The anti-apoptotic members of Bcl-2 family proteins, Bcl-2 and Mcl-1, are considered therapeutic targets of various cancers. In this article, we developed four hydrophobic tag (HyT)-based protein degraders of Bcl-2/Mcl-1, based on a Bcl-2/Mcl-1 dual inhibitor S1-6, and tested their capability in Bcl-2/Mcl-1 degradation and apoptotic induction in MCF-7 cells. Interestingly, different linkers in the HyT degraders led to selective Bcl-2/Mcl-1 degradation, though the degraders S1-D1-S1-D4 maintained the pan-Bcl-2 family binding capacity. Among them, S1-D2 and S1-D4, two compounds bearing a hydrophobic linker or a PEG linker, were observed to potently and selectively induce the ubiquitination and proteasomal degradation of Bcl-2 and Mcl-1 in living cells, with a degradation rate of more than 80% or 60%, respectively. Moreover, the HyT-based degraders showed increased lethality of cancer cells compared to the parent inhibitor S1-6, demonstrating that the advantage of degraders to the occupancy-based inhibitors.

BACKGROUND: The association of genetic variation in the IRAK-1 gene with sepsis outcome has been proved. However, few studies have addressed the impact of the IRAK-4 gene variants on sepsis risk. This study aimed to determine whether the polymorphisms in the IRAK-4 gene are associated with susceptibility to and prognosis of severe sepsis in the Chinese Han ethnic population.METHODS: In this case-control study, 192 patients with severe sepsis hospitalized in the emergency department of Zhongshan Hospital from February 2006 to December 2009 and 192 healthy volunteers were enrolled. Exclusion criteria included metastatic tumors, autoimmune diseases, AIDS or treatment with immunosuppressive drugs. This study was approved by the ethical committee of Zhongshan Hospital, Fudan University. Sepsis patients were divided into a survival group (n=124) and a non-survival group (n=68) according to the 30-day mortality. Primer 3 software was used to design PCR and sequencing primers. Genomic DNA was extracted from peripheral blood mononuclear cells. Seven tagSNPs in IRAK-4 were selected according to the data of the Chinese Han population in Beijing from the Hapmap project and genotyped by direct sequencing. The chi-square test was used to evaluate the differences in genotype and allele frequencies between the two groups.RESULTS: The distributions of all tagSNPs were consistent with Hardy-Weinberg equilibrium. The allele and genotype frequencies of rs4251545 (G/A) were significantly different between the severe sepsis and healthy control groups (P=0.015, P=0.035, respectively). Carriers of the rs4251545A had a higher risk for severe sepsis compared with carriers of the rs4251545G (OR=1.69, 95％ CI: 1.10-2.58). The allele and genotype frequencies of all SNPs were not significantly different between the survival group and non-survival group.CONCLUSION: These findings indicate that the variants in IRAK-4 are significantly associated with susceptibility to severe sepsis in the Chinese Han ethnic population.

OBJECTIVETo explore a method of isolation, culture and chondrogenic phenotype differentiation of mesenchymal stem cell (MSCs) from the bone marrow of rats in vitro and to offer experimental reference for the resources of seeding cells in cartilage tissue engineering.

METHODSMSCs were isolated from bone marrow and purified by density gradient centrifuge and cultured in vitro. The MSC adherence formed and those in passage 3 were chosen to induce into chondrogenic differentiation. After 7, 14, 21 days, immunohistochemical techique was applied to detect the expression of collagen type II. The differentiated cells were implanted on the CPP/PLLA composites. After the cell-scaffold complex was cultured in vitro for one week, the ultrastructure of the scaffold was observed with scanning electron microscopy.

RESULTSThe differentiated cells changed from a spindle-like fibroblastic appearance to a polygonal shape, the capability of proliferation was down markedly. Immunohistochemical staining of collagen II were positive for the pass age, especially in the 21st days. Induced MSCs were well adherent to the scaffold composites and the cells were embedded by the cell-matrix.

CONCLUSIONUnder the induced medium, MSCs can differentiate into chondrogenic phenotype and secrete specificity matrix of cartilage in vitro. MSCs can likely be served as optimal cell source for cartilage tissue engineering.

Animals ; Bone Marrow Cells ; cytology ; physiology ; Cell Differentiation ; Cell Separation ; Chondrocytes ; cytology ; physiology ; Chondrogenesis ; Female ; Male ; Mesenchymal Stromal Cells ; cytology ; physiology ; Rabbits ; Tissue Engineering ; Tissue Scaffolds

OBJECTIVETo summarize the oncological and functional results of patients with fibrous dysplasia in the proximal femur and explore its clinical effect.

