-H to interact with electron donor substrates. The catalytic protocol is applicable to a wide range of substrates in the acetalization reaction and provides excellent chemoselectivity in the acetalization over thioacetalization in the presence of alcohols and thiols, which is otherwise hard to achieve using typical acid catalysts. Experimental and computational studies revealed that the TOB catalysts have multiple preorganized C(sp3)-Hs that serve as a mimic of oxyanion holes, which can stabilize the oxyanion intermediates via multiple C(sp3)-H non-classical hydrogen bond interactions.

Science diplomacy in medical physics - an international perspective.

Purpose: Science diplomacy in medical physics is a relatively young research field and translational practice that focuses on establishing international collaborations to address some of the questions biomedical professionals face globally. This paper aims to present an overview of science diplomacy in medical physics, from an international perspective, illustrating the ways collaborations within and across continents can lead to scientific and professional achievements that advance scientific growth and improve patients care. Methods: Science diplomacy actions were sought that promote collaborations in medical physics across the continents, related to professional and scientific aspects alike. Results: Several science diplomacy actions have been identified to promote education and training, to facilitate research and development, to effectively communicate science to the public, to enable equitable access of patients to healthcare and to focus on gender equity within the profession as well as healthcare provision. Scientific and professional organizations in the field of medical physics across all continents have adopted a number of efforts in their aims, many of them with great success, to promote science diplomacy and to foster international collaborations. Conclusions: Professionals in medical physics can advance through international cooperation, by building strong communication across scientific communities, addressing rising demands, exchange scientific information and knowledge.

An elephant trunk stent graft strayed into the false lumen leading to a death during the Sun's operation: A case report / 中南大学学报(医学版)

Type A aortic dissection (AD) is a critical and severe disease with high mortality. The Sun's operation is a standard surgical method for this kind of disease at present. For the procedure, an elephant trunk stent is inserted into the true lumen of the descending aorta and the aortic arch is replaced. A patient was admitted to the First Hospital of Lanzhou University due to sudden chest and back pain for 6 days. Computed tomography angiography (CTA) showed type A AD. Ascending aorta replacement, Sun's operation, and ascending aorta to right femoral artery bypass grafting were performed. After surgery, the patient's condition was worsened. The digital subtraction angiography (DSA) showed the elephant trunk stent was inserted into the false lumen of AD, leading to the occlusion of the large blood vessel at the distal part of the abdominal aorta and below. Although we performed intima puncture and endovascular aortic repair, the patient was still dead.

Association between IL12B polymorphisms and inflammatory bowel disease in Caucasian population: A meta-analysis.

BACKGROUND: Published studies on association between IL12B (G/A) rs10045431, (T/C)rs6887695 polymorphisms and inflammatory bowel disease (IBD) risk in Caucasian population have yielded conflicting results. The aim of this study was to potentially provide more reliable conclusions by conducting a meta-analysis. METHODS: Published studies concerned association between IL12B rs10045431, rs6887695 polymorphisms and IBD were searched from the Wiley Online Library, PubMed, Web of Science and the CNKI database. The odds ratio (OR) with 95% confidence interval (CI) was calculated to evaluate the strength of the relationship. The false positive report probabilities (FPRPs) test and trial sequential analysis (TSA) was performed to investigated the reliability of results. RESULTS: A total of 20 studies comprising 10761 Crohn's disease (CD), 10921 ulcerative colitis (UC) and 18381 controls were included in this meta-analysis. Overall, the pooled results showed that IL12B rs6887695 polymorphism significantly increased both CD and UC risk under all model, while IL12B rs10045431 polymorphism dramatically decreased both CD and UC risk under all model. FPRP and TSA demonstrated that above associations was confirmed in the present study. CONCLUSION: The results of meta-analysis indicate IL12B rs10045431 and rs6887695 polymorphisms significantly associate with IBD in Caucasian population.

Association between PTGER4 polymorphisms and inflammatory bowel disease risk in Caucasian: A meta-analysis.

