Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.

Diagnosis a fetus with Coffin-Siris syndrome due to variant of SMARCA4 gene by whole exome sequencing / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical phenotype and genetic basis for a fetus suspected for Coffin-Siris syndrome.@*METHODS@#Chromosomal microarray analysis (CMA) and whole exome sequencing (WES) were carried out for the fetus. Candidate variant was verified by Sanger sequencing.@*RESULTS@#Prenatal ultrasound at 23rd gestational week has revealed fetal ventriculomegaly. No abnormality was found by CMA, while WES revealed that the fetus has harbored a de novo heterozygous c.2851G>A (p.G951R) variant of the SMARCA4 gene, which was predicted to be pathogenic.@*CONCLUSION@#Genetic testing should be considered for fetuses featuring progressive widening of lateral cerebral ventricles.

Enlarged multicystic dysplastic kidneys with oligohydramnios during infancy caused by NPHP3 gene mutation / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and genomic abnorm ality of a fetus enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation.@*METHODS@#The fetuse was found to have multicystic dysplastic kidneys with oligohydramnios upon ultrasonography during the second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA, chromosomal microarray analysis (CMA) and whole exome sequencing (WES). Sanger sequencing was used to verify the suspected variants in the family.@*RESULTS@#Antenatal ultrasound examination at 19 weeks showed "polycystic" kidneys with Oligohydramnios. Delivery was by induced labour because of the critically low amniotic fluid volume. Testing of CMA was normal. WES showed a compound heterozygous mutation of c.1817G>A, p.W606X; c.432dupA, p.E145Rfs*18 mutations are novel mutations in this study.@*CONCLUSION@#The research may further expand the NPHP3 gene mutation spectrum. Enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation at least include one or two splice site mutation, frameshift mutation or nonsense mutation foetal poor prognosis.

Study on newborn screening for Duchenne muscular dystrophy and diagnostic strategy / 中华医学遗传学杂志

OBJECTIVE@#To establish a newborn screening system for Duchenne muscular dystrophy (DMD) through assessment of MM isoenzyme of creatine kinase (CK-MM) activity.@*METHODS@#The CK-MM level was detected using dry blood spot filter paper from 10 252 male newborns. The results were grouped based on their gestational age, sampling time and intervals between the experiments. The threshold value for CK-MM necessitating genetic testing was determined. Next-generation sequencing (NGS) was carried out for those with a CK-MM value over the threshold, and the result was verified by multiplex ligation-dependent probe amplification (MLPA).@*RESULTS@#Based on the result of non-parametric rank sum test, the median CK-MM concentration has increased with the gestational age, and was inversely correlated with the age of the newborns among unaffected specimens. CK-MM on dry blood spot filter paper can be stable for 14 days at 2-8℃. Statistical analysis of CK-MM value of the 10 252 neonates suggested that the threshold may be set as 700 ng/mL. Exonic deletions were found in 2 confirmed cases, whose CK-MM level was greater than 2000 ng/mL.@*CONCLUSION@#Detection of CK-MM in dry blood spot filter paper has provided an effective method for newborn screening of DMD. This simple and inexpensive method can be used for large-scale screening, which is of great value to the early intervention and treatment of the disease.

Role of circadian clock genes in the development and progression of nonalcoholic fatty liver disease / 临床肝胆病杂志

Circadian clock is an inherent biological rhythm of organism which forms in the long process of evolution to adapt to the changes in light and temperature due to day-night alternation. Circadian clock in humans is accurately regulated by various circadian clock genes at the molecular level and are hierarchically regulated by the central clock and the peripheral clock at the anatomical level. Recent studies have found that circadian clock genes can participate in intracellular lipid metabolism by regulating downstream clock-controlled genes, and the disorder of circadian clock genes can result in abnormal lipid metabolism, oxidative stress, insulin resistance, and abnormal secretion of glucocorticoids and inflammatory factors, which are closely associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The disorder of circadian clock genes can also increase the susceptibility to fatty liver disease and thus acts as a bridge that connects circadian clock genes and NAFLD. The pathogenesis of NAFLD remains unclear at present, and therefore, this article summarizes the recent studies on the association between circadian clock genes and NAFLD, so as to provide a theoretical basis for further clarifying the pathogenesis of NAFLD.

