Cancer, also known as malignant tumor, is the second largest disease after heart disease, which is characterized by genomic instability and mutagenicity. Ataxia telangiectasia and RAD3-related kinase (ATR) are members of phosphatidylinositol 3-kinase (PIKK) family, belonging to serine/threonine kinase, one of the key kinases in DNA damage response (DDR) and DNA repair pathway. This paper reviews the latest progress in the ATR inhibitor field including mechanism of action (MOA), therapeutic applications, and the combination therapy from the perspective of medicinal chemistry. It also discusses the possible challenges and future directions of developing ATR inhibitor antitumor drugs, which could provide the scientists in this field the convenience for access the information and application guidance for clinical studies.

As one of the major sources of infection, viruses could infect all organisms including bacteria, plants, animals, and humans. Infectious diseases caused by viruses pose a great threat and damage to human health and economic activities all over the world. Adaptor-associated protein kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and a specific key kinase regulating the phosphorylation of AP-2 protein μ2 subunit T156. In the past, AAK1 has been regarded as a feasible biological target for the treatment of nerve pain. Recently, scientists have found that inhibiting AAK1 can regulate endocytosis and inhibit virus invasion into cells. Therefore, AAK1 could be the potential target of anti-virus therapy. This paper reviews the research progress of small molecule AAK1 inhibitors in the field of antiviral, analyzes the future research directions and challenges, and provides new ideas for the development of antiviral drugs targeting AAK1.

OBJECTIVETo develop a human ovarian carcinoma SKOV3 model in severe combined immunodeficiency (SCID) mouse and to study its biologic characteristics.

METHODSHuman ovarian carcinoma SKOV3 cells were injected intraperitoneally into female SCID mouse to establish a transplantation model of human ovarian carcinoma. The biological characteristics, metastasis and morphology of transplanted tumors were studied.

RESULTAll tumors grew progressively with no sign of regression. The tumor cells spread around the peritoneal cavity and mainly on the diaphragm, mesentery, peritoneum and around the liver, which was confirmed by histopathology. The morphology, growth pattern and CA125 secretion of primary culture of transplanted cells remained as same as those of ovarian carcinoma cell line SKOV3.

CONCLUSIONAn intraperitoneal transplantation model of human ovarian carcinoma SKOV3 in SCID mice has been developed successfully, which can simulate the biological behavior of peritoneal metastasis of human ovarian carcinoma.

Animals ; Disease Models, Animal ; Female ; Humans ; Mice ; Mice, SCID ; Neoplasm Transplantation ; Ovarian Neoplasms ; pathology ; ultrastructure ; Peritoneal Neoplasms ; secondary ; Transplantation, Heterologous

OBJECTIVETo study the effect of biological protective dressing made from porcine peritoneum in covering wounds with microskin grafts.

METHODSTwenty New Zealand rabbits were divided into ten couples according to the random number table. Rabbits in each couple underwent surgery at the same time. A piece of full-thickness skin of 5 cm in diameter was removed symmetrically from the left and right sides of the back of each rabbit, thus forming two wounds with full-thickness skin defect. One fifth of one piece of skin of one rabbit was cut into tiny pieces of 0.2-0.5 mm in size (microskin). Then the microskin pieces were spread on the two wounds of the donor rabbit with the microskin/wound area ratio 1:10. The two wounds of each rabbit covered with microskin were divided into two groups according to the random number table. One wound was covered with biological protective dressing prepared with porcine peritoneum as experiment group, and the other was covered with the rest allograft in full size obtained from the other rabbit of each couple as control group. The general condition of wound was observed at post operation week (POW) 1-4. Wound healing rate was calculated at POW 3 and 4. Wound healing time was recorded. Specimens were harvested from wounds for histological observation at POW 1-4. Data were processed with paired t test.

RESULTS(1) At POW 1, the biological protective dressings were found to attach firmly to the wounds in experiment group without obvious inflammatory response; the allografts survived well on the wounds in control group. At POW 2, the coverings attached well to the wounds of both groups, but became drier and darker as compared with those at POW 1. At POW 3, some wounds of the two groups healed when the coverings desiccated and separated. At POW 4, all the wounds of both groups healed without obvious difference in appearance. (2) The wound healing rates of the experiment and control groups were respectively (92.8 ± 6.2)% and (91.3 ± 7.3)% (t = 0.54, P > 0.05) at POW 3 and (98.1 ± 2.3)% and (97.0 ± 4.6)% (t = 0.38, P > 0.05) at POW 4. (3) The wound healing time was (25.0 ± 3.9) d in experiment group and (24.8 ± 2.3) d in control group. The difference between them was not statistically significant (t = 0.82, P > 0.05). (4) Histological observation showed that wounds of the two groups were all infiltrated by inflammatory cells, and new blood vessels were observed at POW 1 and 2. The survived microskin proliferated under the coverings. At POW 3 and 4, the coverings on the wounds of two groups were gradually degenerated and became necrotic and separated from the wound beds, while the wounds underneath were re-epithelialized.