BACKGROUND: The results from previous studies on association between prostaglandin E receptor 4 (PTGER4) polymorphisms and inflammatory bowel disease (IBD) risk in Caucasian were conflict. The present study aimed to investigate the genetic association by conducting a meta-analysis. METHODS: Systematic literature search was conducted through Wiley Online Library, Chinese National Knowledge Infrastructure (CNKI), and PubMed databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to investigate the associations between rs4613763 T/C, 17234657T/G polymorphisms, and IBD risk in Caucasian. RESULTS: Twenty case-control studies consisting of 18,495 Crohn disease (CD) patients and 4203 ulcerative colitis (UC) patients, as well as 26,063 controls were included in this meta-analysis. The rs4613763T/C polymorphism had obvious influence on CD, UC risk in Caucasian. However, rs17234657T/G polymorphism had obvious influence on CD but not UC in Caucasian. CONCLUSION: This meta-analysis suggested that both the rs4613763 T/C, rs17234657T/G polymorphisms had obvious influence on risk of CD in Caucasian. In addition, rs4613763 T/C, polymorphism had obvious influence on risk of UC in Caucasian.

Incidence of extrahepatic cancers among individuals with chronic hepatitis B or C virus infection: A nationwide cohort study.

This study examined the association between chronic HBV or HCV infection and the risk of extrahepatic cancers. A total of 537 103 adults aged ≥20 years without history of cancer were identified from the Korean National Health Insurance Service-National Sample Cohort between 2003 and 2013. The difference in cancer incidence was compared between those with and without chronic HBV or HCV infection. During 3 854 130 person-years of follow-up (median follow-up: 8.0 years), 19 089 participants developed cancer. After adjusting for sex, body mass index, smoking, drinking, income percentile, residential area and comorbidities, hazard ratios (HRs) for incident extrahepatic cancer were significantly higher in participants with chronic HBV infection (HR: 1.27, 95% confidence interval [CI]: 1.20-1.35), HCV infection (HR: 1.31, 95% CI: 1.16-1.48) or HBV/HCV dual infection (HR: 1.41, 95% CI: 1.31-1.72) compared to participants without HBV or HCV infection. In chronic HBV infection, the cancer risk was higher for haematologic malignancy [HR (95% CI) = 2.46 (1.92-3.15)], gallbladder [1.55 (1.05-2.29)], pancreas [1.52 (1.07-2.15)], stomach [1.39 (1.22-1.58)], lung [1.27 (1.04-1.55)], colorectum [1.21 (1.03-1.42)] and thyroid cancer [1.20 (1.05-1.36)]. In chronic HCV infection, the cancer risk was higher for testis [10.34 (1.35-79.78)], gallbladder [2.90 (1.62-5.18)], prostate [2.51 (1.65-3.82)] and thyroid cancer [1.46 (1.10-1.93)]. In conclusion, chronic HBV or HCV infection was not only associated with an increased risk of liver cancer, but also associated with an increased risk of multiple extrahepatic cancers.

Clinical significance of STMN1 expression in cervical cancer and effect of inhibition of its expression on viability and apoptosis of cervical cancer Si-Ha cells / 中国病理生理杂志

AIM:To investigate the clinical significance of stathmin 1 (STMN1) expression in cervical cancer and the influence of its expression on the viability and apoptosis of cervical cancer cells. METHODS:Western blot was used to detect the protein expression of STMN1 in cervical cancer tissues, and the relationship between the expression and clinical characteristics of cervical cancer was analyzed. STMN1-siRNA was transfected into cervical squamous-cell carcino-ma SiHa cells. The protein levels of STMN1, STAT3, p-STAT3 and survivin were determined by Western blot after trans-fection for 48 h. The cell viability was measured by MTT assay. The apoptosis was analyzed by flow cytometry. DCFH-DA probe was used to detect the level of reactive oxygen species (ROS). RESULTS:The protein expression of STMN1 in cer-vical cancer tissues was significantly higher than that in paracancerous tissues (P<0.01). The STMN1 protein expression level was not correlated with age and histological types of cervical cancer patients, but was related to clinical stage, histo-logical differentiation and lymph node metastasis ( P<0.01). Transfection with STMN1-siRNA significantly reduced the expression of STMN1 in SiHa cells. Compared with control group, the cell viability in STMN1-siRNA group was significant-ly decreased, the apoptotic rate and ROS content were increased, and the protein levels of p-STAT3 and survivin were down-regulated (P<0.01). However, no significant difference of the STAT3 protein level was observed between STMN1- siRNA group and control group. CONCLUSION:STMN1 is highly expressed in cervical cancer, and its expression is re-lated to clinical stage, histological differentiation and lymph node metastasis. Inhibition of STMN1 expression reduces the viability and promotes apoptosis of cancer cells by down-regulating STAT3 signaling pathway.