METHODSFrom Apr. 2007 to Jan. 2009, 15 patients with fibrous dysplasia in proximal femur were treated. There were 9 males and 6 females, ranging in age from 16 to 32 years with an average of 25 years. The course of disease was from 2 months to 16 years with an average of 2 years. Among them, 12 cases were unilateral affection and 3 cases were hibateral affections; 12 cases were one bone and 3 cases more than two bones. The collodiaphyseal angles of 2 cases with coxa adducta was 80 degrees and 100 degrees respectively; and femur lengths were shorter than opposite side (5 cm and 3 cm, respectively). The curettage and allogenous and/or autogenous bone-grafting combined with internal fixation were performed in all patients and valgus osteotomies was performed in 2 case with shepherd's crook deformity.

RESULTSAll patients were followed up from 12 to 32 months. Two cases with shepherd's crook deformity, the collodiaphyseal angles recovered after surgery, the relative length of femur was increased 4 cm and 3 cm respectively and they can walk with stick at 4 months after operation. No found recurrence and loosening of internal fixation. Bone graft was absorbed at 3 months and bone healing at 8-12 months after operation. The pain vanished and functions were normal.

CONCLUSIONIt is an effective method to treat fibrous dysplasia in proximal femur with curettage and bone-grafting combined with internal fixation. Corrective osteotomy and internal fixation with a dynamic hip screw is a good and effective method in treating severe symptomatic shepherd's crook deformity.

Adolescent ; Adult ; Bone Transplantation ; Female ; Femur ; surgery ; Fibrous Dysplasia of Bone ; surgery ; Humans ; Male

The aim of the study was to look for the chemical constituents of the herb of Lysimachia foenum-graecum. The herb of Lysimachia foenum-graecum was extracted with 70% EtOH. The isolation and purification was performed with a combination of multi-column chromatography and the structure was determined by spectral analysis. The flavonoid compound was obtained and elucidated as kaempferol-7-O(4"-(E)-p-coumaroyl-)-alpha-L-rhmanopyranosyl)-3-O-beta-D-glucopyranosyl (1-->4)-alpha-L-rhmanopyranosyl (1-->2)-beta-D-glucopyranoside. It is a new flavonoid compound.
Flavonoids ; chemistry ; isolation & purification ; Glucosides ; chemistry ; isolation & purification ; Molecular Conformation ; Molecular Structure ; Plant Components, Aerial ; chemistry ; Plants, Medicinal ; chemistry ; Primulaceae ; chemistry

OBJECTIVETo describe the incidence and mortality rates of esophageal cancer from 1974-2002 in Cixian county of Hebei province. Basic information on comparative geographical, epidemiological, and clinical research was collected.

METHODSIn early 1970s, cancer registry system in Cixian was established, collecting information on all the esophageal cancer cases in Cixian. Data was checked manually, then computerized, coded and analyzed using the software--SPSS 11.5.

RESULTSFrom 1974 to 2002, there were 18 471 esophageal cancer cases in Cixian, with 11 068 males and 7403 females, respectively. The age standardized incidence rate (ASR) for males was 208.77 per 100,000, while 120.47 per 100,000 for females. The trend of incidence rate of esophageal cancer had decreased during the 29 years from 1974 to 2002 (trend chi(2) = 19.94, P < 0.001). From 25 years of age onward, the incidence rates of the lower age groups declined with the increase of age. As for geographic distribution, the incidence rate in mountainous areas and hilly areas showed a significant declining trend in mountainous areas, chi(2) = 195.00, P < 0.001; hilly areas, chi(2) = 46.08, P < 0.001. The esophageal cancer incidence in plain areas remained steady, but had a slight increase in recent years. From 1969 to 2002, there were 18,736 cases died of esophageal cancer with 11 598 males and 7138 females. The ASR for male was 127.17 per 100,000 and 101.57 per 100,000 for female. Compared with the year 1969, the mortality rate of esophageal cancer in 2002 had a 37.96% decline. The proportion of esophageal cancer among malignant tumors in different decades decreased significantly.

CONCLUSIONThe trend of the incidence rate of esophageal cancer had been decreasing for the last 29 years. The incidence rate in mountainous areas and hilly areas showed a declining trend while in the plain areas it remained steady but having slight increase in the recent years. The mortality rate of esophageal cancer had a significant decrease from 1969 to 2002.

Adult ; Age Factors ; China ; epidemiology ; Esophageal Neoplasms ; epidemiology ; mortality ; Female ; Humans ; Incidence ; Male ; Registries ; Software

OBJECTIVETo assess the efficacy and safety of implantation of multiple drug-eluting stents.