CONCLUSIONSThe effect of biological protective dressing in covering wounds grafted with microskin is as good as that of the allograft, as they both help the auto-microskin proliferate and repair the wound. It could be considered to be new biological material for clinical application.

Animals ; Biocompatible Materials ; Biological Dressings ; Male ; Peritoneum ; Rabbits ; Skin Transplantation ; methods ; Swine ; Wound Healing

OBJECTIVETo investigate the relevant applied technique and clinical value of endoscope-assisted repair of zygomatic arch fracture via a short hidden preauricular incision.

METHODSThere were 7 cases of unilateral zygomatic arch fracture and 10 cases of unilateral zygomatic fracture. Reduction and fixation of zygomatic arch in all cases were performed via a short preauricular incision assisted by endoscope.

RESULTSSymmetric malar was achieved in all cases after operation. There was no difficulty in opening mouth, no chewing problems or severe complications.

CONCLUSIONSEndoscope-assisted repair of zygomatic arch fracture via a short hidden preauricular incision can be an alternative operation for zygomatic arch fracture.

Adult ; Endoscopes ; Female ; Fracture Fixation, Internal ; methods ; Humans ; Male ; Zygoma ; injuries ; surgery ; Zygomatic Fractures ; surgery

BACKGROUNDTo understand the characterization of genome of a strain of avian influenza A H9N2 virus repeatedly isolated from a child with influenza illness. Thereafter to reveal the origin of this H9N2 virus.

METHODSViruses were passed in embryonated hen eggs and virion RNA was extracted from allantoic fluid and reverse transcribed to synthesize cDNA. cDNA was amplified by PCR and the PCR product was purified with a purification kit. Afterwards RNA sequence analysis was performed by dideoxynucleotide chain termination and a cloning method. Finally, phylogenetic analysis of the sequencing data was performed with MegAlign (Version 1.03) and Editseg (Version 3.69) softwares.

RESULTSGenome of A/Guangzhou/333/99 (H9N2) virus was closely related to avian influenza A H9N2 virus, but obvious difference from that of A/Duck/Hong Kong/Y439/97(H9N2) virus, as well as its genome did not include any RNA segment derived from human influenza A virus. However, the genes encoding the HA,NA,NP and NS proteins of A/Guangzhou/333/99 virus were derived from those of G9 lineage virus, the rest genes encoding the M and three polymerase (PB2,PB1 and PA) proteins were derived from G1 lineage strain.

CONCLUSIONSA/Guangzhou/333/99 virus was a reassortant derived from reassortment betweenG9 and G1 lineages of avian influenzaA(H9N2) viruses. Therefore, the most possibility is that it is derived from avian influenza A virus directly. The results do not only demonstrate that avian influenza A (H9N2) virus could infect men, but also firstly prove that the genetic reassortment could be occurred between different genetic lineages of avian influenza A (H9N2) viruses in the nature.

Animals ; Base Sequence ; Chick Embryo ; Child ; Genome, Viral ; Humans ; Influenza A Virus, H9N2 Subtype ; Influenza A virus ; genetics ; Influenza, Human ; virology ; Phylogeny

BACKGROUNDCathepsin B plays an important role in cell cycle, extracellular matrix changes and cutaneous tumorigenesis: whether it plays a role in photoaged skin remains unknown. This study aimed to investigate the role of cathepsin B in skin photoaging in vivo and in vitro.

METHODSThe expressions of cathepsin B were compared with immunohistochemical methods in solar exposed skin and solar protected skin of six healthy Chinese volunteers. The mRNA and protein expression of cathepsin B in ultraviolet light A (UVA) induced premature senescence fibroblasts in vitro were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting technique.

RESULTSDecreased expression of cathepsin B was observed in photoaged skin compared with that of the solar protected skin. In the UVA induced, premature senescence fibroblasts, a lower expression of cathepsin B was detected by Western blotting and a decreased synthesis of cathepsin B mRNA in the same cells was revealed by real-time RT-PCR.

CONCLUSIONSThe results demonstrated a significant negative correlation between skin photoaging and cathepsin B in vitro and in vivo. We propose that cathepsin B, besides matrix metalloproteinases and antioxidant enzymes, is involved in the process of skin photoaging in that it contributes to extracellular matrix remodelling and is a dominant protease in cellular apoptosis and senescence.