Clinical Observation of Tianqi Jiangtang Capsules Combined with Metformin in the Treatment of Elderly Patients with Type 2 Diabetes Mellitus Complicated with Cerebral Microvascular Lesions / 中国药房

OBJECTIVE:To observe clinical efficacy and safety of Tianqi jiangtang capsules combined with metformin in the treatment of elderly patients with type 2 diabetes mellitus complicated with cerebral microvascular lesions. METHODS:A total of 96 elderly patients with type 2 diabetes mellitus complicated with cerebral microvascular lesions were randomly divided into control group(48 cases)and observation group(48 cases). Control group was given Metformin hydrochloride tablets 0.5 g orally,3 times a day. Observation group was additionally given Tianqi jiangtang capsules 1.6 g orally,3 times a day,on the basis of control group. Both groups received treatment for 4 weeks. Clinical efficacies of 2 groups were observed as well as total score of TCM symptoms,the levels of blood glucose(FPG,2 hPG,HbA1c),blood lipid(TC,TG,HDL-C,LDL-C),hs-CRP,ET-1,blood rheology and oxidative stress indexes(MDA,SOD),the occurrence of ADR. RESULTS:The total response rate of observation group was significantly higher than that of control group(89.58% vs. 70.83%),with statistical significance(P<0.05). After treat-ment,total score of TCM symptoms,the levels of blood glucose,hs-CRP,ET-1,TC,TG,LDL-C,blood rheology indexes and MDA in 2 groups were significantly lower than before;total score of TCM symptoms,the levels of FPG,2 hPG,hs-CRP,ET-1, TC,TG,LDL-C,blood rheology indexes and MDA in observation group were significantly lower than control group;the level of SOD in 2 groups were significantly higher than before,and the observation group was significantly higher than control group,and the level of HDL-C in observation group was significantly higher than before treatment and control group,with statistical signifi-cance(P<0.05). No obvious ADR was found in 2 groups during treatment. CONCLUSIONS:Tianqi jiangtang capsules combined with metformin show significant therapeutic efficacy in the treatment of elderly patients with type 2 diabetes mellitus,and can re-duce the levels of blood glucose and lipid,improve blood rheology and oxidative stress reaction,with goud safety.

Effects of Gegen (Puerariae lobatae Radix) water extract on improving detrusor overactivity in spontaneously hypertensive rats.

AIM: Ex vivo experiments showed that the water extract of Puerariae lobatae Radix (named Gegen in Chinese) induced detrusor relaxation. The aim of this study was to prove the in vivo efficacy of Gegen on improving detrusor overactivity and its possible synergism with darifenacin (a first-line muscarinic receptor-3 inhibitor) in spontaneously hypertensive rats (SHR), a rat model exhibiting symptoms of detrusor overactivity. METHOD: After daily oral administration of Gegen 30 (Gegen, 30mg/kg); Gegen 300 (Gegen, 300mg/kg); Low_Dar (darifenacin, 3mg/kg); High_Dar (darifenacin, 30mg/kg) Low_Dar+Gegen 30 or High_Dar+Gegen 30 for 3 weeks, bladder detrusor strips of the rats were isolated and assessed with different stimulators for the measurement of tonic and phasic contractile activities (including phasic amplitude and frequency). Modes of stimulation included the use of carbachol, isoprenaline and electrical field stimulation (EFS). RESULTS: All drug treatments significantly reduced carbachol-stimulated tonic contractile activities, but did not change the phasic amplitude. Meanwhile, the treatments with Gegen 300; Low_Dar; Low_Dar+Gegen 30; and High_Dar+Gegen 30 decreased carbachol-stimulated phasic frequency. Gegen 300 and Low_Dar+Gegen 30 showed stronger potency on lowering EFS-induced responses. Under isoprenaline-induced relaxation, only Gegen 300 significantly enhanced this relaxation by decreasing tonic contraction; Gegen 300; Low_Dar; Low_Dar+Gegen 30; and High_Dar+Gegen 30 increased the reduction of phasic frequency, but all treatment did not alter their phasic amplitude. Combination Index (CI) showed that the combination with Low_Dar and Gegen 30 had very strong synergism (CI <0.1) on inhibiting EFS-induced contractile response. CONCLUSION: Gegen improved detrusor overactivity through neurogenic and anti-muscarinic mechanisms. Gegen and darifenacin together attained synergism for detrusor overactivity treatment via the neurogenic pathway.

Complete mitochondrial genome of Peronia verruculata (Gastropoda: Pulmonata: Systellommatophora: Onchidiidae).

