Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

Neurotrophic receptor kinase (NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors, and tropomyosin receptor kinase (TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions. Currently, two generations TRK inhibitors have been developed. The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations. However, xDFG (TRKAG667C/A/S, homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance. Additionally, we concluded our perspectives on new challenges and future directions in this field.

Role of epithelium-derived cytokines interleukin-33, interleukin-25 and thymic stromal lymphopoietin in the pathogenesis of atopic dermatitis / 中华皮肤科杂志

Epidermal barrier defects and immune abnormalities are the main pathophysiological changes in the development of atopic dermatitis (AD) . Skin keratinocytes can release a variety of inflammatory factors and mediators under the treatment with various harmful factors. Three epithelium-derived cytokines interleukin (IL) -33, IL-25 and thymic stromal lymphopoietin are considered to be effective inducers of Th2 immune response in skin or mucosal barrier, which can activate immune cells, cause the secretion of Th2 cytokines, enhance the Th2 immune response, and participate in the occurrence and development of AD. This review focuses on the role of the above 3 epithelium-derived cytokines in the pathogenesis of AD.

Transcriptomics in atopic dermatitis / 中华皮肤科杂志

With the development of transcriptomic technologies such as gene chip technology and RNA sequencing technology, important related factors in the pathogenesis of atopic dermatitis (AD) have been gradually identified, such as different T helper (Th) cell subtypes and other immune-related cells (macrophages and Langerhans cells) ; abnormal changes in active substances such as interleukin-4, interleukin-13, fillagrin and loricrin released by immune-related cells such as Th2 cells and keratinocytes have been found to play major roles in pruritus and skin barrier damage in AD. In recent years, transcriptomic technologies have been applied to the analysis of changes in transcriptomic profiles of patients before and after treatment to evaluate patients′ condition and therapeutic effect. This review summarizes research progress in transcriptomics in AD in recent years.

Analysis of serum vitamin B levels and its correlation with social function in children with attention deficit hyperactivity disorder / 中华实用儿科临床杂志

Objective:To analyze the associations between attention deficit hyperactivity disorder (ADHD) and serum vitamin B levels in children.Methods:A total of 103 ADHD children who were diagnosed in the Department of Child and Adolescent Healthcare of Children′s Hospital of Soochow University from September 2018 to April 2019 were selected as the ADHD group, and 89 children of the same age who underwent routine physical examinations served as the healthy control group.The serum levels of vitamin B, including vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 9, and vitamin B 12, were measured by the methods of electrochemistry.Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) was applied to analyze the correlation between social function scores and vitamin B levels in ADHD children. Results:The levels of vitamin B 9[(12.55±2.22) nmol/L vs.(13.26±2.54) nmol/L] and vitamin B 12 [(278.54±32.00) ng/L vs.(288.90±31.32) ng/L] in ADHD children were significantly lower than those in healthy children( t=-2.064, -2.261, all P<0.05). No significant difference was observed in serum levels of vitamin B 1, vitamin B 2 and vitamin B 6 between the 2 groups (all P>0.05). Correlation analysis displayed that only vitamin B 12 level was significantly and negatively correlated with social function in the learning/school dimension ( r=-0.208, P=0.035), and no significant correlation was found between other vitamin B levels and social function (all P>0.05). Conclusions:The serum levels of vitamin B 9 and B 12 in ADHD children were obviously lower than those in healthy children of the same age.Serum vitamin B 12 deficiency had an influence on the social function of the learning/school in ADHD children.Attention to the monitoring and timely supplementation of vitamin B in childhood, especially vitamin B 9 and B 12, may be of positive significance in the prevention of the occurrence and development of ADHD to some extent.