Blotting, Western ; Cathepsin B ; analysis ; genetics ; physiology ; Female ; Fibroblasts ; radiation effects ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Skin ; radiation effects ; Skin Aging ; Ultraviolet Rays ; beta-Galactosidase ; analysis

·AIM:To explore the effectiveness of a new non-inverted pedicle internal limiting membrane ( ILM ) flap transposition technique in the treatment of large macular holes (MH). ·METHODS: This was a prospective pilot study which included 9 patients with 10 eyes in Jiangsu Province People's Hospital from December 2016 to February 2017. All patients was diagnosed with large MH (size >400μ m) by the spectra- domain optical coherence tomography (SD-OCT) and underwent the non-inverted pedicle ILM flap transposition surgery. Best-corrected visual acuity (BCVA), SD-OCT images, and MP-1 microperimetry tests were performed pre-operation, 1d, 1wk, 1, 3, and 6mo post-operation. ·RESULTS:The macular hole closure rate after 6mo was 100%. The averaged BCVA improved from 1. 19 ± 0. 54 (LogMAR) pre-operation to 0.70 ± 0.50 (LogMAR) post-operation (P=0.005). The mean retinal sensitivity within 8° and 2° improved from 3.14±4.52dB to 8.91±5.53dB(P=0.008), and 1.46 ± 2.94dB to 6.33 ± 4.90dB (P=0.008) respectively. Preoperative unstable fixation in seven eyes resolved at the last postoperative follow-up.·CONCLUSION: Our non-inverted pedicle internal ILM flap transposition technique shows effectiveness in the treatment of large macular holes with high MH closure rate and improving visual function.

AIM:To investigate the effect of ozone bath on the pathological changes and the expression of cyto-kines,platelet-derived growth factor (PDGF), transforming growth factor-β3(TGF-β3), and tumor necrosis factor-α (TNF-α),in the wounds of deep second-degree burns in rats. METHODS:Male clean-grade SD rats(n=80) were ran-domly divided into 2 groups, ozone bath group and routine dressing group (control group), with 40 rats in each group. Deep second-degree burn wound was established on the back of the rats,and then the examinations were conducted at 3 d, 7 d,14 d and 21 d after burn. For the routine dressing group,the wound was cleaned by normal saline and covered with io-dophor vaseline gauze every 2 d. For the ozone bath group,before the dressing,the rats were put into the clean foam box to accept ozone fumigation for 20 min(50 mg/L),and then accepted dressing change as the same as that in control group every 2 d. At each time point,the tissue specimens from these rat wounds(at wound center) were taken. The rats in ozone bath group received cleaning by saline cotton and then the ozone bath fumigation, while the rats in control group only re-ceived cleaning by saline. After that,the tissue specimens were taken again for HE staining,immunohistochemical staining and semiquantitative observation combined with image data analysis. The concentrations of the cytokines PDGF, TGF-β3 and TNF-α in the wound were measured by double-antibody sandwich ELISA. RESULTS:In ozone bath group, the wounds were smooth with clear edge and slight inflammatory reaction,swelling and exudation were weaker,and the wound healing rate was higher than that in control group with significant difference. Under microscopic observation with HE stai-ning,slighter inflammatory reaction in ozone bath group was observed than that in control group at each time point,and the numbers of fresh capillaries,fibroblasts and epithelial cells were significantly larger than those in control group. The ex-pression levels of PDGF and TGF-β3in the wound tissue homogenate in ozone bath group were higher,and the expression level of TNF-α was significantly lower than those in control group at each time point with significant difference. CONCLU-SION:The ozone bath therapy improves the local pathological changes and promotes the expression of cytokines PDGF and TGF-β3,which are associated with wound healing,as well as reduces the expression of inflammatory mediator TNF-α in the rats with deep second-degree burns,thus promoting the wound healing and anti-inflammatory responses.

OBJECTIVETo explore the correlation of c-met protein with the clinical staging and cell differentiation of esophageal squamous cell carcinoma (ESCC).

METHODSA total of 100 patients with ESCC were enrolled were examined for expression of c-met protein using immunohistochemistry, and the patients in negative and positive c-met expression groups were compared for clinicopathological characteristics and overall survival.

RESULTSs The 100 ESCC patients included 67 male and 33 female patients with a median age of 59 years; 49 of the patients were negative and 51 were positive for c-met expression. Positive c-met expression was significantly correlated with advanced TMN stages and lower tumor differentiation. Kaplan-Meier survival curve showed that the median survival time of c-met-positive patients was significantly reduced compared with that of c-met-negative patients (30.9 vs 48.2 months, P<0.05). COX regression analysis showed that c-met was a independent risk factor for the overall survival of the patients (HR: 2.34, 95% CI: 1.63-4.54, P<0.05).

CONCLUSIONA positive expression of c-met protein is significantly correlated with an advanced TMN stage, lower tumor differentiation and a poor prognosis, and may serve as a indicator for predicting the prognosis of ESCC.

Carcinoma, Squamous Cell ; diagnosis ; metabolism ; Esophageal Neoplasms ; diagnosis ; metabolism ; Female ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Proto-Oncogene Proteins c-met ; metabolism ; Risk Factors