Study of brainstem auditory evoked potentials in children with Bell's palsy / 中国小儿急救医学

Objective To evaluate the function of auditory nerve and brainstem in children with Bell's palsy by using brainstem auditory evoked potential ( BAEP) . Methods A retrospective study was car-ried in total of 69 patients with Bell's palsy admitted in the pediatric department of Shengjing Hospital of China Medical University from January 2017 to January 2018. There were 33 males and 36 females,aged 1 to 12 years old. Sixty healthy children served as control group. BAEP were determined in 69 patients and 60 healthy subjects. EEG and CT or MRI of brain were performed to exclud tumor,intracranial infection and so on. The patients in the case group were divided into 2 groups:1-3 years old group (38 cases) and 4-12 years old group (31 cases). Sixty healthy children were also divided into 2 groups:1-3 years old group (30 cases) and 4-12 years old group (30 cases). Results The hearing threshold was normal in the children of the control group. There was no significant difference not only in potential latency but also internal potential latency of BAEP between right and left ear. The abnormal rate of BAEP was 39. 1％ ( 27/69 ) in case groups,19 cases of them recovered(70. 4％,19/27) after 2 weeks of clinical treatment. Another 8 patients re-covered after 2 months. The abnormality rate of EEG was 5. 8％ (4/69),and the abnormality rate of CT or MRI in head was 14. 5％ (10/69). Both were nonspecific changes. In the two groups,Ⅰ-Ⅲinternal potential latency was significantly shortened ( P <0. 05 ) , and Ⅲ-Ⅴinternal potential latency was significantly pro-longed (P<0. 05)respectively,between the normal side and abnormal side. There were significant differences in the Ⅲ potential latency(P<0. 05),Ⅰ-Ⅲinternal potential latency (P<0. 01),and Ⅲ-Ⅴ internal poten-tial latency ( P <0. 01 ) respectively, between pretherapy and post-treatment. Conclusion Bell's palsy of children could cause abnormal of auditory nerve conduction,and BAEP could find the electro physiologic ab-normality in nervous system,and guide clinical intervention.

Progress of Research on Intestinal Mucosal Injury Induced by Acute Exposure to High Altitude / 胃肠病学

High altitude environment is a special ecological environmental system. The specificity of this environment is the main reason of gastrointestinal reaction caused by acute exposure to high altitude. With the development of economy, more and more people come to the plateau,and gastrointestinal reaction caused by acute exposure to high altitude has attracted wide attention by scholars. This article briefly reviewed the mechanism of intestinal mucosal injury induced by acute exposure to high altitude.

Spontaneous bilateral internal carotid artery dissection:a case report and literature review / 中华全科医师杂志

A patient with multiple ischemic stroke due to spontaneous bilateral internal carotid artery dissection (ICAD) was reported and the epidemiology, neuroimaging, clinical characteristics and treatment of spontaneous bilateral ICAD were reviewed.Spontaneous bilateral ICAD mostly occurs in young and middle-aged individuals and the clinical manifestations are mainly stroke(71.1%), headache and neck pain(62.2%), Horner's syndrome(15.6%) and cranial nerve palsy(11.1%).Cervical axial T1-weighted fat-suppressed image is an alternative to DSA to make the definite diagnosis.Antithrombotic therapy is regularly used and the general clinical outcome is good.Cervical arterial dissection is one of the most common causes of stroke in young and middle-aged patients.Cervical MRI T1-weighted fat suppressed image is crucial for timely diagnosis and initiation of appropriate clinical intervention.