Design, synthesis, and biological evaluation of Bcr-Abl PROTACs to overcome T315I mutation

Bcr-Abl threonine 315 to isoleucine 315 (T315I) gatekeeper mutation induced drug resistance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia (CML). Chemical degradation of Bcr-Abl

Biocatalysis of formaldehyde to L-xylose / 生物工程学报

It is of great significance to use biosynthesis to transform the inorganic substance formaldehyde into organic sugars. Most important in this process was to find a suitable catalyst combination to achieve the dimerization of formaldehyde. In a recent report, an engineered glycolaldehyde synthase was reported to catalyze this reaction. It could be combined with engineered D-fructose-6-phosphate aldolase, a "one-pot enzyme" method, to synthesize L-xylose using formaldehyde and the conversion rate could reach up to 64%. This process also provides a reference for the synthesis of other sugars. With the increasing consumption of non-renewable resources, it was of great significance to convert formaldehyde into sugar by biosynthesis.

Enzymatic synthesis of xylulose from formaldehyde / 生物工程学报

Xylulose as a metabolic intermediate is the precursor of rare sugars, and its unique pattern of biological activity plays an important role in the fields of food, health, medicine and so on. The aim of this study was to design a new pathway for xylulose synthesis from formaldehyde, which is one of the most simple and basic organic substrate. The pathway was comprised of 3 steps: (1) formaldehyde was converted to glycolaldehyde by benzoylformate decarboxylase mutant BFD-M3 (from Pseudomonas putida); (2) formaldehyde and glycolaldehyde were converted to dihydroxyacetone by BFD-M3 as well; (3) glycolaldehyde and dihydroxyacetone were converted to xylulose by transaldolase mutant TalB-F178Y (from Escherichia coli). By adding formaldehyde (5 g/L), BFD-M3 and TalB-F178Y in one pot, xylulose was produced at a conversion rate of 0.4%. Through optimizing the concentration of formaldehyde, the conversion rate of xylulose was increased to 4.6% (20 g/L formaldehyde), which is 11.5 folds higher than the initial value. In order to further improve the xylulose conversion rate, we employed Scaffold Self-Assembly technique to co-immobilize BFD-M3 and TalB-F178Y. Finally, the xylulose conversion rate reached 14.02%. This study provides a new scheme for the biosynthesis of rare sugars.

Analysis of pregnancy outcome of pregnant women with Eisenmenger syndrome / 中国医师进修杂志

Objective To explore the maternal and fetal outcomes and treatment strategies of pregnant women with Eisenmenger syndrome. Methods Datas of pregnant women with Eisenmenger syndrome from September 2009 to March 2017 were analyzed retrospectively. Results Three patients did not accept regular prenatal care. Two patients suffered from eclampsism. Two patients suffered from arrhythmia. One patient suffered from pulmonary infection. Four patients suffered from congestive heart failure. One patient had no complications. One patient died from pulmonary hypertension crisis within 72 h of postpartum. Four of the seven perinatal infants died from premature complications. Conclusions Patients with Eisenmenger syndrome have tendency to become heart failure and so are unsuitable for pregnancy. Once paitents have pregnancy, high mortality exists. So progestation counseling and management should be strengthened. Early pregnancy should be terminated. In mid or late trimester of pregnancy, regular prenatal care should be needed to help mothers and fetuses get better outcomes.

Analysis of pregnancy outcome of pregnant women with Eisenmenger syndrome / 中国医师进修杂志

Objective To explore the maternal and fetal outcomes and treatment strategies of pregnant women with Eisenmenger syndrome. Methods Datas of pregnant women with Eisenmenger syndrome from September 2009 to March 2017 were analyzed retrospectively. Results Three patients did not accept regular prenatal care. Two patients suffered from eclampsism. Two patients suffered from arrhythmia. One patient suffered from pulmonary infection. Four patients suffered from congestive heart failure. One patient had no complications. One patient died from pulmonary hypertension crisis within 72 h of postpartum. Four of the seven perinatal infants died from premature complications. Conclusions Patients with Eisenmenger syndrome have tendency to become heart failure and so are unsuitable for pregnancy. Once paitents have pregnancy, high mortality exists. So progestation counseling and management should be strengthened. Early pregnancy should be terminated. In mid or late trimester of pregnancy, regular prenatal care should be needed to help mothers and fetuses get better outcomes.