The complete mitochondrial genome sequence of Peronia verruculata is firstly described in the article. The mitogenome (13,861 bp) contains 22 tRNA genes, 2 ribosomal RNA genes and 13 protein-coding genes. The characteristic is the typical bivalvia mitochondrial gene composition.

The treatments of perioperative vascular vagus reflex in CARTO guided radiofrequency ablation in the treatment of atrial arrhythmia / 重庆医学

Objective To investigate the effective therapic methods of the perioperative vasovagal reflex(RV)in patients with atrial arrhythmias(AAs)underwent by catheter ablation .Methods The clinical data in the patients with atrial arrhythmias(AAs) complicated by vasovagal reflex(RV)were retrospectively analyzed during the perioperative procedure of catheter ablation guided by three dimensional mapping system CARTO ;the clinical data were compared between patients with RV and without RV .Results A total of 535 patients with AAs underwent catheter ablation guided by three dimensional mapping system were collected from Janu‐ary 2010 to December 2012 ,and 35 cases of intraoperative RV were found .Compared by patients without RV ,the patients with RV had more elderly cases and the cases of hypertension ,coronary heart disease and diabetes .The RV occurrence was also associated with the fasting ,painful stimuli ,operation time and skill .Conclusion The perioperative RV often is occurred in the cases of high risk and have the precipitating factors ,and the good prognosis could be obtained by the detect and treatment as early as possible .

Chronic ketamine treatment-induced changes in contractility characteristics of the mouse detrusor.

PURPOSE: To understand bladder contractility changes induced by chronic ketamine treatment, noting the prevalence of its abuse worldwide. METHODS: A mouse model of chronic ketamine treatment was used and detrusor strip contractility was measured. Rising and falling phases of contractile responses as well as maximal, average sustained and phasic contractions were measured. RESULTS: While maximal contractility of ketamine-treated strips was identical to the saline controls, the former displayed slower contraction rates under K(+)-Krebs, carbachol and electrical stimulation. The decay phase of electrically stimulated responses was also slower at most stimulation frequencies in the ketamine-treated strips. Greater sensitivity to varying the strengths of stimuli was observed in the ketamine-treated strips. CONCLUSIONS: Altered contractility characteristics of the bladder after chronic ketamine treatment were revealed, which could potentially be useful in the development of improved treatment regimens.

Low concentrations of niflumic acid enhance basal spontaneous and carbachol-induced contractions of the detrusor.

PURPOSE: The urinary bladder expresses Ca(2+)-activated Cl(-) channels (CACC), but its physiological role in governing contractility remains to be defined. The CACC modulator niflumic acid (NFA) is widely used despite the variable results arisen from different drug concentrations used. This study was designed to examine the effects of NFA at low concentrations on detrusor strip contractility. METHODS: Rat detrusor strips with mucosa-intact (+MU) and mucosa-denuded (-MU) were prepared in transverse (Tr) and longitudinal (Lg) with respect to the bladder orientation. Isometric force measurements were made at baseline (for spontaneous phasic contractile activity) and during drug stimulation (by carbachol, CCh) with and without NFA. RESULTS: NFA (1 and 10 µmol/L) pretreatment enhanced CCh-induced contractions more in +MU than -MU strips with no selectivity on contractile direction. For spontaneous phasic contractions, NFA-treated strips in the Tr direction showed increased phasic amplitude, while phasic frequency was unchanged. CONCLUSIONS: The findings suggest low concentrations of NFA having a potentiating effect on detrusor contractions that was sensitive to the MU and contractile direction.

Predictive value of antithyroglobulin antibody on recurrence or metastasis following ablation in differentiated thyroid carcinoma / 中华内分泌代谢杂志

Objective To investigate the value of serum thyroglobulin (Tg) and antithyroglobulin antibody (TgAb) in differentiated thyroid carcinoma complicated with Hashimoto's thyroiditis after thyroid ablation.Methods Serum Tg and TgAb levels and the status of illness in 154 differentiated thyroid carcinoma patients with coexistent Hashimoto's thyroiditis and confirmed pathology after surgery followed by remnant ablation were performed during three years follow up.Tg and TgAb levels were assessed by chemiluminescent immunoassay assay.The cases were divided into three groups (according to the level of Tg):Tg ≤ 1 μg/L group,1 μg/L＜Tg ≤ 10 μg/L group and 10 μg/L＜Tg≤ 100 μg/L group.TgAb＞40 kIU/L was considered as positive,Cox's proportional hazard model was used to analyse prognostic value in different levels of Tg and TgAb for disease-free survival and recurrence.Results Compared with 1 μg/L＜Tg≤ 10 μg/L group and 10 μg/L＜Tg≤ 100 μg/L group,the relative risk in reflecting cancer recurrence (TgAb＞40 kIU/L) in Tg ≤ 1 μg/L group was 27.000 (95 ％ CI 6.727-108.374).The value of TgAb＞40 kIU/L in Tg≤ 1 μg/L group was greatly increased and highly correlated with metastasis.However,In the condition of Tg＞ 1 μg/L,the disease will be based on the level of TgAb.Conclusion The value of TgAb＞40 kIU/L in Tg ≤ 1 μg/L group seems to be the optimal cutoff value correlated with recurrence and metastasis of differentiated thyroid carcinoma.