Application of electromyography combined with magnetic resonance imaging in the diagnosis of brachial plexus injury in newborns / 中国小儿急救医学

Objective To investigate the characteristics of electromyography(EMG) and MRI in the diagnosis of brachial plexus injury in newborns.Methods First,the EMG examination was conducted in 30 newborns with brachial plexus injury,where the brachial plexus of the five major nerve conduction and muscle EMG activity were measured.Second,the brachial plexus MRI was conducted to compare with the first examination.Results EMG revealed that 25 cases of upper and middle trunk palsy(83.3%),4 cases of total plexus palsy(13.3%) and 1 case of lower trunk palsy(3.3%) in the 30 cases,as well as 6 cases of plexus pre-ganglionic injury(20.0%),7 cases of complete injury(23.3%),23 cases of incomplete injury (76.7%).MRI showed that 5 cases of upper and middle trunk palsy(16.7%),1 case of total plexus palsy (3.3%),1 case of lower trunk palsy(3.3%),and 7 cases of plexus pre-ganglionic injury(23.3%)in the whole 30 cases.Conclusion EMG and MRI are both helpful to localize the brachial plexus injury.But EMG performs better compared with MRI towards the slight incomplete injury.Therefore,the combination of both methods can provide an accurate guidance for diagnosis.

Effect of Annexin A1 on the Cardiac Function and Inflammatory Response of Diabetic Rats / 中国医科大学学报

Objective To study the effect of annexin A1 on cardiac function,tumor necrosis factorα(TNF?α),and interleukin 1β(IL?1β)in diabetic rats. Methods Twenty?four SD rats were randomly divided into normal control and diabetic groups. The type 2 diabetes model was in?duced with a high?glucose and high?fat diet and administration of low?dose streptozotocin.Left ventricular end?diastolic volume(LVEDV),left ven?tricular end?systolic volume(LVESV),peak velocity of early diastolic mitral?to?late diastolic peak velocity(e/a)ratio,left ventricular ejection frac?tion(LVEF),and stroke volume(SV)were measured by using color Doppler ultrasonography at the end of week 8. The expression levels of TNF?αand IL?1βin blood were measured by using enzyme?linked immunosorbent assay,and the expression level of annexin A1 in blood was measured at weeks 0,4,and 8 by using real?time polymerase chain reaction. Results Compared with the normal control group,the diabetic group had de?creased LVEDV,e/a,and SV(P<0.05).The annexin A1 expression level in the diabetic group decreased significantly after 8 weeks(P<0.01). The TNF?αand IL?1βlevels in the diabetic group were significantly higher than those in the normal control group(P<0.05)and increased signifi?cantly after 8 weeks(P<0.01). Annexin A1 level correlated with the TNF?αand IL?1βlevels in the diabetic group(P<0.01). Conclusion Annexin A1 expression shows an anti?inflammatory effect that improved the cardiac function of diabetic rats.

Manual acupuncture versus electroacupuncture for menopausal syndrome:a randomized controlled trial / 中国针灸

<p><b>OBJECTIVE</b>To compare the clinical therapeutic effects and safety on menopausal symptoms between manual acupuncture (MA) and electroacupuncture (EA).</p><p><b>METHODS</b>Fifty patients were randomized into an MA group (25 cases) and an EA group (25 cases). In the MA group, the regular needling technique and pseudo-EA were used at Guanyuan (CV 4), Zigong (EX-CA 1), Tianshu (ST 25) and Sanyinjiao (SP 6). In the EA group, the acupoints were the same as the MA group and stimulated with EA and pseudo-MA (no manipulation applied in treatment), with disperse-dense wave, 10 Hz/50 Hz, 0.5 to 1.0 mA. In the two groups, the needles were retained for 30 min. The treatment was given once every two days, three times a week, totally for 8 consecutive weeks. The results of the menopause rating scale (MRS), the menopause-specific quality of life (MENQOL), the self-rating anxiety scale (SAS) and the self-rating depression scale (SDS), follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E) as well as adverse reactions were evaluated before treatment, in 4 and 8 weeks of treatment separately.</p><p><b>RESULTS</b>Compared with those before treatment, the scores of MRS, MENQOL, SAS and SDS were all reduced in the 4 and 8 weeks of treatment in the two groups (all<0.05). The results in 8 weeks of treatment were lower than those in 4 weeks of treatment in the two groups (all<0.05). The differen-ces were not significant statistically between the two groups (all>0.05). Compared with those before treatment, the levels of FSH and LH reduced and Eincreased after treatment in the two groups, without significant differences (all>0.05). The differences were not significant statistically between the two groups (all>0.05). The severe adverse reactions were not found in the treatment of the two groups.</p><p><b>CONCLUSIONS</b>Both manual acupuncture and electroacupuncture relieve the symptoms of depression and anxiety in menopausal syndrome,improve the living quality and do not induce apparent changes in serological sex hormones in the patients.</p>