Development of tumor targeting PHBHHx nanoparticles by PhaP mediated immobilization of EGFR-targeting peptide / 生物工程学报

PHA granule binding protein phasin (PhaP) has a high affinity for hydrophobic materials and can bind to hydrophobic polymers via strong hydrophobic interaction. In this study, an EGFR-targeting peptide (ETP) was fused with PhaP and the fusion protein ETP-PhaP was produced in recombinant Escherichia coli BL21 (DE3) (pPI-ETP-P) and then purified by Ni affinity purification. The tumor targeting PHBHHx nanoparticles were developed based on PhaP mediated ETP immobilization and the cellular uptake of the ETP-PhaP modified PHBHHx NPs and none modified PHBHHx NPs by cervical cancer cell lines SiHa (EGFR over expressed) and CaSKi (EGFR low expressed) were analyzed. The purified ETP-PhaP could be adsorbed onto the hydrophobic surface of PHBHHx NPs. The ETP-PhaP modified PHBHHx NPs could target to EGFR over expressed cervical cancer cells SiHa more efficiently than to the EGFR low expressed CaSKi cells. These results demonstrated the advantage in effectiveness and convenience of PhaP mediated ETP adsorption on PHBHHx nanoparticles, providing a novel strategy for hydrophobic nanocarrier surface modification.

The value of renal CT arteriography in the pre-operation evaluation of patients with renal tumors / 中国医师杂志

Objective To investigate the value of renal CT arteriography in the preoperation evaluation of patients with renal tumors.Methods From Jan 2007 to June 2012,372 patients with renal tumors took renal CT arteriography (with Philips Brilliance 16) to evaluate the variations of their renal arteries.We executed plain scan first,then artery phase,venous phase scan and delaying scan by turns after injections of Omnipaque.All images were delivered to imaging workstation and reconstructed to 3D views of renal arteries to supply imageological supports for surgeons.Results Tumors in solitary kidneys were detected in 21 patients,and masses in both kindneys were detected in 4 cases.We collected data of 376 kidneys finally.We found premature branching renal arteries on 46 kidneys (12.2％) and accessory renal arteries on 74 kidneys (19.7％).Double accessory renal arteries were seen on 10 kidneys (2.7％),and there were 84 accessory renal arteries in summary.7 accessory renal arteries (7.2％) came from arteria phrenica and 77 (91.7％) came from abdominal aorta (x2 =65.68,P ＜ 0.01).We found the regions where the accessory renal arteries entered kidneys:65.5％ (55/84) in upper poles,19.0％ (16/84) in central regions and 15.5％ (13/84)in inferior poles.Routine CT scans found 44 variations of renal arteries in 218 cases who underwent surgeries,and then renal CT arteriography found 63 variations in the same cases (20.2％ vs 28.9％,x2 =4.47,P ＜ 0.05).Finally,surgeons found 60 variations of renal artries in operations in the 63 cases with variations found by renal CT arteriography before surgeries.Conclusions There is limitations of routine CT scan (plain scan and with contrast medium) in detection of renal artery variations.Renal CT arteriography can supply reliable supports for establishment of surgical plans for renal tumors.

Biocompatibility of surface modified PHBHHx with rat embryonic neural stem cells / 生物工程学报

To study the attachment, proliferation and differentiation of neural stem cells (NSCs) on surface modified PHBHHx films and to establish the theory of PHBHHx application in NSCs-based brain tissue engineering. PHBHHx film was fabricated by a solution-casting method, and the morphology of the film was observed under scanning electron microscopy(SEM). The films were treated by NaOH or lipase, then the surface hydrophilic property was characterized using water contact angle measurement. NSCs were isolated from the cerebral cortex of rat embryos on embryonic day 14.5, and cultured on surface treated PHBHHx films. The morphology of NSCs attached on the film was visualized under SEM, and the survival and differentiation of NSCs were observed through immunocytochemical staining. Compared with the untreated PHBHHx films, the water contact angle of NaOH or lipase treated PHBHHx films decreased dramatically, and the number of NSCs attached significantly increased. NSCs survived well on treated PHBHHx films and differentiated into neurons and glial cells. The amelioration of hydrophilic property of PHBHHx film improved its biocompatibility with NSCs. PHBHHx can serve as a novel CNS tissue engineering biomaterial applied for NSCs transplantation, brain repairing and regeneration.