Effect of tea polyphenols on oxidative stress and micro inflammatory condition in maintenance hemodialysis patients / 中国生化药物杂志

Objective To investigate the influence and the possible mechanism of tea polyphenols on maintenance hemodialysis (MHD)patients’ oxidative stress and micro inflammatory condition.Methods 60 cases of MHD patients were randomly divided into routine group and tea polyphenols group.30 healthy subjects were chosen as normal control group.After 3 months,MDA,AOPP,SOD,TNF-α,CRP,IL-6 and NF-κB of routine group and tea polyphenols group were detected.Results Before treatment,compared with normal control group,MDA and AOPP of routine group and tea polyphenols group increased (P <0.01 ),SOD decreased (P <0.01 );after treatment,compared with routine group,MDA and AOPP of tea polyphenols group decreased (P<0.01),SOD increased (P<0.01).After treatment,compared with normal control group,NF-κB,TNF-α,CRP, IL-6 and oxidative index of routine group and tea polyphenols group increased,and the difference was statistically significant (P<0.01);compared with routine group,oxidative index of tea polyphenols group decreased,and the difference was statistically significant (P <0.01 ).Conclusion Tea polyphenol can improve MHD patients’oxidative stress and micro inflammatory state.

Current Evidence of Chinese Herbal Constituents with Effects on NMDA Receptor Blockade.

NMDA receptor (NMDA-R) is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer's Disease) is attributed to NMDA-mediated neurotoxicity. With greater understanding of the NMDA-R structure, antagonists with varying degrees of binding-site and subtype selectivity have been developed and put into clinical use. Discovery of target-specific Chinese herbs have also been made in parallel. This article provides an overview of the known active sites on the NMDA-R, followed by a discussion of the relevant herbs and their constituents. Experimental evidence supporting the inhibitory role of the herbal compounds on the NMDA-R is highlighted. For some of the compounds, potential research directions are also proposed to further elucidate the underlying mechanisms of the herbs. It is envisaged that future investigations based on the present data will allow more clinically relevant herbs to be identified.

Complete mitochondrial genome of Paraoncidium reevesii (Gastropoda, Pulmonata, Systellommatophora, Onchidiidae).

The complete mitochondrial genome of Paraoncidium reevesii was firstly determined in this paper. The mitogenome (13,842 bp) consists of 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes, and 1 putative control region (CR). CR is not well characterized due to lack of discrete conserved sequence blocks. This characteristic is similar with CRs of other invertebrate mitochondrial genomes.

Complete mitochondrial genome of the jackknife clam Solen grandis (Veneroida, Solenidae).

The complete mitochondrial genome sequence of Solen grandis that lives in sub-tidal waters and being buried in muddy to fine sand substrates, is described in this paper. The mitogenome (16,794 bp) consists of 12 protein-coding genes (loss of ATPase subunit 8), 22 tRNA genes, 2 rRNA genes and 1 putative control region. It is the typical bivalve mitochondrial gene composition.

Choroidal neovascularization secondary to sorsby fundus dystrophy treated with intravitreal bevacizumab.

PURPOSE: To report a case of extrafoveal choroidal neovascularization secondary to Sorsby fundus dystrophy that maintained 20/20 visual acuity over 14 months with intravitreal bevacizumab therapy. METHODS: Interventional case report of as-needed treatment with intravitreal bevacizumab of a 38-year-old lady with choroidal neovascularization from Sorsby fundus dystrophy. RESULTS: Three injections of intravitreal bevacizumab were given over 14.5 months, maintaining visual acuity at 20/20. CONCLUSION: Intravitreal bevacizumab therapy appears to maintain vision in patients with choroidal neovascularization from Sorsby fundus dystrophy.