Anti-inflammatory and analgesia effects of electroacupuncture device of point injection on rats of inflammatory pain / 中国针灸

<p><b>OBJECTIVE</b>To explore the anti-inflammatory and analgesia mechanism of electroacupuncture (EA) device of point injection (PI) on rats of inflammatory pain.</p><p><b>METHODS</b>48 Sprague Dawley (SD) rats were randomly assigned into a control group, a model group, an EA+PI group, an EA device of PI (EAPI) group, an EA group and a PI group, eight rats in each one. The rats in the control group were subcutaneously injected with 50 μL of liquid paraffin oil solvent into the dorsum of left hindpaw, while rats in the remaining groups were treated with 50 μL of complete freund's adjuvant (CFA) at identical location to induce the model of inflammatory pain. After model establishment, the rats in the EA+PI group, EAPI group, EA group and PI group were treated with EA+PI,EA device of PI, EA and PI, respectively, once every other day (the 2nd day, 4th day and 6th day). Each treatment was given for 30 min. The mechanical withdrawal threshold, thermal withdrawal threshold and foot swelling before and 1 d to 6 d after model establishment were observed; the western blotting method was applied to measure IL-1β expression in inflammatory tissue of skin.</p><p><b>RESULTS</b>After model establishment, compared with the control group, the mechanical withdrawal threshold and thermal withdrawal threshold were reduced (all<0.05) and the foot swelling was increased in the rest groups (all<0.05). After treatment, the mechanical withdrawal threshold and thermal withdrawal threshold in the EAPI group were significantly increased compared with those in the EA+PI group, EA group and PI group (all<0.05), but the foot swelling was reduced (all<0.05). The IL-1β expression in the model group was higher than that in the control group (<0.05); after treatment, the IL-1β expression in the EAPI group was lower than that in the model group, EA group and PI group (all<0.05), but no significantly different from that in the EA+PI group (>0.05).</p><p><b>CONCLUSIONS</b>The efficacy of EA device of PI on inflammatory pain is superior to EA combined with PI, EA alone and PI alone, which is suitable for further popularization and application.</p>

Rescuing Bombyx mori bidensovirus in BmN cells in vitro / 生物工程学报

Bombyx mori bidensovirus (BmBDV) has been identified as causing chronic densonucleosis in Bombyx mori specifically. The replication mechanism of BmBDV remains unknown. Its genome comprises two single stands DNA (VD1 and VD2). In order to rescue infectious virions in vitro, we obtained the total viral DNA extracted from the BmBDV-infected larvae midguts, subsequently cloned the full-length sequence of BmBDV genome fragments by PCR and constructed recombinant plasmids pMD18T-VD1 and pUC-VD2. The linear genome fragments were obtained by digesting recombinant plasmids with corresponding restriction enzymes, and then collectively transfected BmN cells by the method of liposome-embedding. We determined the replication of the virus gene by PCR with the template of demethylated total DNA extracted from the post-transfect BmN cells. Meanwhile, we collected the total proteins from the post-transfect BmN cells and the larvae midgut of feeding the post-transfect BmN cells to perform Western blotting analysis, and detected the expression of viral genes. Here we firstly confirm that infectious virions can be rescued in BmN cells by linear co-transfect method.