METHODSA retrospective study of 151 cases was conducted, including 34 with implantation of at least 3 drug-eluting stents in the coronary artery (MS group), 53 with implantation of two stents (TS group), and 64 with a single stent (OS group). The incidence of major adverse cardiovascular event (MACE) and restenosis was evaluated.

RESULTSNo significant difference was found between the 3 groups in the incidence of MACE or in the stent thrombosis rate 30 days after the implantation. Follow-up of the patients for 6 months still showed comparable restenosis rate and MACE incidence between the 3 groups.

CONCLUSIONImplantation of multiple drug-eluting stents does not increase the risk of restenosis or MACE, and has comparable safety and efficacy with implantation of single and two stents.

Angioplasty, Balloon, Coronary ; adverse effects ; methods ; Coronary Artery Disease ; therapy ; Coronary Restenosis ; diagnosis ; etiology ; Drug-Eluting Stents ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome

OBJECTIVETo detect the levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in aqueous humor of patients with active choroidal neovascularization (CNV).

METHODSAqueous humor samples were obtained from 32 patients with active CNV. The concentrations of VEGF and PEDF in aqueous humor were measured by enzyme linked immunosorbent assay (ELISA) for quantitative analysis. VEGF and PEDF in 10 samples of aqueous humor from patients with cataract were also detected by the same methods as control.

RESULTThe mean VEGF and PEDF concentrations in aqueous humor of active CNV patients were higher than those in the control group (P=0.000).

CONCLUSIONThe patients with active CNV exhibit significantly higher VEGF and PEDF levels than those in control, indicating that VEGF along with PEDF may modulate the formation of CNV.

Adult ; Aged ; Aged, 80 and over ; Aqueous Humor ; chemistry ; Choroidal Neovascularization ; metabolism ; Eye Proteins ; analysis ; Female ; Humans ; Male ; Middle Aged ; Nerve Growth Factors ; analysis ; Serpins ; analysis ; Vascular Endothelial Growth Factor A ; analysis

BACKGROUND: The occurrence and development of osteoporosis are shown to be directly related to the inflammatory response induced by immune dysfunction. OBJECTIVE: To summarize the mechanisms of osteoclast differentiation and formation at cellular and molecular levels, as well as the underlying mechanisms of several kinds of medical herbs against osteoporosis, thus paving ways for finding more effective and safe herbs for anti-osteoporosis.METHODS: PubMed database was retrieved using the English keywords of (osteoporosis OR bone loss) AND lipopolysaccharide AND bone resorption", and WanFang database was searched with the Chinese keywords of "osteoarthritis, receptor activator of nuclear factor-κB ligand, lipopolysaccharide,Dendrobium moniliforme,Portulaca oleracea,Ampelopsis sinica,Schizonepeta".The literatures addressing osteoporosis, inflammation and herbal medicine were screened, and those using lipopolysaccharide-induced mouse models were included. Finally, four eligible literatures were enrolled for review. RESULTS AND CONCLUSION:In vivo experiments,CT images and pathological sections of the cancellous bone in the mouse distal femur show that Dendrobium moniliforme,Purslane oleracea,Ampelopsis sinica,and Schizonepeta exert inhibitory effects on lipopolysaccharide-induced osteoporosis.In vitro experiments reveal that these four kinds of herbs fight against osteoporosis by inhibiting osteoclast differentiation and further reducing bone resorption.

Formaldehyde is one of the simplest organic small molecules containing C, H and O elements in the early stage of earth's evolution; however, it has been found to be existed in every eukaryotic cell and participate in "one carbon metabolism". Recent studies have shown that formaldehyde may act as a signal molecule to regulate memory formation. After electrical stimulation or learning activity, the levels of formaldehyde in rat brains were increased instantly, and N-methyl-D-aspartate (NMDA) receptor was activated to promote the formation of long-term potentiation (LTP) or spatial memory. On the contrary, after reducing the levels of formaldehyde in the brains, NMDA receptor could not be activated, which was accompanied by the deficits in both LTP and memory. Moreover, in the brains of normal aged rats and APP/PS1 transgenic mice, the concentrations of formaldehyde were abnormally increased, which directly inhibited NMDA receptor activity and impaired spatial memory. This article reviewed the physiological and pathophysiological functions of endogenous formaldehyde in learning and memory.
Animals ; Formaldehyde ; Hippocampus ; Long-Term Potentiation ; Maze Learning ; Memory ; Memory Disorders ; Mice ; Rats ; Receptors, N-Methyl-D-Aspartate