Value of a diagnostic criterion of capsule endoscopy for small bowel Crohn's disease / 中华消化内镜杂志

Objective To investigate the value of a diagnostic criterion of capsule endoscopy (CE)for small bowel Crohn's disease (CD). Methods The clinical data of 50 patients with suspected CD who underwent CE from March 2003 to October 2008 were analyzed retrospectively. Diagnoses were made based on a criterion proposed by De Bona et al. Patients were grouped and followed up for 1 to 5 years. Results A total of 50 patients were enrolled and divided into 3 groups according to the results of CE. Group A included 25 patients as having small intestine CD on CE, in which 3 received surgery and was confirmed by pathology, and the other 22 got improved after treatments for CD. Group B was comprised of 15 patients who were clinically diagnosed as small intestinal CD and received experimental treatments, in which 13 patients improved and 2 others received surgery and were confirmed to be small intestine diverticula. Patients in group C ( n = 10) were diagnosed as non-specific enteritis and received medication of Bifico and metronidazole for at least 3 months. All patients were followed up for 1 to 5 years and no recurrence was observed. Conclusion This diagnostic criterion of CE for small bowel CD enables early diagnosis of the disease.

Clinical features of Crohn's disease at different location / 中华消化内镜杂志

Objective To study the clinical features of Crohn's disease(CD)at different location,I.e.small intestine.colon and ileocolon,to facilitate the knowledge of the disease.Methods Data of 103 patients,hospitalized to our department from 2000 to January 2008,were retrospectively analyzed,including general status,clinical manifestations,laboratory findings and pathological changes.Results The cohort included 70 males and 33 females,with the age when the diagnosis was confirmed ranging from 12 to 70,with a peak at 20-29 yr.The location of the main lesion was at small bowel(L1)in 39(38%),at colon (L2)in 16(16%)and at ileum-colon(L3)48(46%).There was no significant difference between each group,regarding the age of onset or the when the diagnosis was confirmed.The incidence of intestinal obstruction was higher in L1 patients than that in L3(P＜0.05).In group L1,12(30.8%)were diagnosed by capsule endoscopy,and 17(44%)were confirmed by colonoscopy.Diagnostic rates of L2 and L3 with reference to clinical manifestations.combined with colonoscopy and pathology were 87.5%and 83.3%,respectivelv.In this cohort,there were 23(22.3%)mild cases,58(56.3%)moderate cases and 22 (21.4%)severe cases,according to simplified CD activity index(CDAI).The rate of severe case in L3 was 59.0%(13/48),which was significantly higher than that in L1(P＜0.05).Conclusion In patients with CD,L1 is characterized by delayed diagnosis and need of emergent surgery,while L3 is featured with extensive involvement.severe complications and systemic manifestations.Severe case is common in 13 patient,capsule endoscopy and Colonoscopy are important in early detection of the disease to decrease operation rate and delay the time of first operation.

Clinical analysis of 33 cases of primary gastrointestinal malignant lymphoma / 中华消化内镜杂志

Objective To investigate the early diagnosis and treatment of primary gastrointestinal malignant lymphoma( PGIML). Methods The clinical materials of 33 cases with PGIML from 1997 to 2005 were retrospectively studied. Results The diagnosis rate of gastroenteroscopy was 44. 4% . The most common immune phenotype was B-cell lineage (90. 9% ). Of the 33 PGIML patients, 30 were treated with operation, 2 with H. poli elimination and 1 gave up treatment. Among the operation cases and operation plus chemotherapy cases 19/21 cases (90. 5% )and 6/9 cases (66. 7% ) survived more than 2 years respectively, the other 6 cases died. Conclusion It is hard to diagnose PGIML in early stage. The effectiveness of surgery on treating PGIML should be further confirmed by profound prospective randomized trials.