Effects of Total Flavonoids from Portulaca on Transforming Growth Factor β1 in Rats with Hepatic Fibrosis / 医药导报

Objective To explore the effects of total flavonoids from portulaca against liver fibrosis in rats by detecting TGF-β1 gene and protein expressions. Methods A total of 48 SD rats were randomly divided into normal control, model control, glucyrrhizin aqueous,and total flavonoids groups,with 12 rats in each group. Except those in the normal control group, rats in other groups were intraperitoneally injected with 2 mL · kg-1 · d-1 carbon tetrachloride to induce liver fibrosis. Rats in glucyrrhizin aqueous group and total flavonoids ones were intragastrically administered with 15. 75 mg · kg-1 of glycyrrhizin aqueous solution or 35. 6 mg·kg-1 of total flavonoids aqueous solution,respectively. The normal and model control groups were administered with equal volume of aqueous solution. Thirty days later,rats were sacrificed by anesthesia. Livers were obtained to detect TGF-β1 gene and protein expressions by RT-PCR and Western-Blot. Results Relative gene expression of TGF-β1 in the normal control,model control,glucyrrhizin aqueous and flavonoids groups was 0. 725±0. 130,7. 493±1. 410,3. 016±1. 240,and 2. 668±1. 150,respectively. Total flavonoids from portulaca significantly reduced the gene (P<0. 01) and protein (P<0. 01) expressions of TGF-β1 . Conclusion Efficacy of total flavonoids from portulaca in treating hepatic fibrosis may be related to decreased TGF-β1 expression in rats.

Value of brainstem auditory evoked potential in early diagnosis of hand, foot and mouth disease with nervous system damage / 中国小儿急救医学

Objective To investigate the value of brainstem auditory evoked potential (BAEP) in early diagnosis of severe hand,foot and mouth disease (HFMD) with the nervous system damage.Methods BAEP was performed in 297 cases with HFMD.The patients were divided into 4 groups by the HFMD clinical classification and their ages.Group A included the general cases who were younger than three years (n =80).Group B included the severe cases who were younger than three years(n =94).Group C included the general cases who were three years or older(n =38).Group D included the severe cases who were three years or older(n =85).The electroencephalogram (EEG) and MRI results of patients in the groups were retrospectively studied and the results were compared with that of BAEP.Results (1) The BAEP abnormal rate of group B (18/94,19.15％)was higher than that of group A (3/80,3.75％),and the BAEP abnormal rate of group D (13/85,15.29％) was higher than that of group C (1/38,2.63％) (P ＜ 0.05).(2) The EEG abnormal rate in group B was low(2/94,2.13％) and there was no case with abnormal EEG in group A.(3) The EEG abnormal rate of group D (49/85,57.65％) was higher than that of group C (6/38,15.79％) (P ＜0.05),and higher than the BAEP abnormal rate of group D.(4) The MRI abnormal rate of group B (9/94,9.57％) was higher than that of group A (1/80,1.25％) (P ＜ 0.05),and the MRI abnormal rate of group D (9/85,10.59％)was higher than that of group C (0).(5) The BAEP abnormal rate of the children with severe HFMD (31/179,17.32％) was higher than the MRI abnormal rate (18/179,10.06％) (P ＜0.05).Conclusion BAEP has clinical significance for early diagnosis of severe HFMD with nervous system damage,and can provide objective basis for the diagnosis.

Application of transcranial doppler ultrasonography in the disease of increased intracranial pressure in children / 中国小儿急救医学

The transcranial doppler ultrasonography (TCD) is a non-invasive detection methods of evaluating intracranial artery.Since the 1980s,TCD has been extensively used in various fields of clinical work.Because of its simple operation,good repeatability,and the continuous bedside observation of patients,TCD is especially suitable for severe patients.Increased intracranial pressure is one of the important reasons for the deadly disease in children,it can make the cerebral blood flow perfusion decreased,causing serious consequences,such as brain dysfunction,so intracranial pressure monitoring has important clinical significance.TCD as a noninvasive monitoring tool,can monitor the patients with increased intracranial pressure dynamically,according to the blood flow velocity,the related parameters and the wave of cerebral hemodynamics,so as to achieve the purpose of monitoring intracranial pressure change.This article focused on the TCD application progress in several common children's diseases of increased intracranial pressure.