Diversity-oriented synthesis (DOS) aims to efficiently generate collections of small molecules with diverse appendages, functional groups, stereochemistry and skeletons, thus yielding diverse biological activities capable of modulating a wide variety of biological processes. In this review, we discussed the common strategies employed in DOS with specific examples from recent literature, including reagent-based approach, substrate-based approach, build-couple-pair strategy and privileged substructure-based DOS. The application of some DOS libraries in drug discovery is also presented.
Drug Design ; Drug Discovery ; Small Molecule Libraries

Extranodal NK/T cell lymphoma is a kind of disease that is associated with EB virus infection and characterized by progressive distruction and necrosis of the nasal cavity and midline facial tissues, with histological features of diffuse lymphomatous cells inflitrate and inflammatory cells as abackground or angiocentric and angioinvasive inflitrate.The prognosis is poor,as it is highly aggressive and it can progress rapidly.This article mainly discusses and reviews the progress in treatment methods.

This paper presented the effects of experimental hyperinsulinemia on the main apolipoproteins (At, B) and on tbe process of reverse cholesterol transport in rabbit, which consisted of 1) uptake of cholesterol from peripheral tissue by HDL; 2) cholesterol esterification and 3) cholesterol ester transfer. The results showed that insulin could significantly decrease both serum and lymph Apo A1 levels and inhibit all the three steps of reverse cholesterol transport. The larger the dose of insulin, the greater the effects. Apo B did not seem to be influenced by insulin. It was further demonstrated by a series of statistical analyses that insulin had both direct and indirect inhibitory actions, to different extent, on each of the three main steps of reverse cholesterol transport.

Objective To compare the efficiency and safety of clopidogrel of different loading-dose in acute coronary syndromes(ACS) patients with percutaneous coronary intervention(PCI) therapy, and, give an assessment of security about higher loading dose of clopidogrel. Methods 120 patients from January 2008 to January 2009 in our hospital were included.They were randomly divided into 3 groups(na=nb=nc=40)and were given 600 mg,450 mg and 300 mg clopidogrel on the 6 hour before PCI. There was no significant difference between the three groups' basic clinical information(p>0.05),such as age, sex and so on. Four points were selected to observe: the platelet aggregation induced by ADP with 5umol/L before and two hours、four hours, six hours after taking medicine; Primary endpoint events, which include shock during hospitalization, death, target revascularization, myocardial infarction, recurrent angina, stroke in 30 days,and Postoperative Bleeding events and adverse Reactions after Surgery in 30 days. Results compared to the standard dose of 300 mg clopidogrel, 600 mg doses clopidogrel can give a greater degree of inhibition on platelet activating than 450 mg doses in the pre-6 h after administration. Increase Clopidogrel loading dose can reduce the occurrence of major cardiovascular events rate. Bleeding events and the occurrence of adverse events was no significant difference among three groups. Conclusions compared to the standard dose of 300 mg clopidogrel, a higher loading dose of clopidogrel can produce much more faster, greater platelet inhibition, and similar security.

Objective To study changes of trigemino-cervical reflex (TCR) in patients with Kennedy's disease (KD). Methods The parameters of TCR were analyzed among patients with KD, amyotrophic lateral sclerosis and healthy controls. Results The parameters of ipsilateral P19, N31, A and contralateral P19, N31, A among patients with KD were (23.91±4.84), (35.45±4.76) ms, 1.24± 0.33 and (24.34±4.82), (36.20±4.91) ms, 1.19±0.25, respectively. Compared with the healthy controls((18.37±2.16), (28.50±1.56) ms, 1.90±0.43; (18. 72±2. 18), (29. 19±1.43) ms, 1.84 ± 0. 40), the difference in each parameter was significant (ipsilateral : t = 5.77, 8. 19, -6. 64; contralateral:5.05, 7.62, -7.77, all P<0.01). Conclusion The parameters of TCR were abnormal in KD patients, indicating that the trigeminal nerves and the bulbar may be involved in the disease.

Objective To investigate the expression of autophagy and the effect of complement C5a/C5aR pathway on autophagy induced by renal ischemia reperfusion injury (IRI).Methods MaleWT and C5aR gene knockout (BALB/C background) mice were selected.The model of renal IRI was established by occluding bilateral renal pedicles with microaneurysm clamps.Mice were divided into wild type BALB/C (WT) group and C5aR gene knock out (C5aRKO) group.The pathology of kidney was assessed by HE staining.The levels of BUN and KIM-1 were detected 24 h after reperfusion.The expression of the autophagy-associated protein (LC3 Ⅱ/LC3 Ⅰ and P62) was measured by Western blotting and immunofluorescence.In vitro,human renal tubular epithelial cells (HK2) were cultured.The expression of LC3 in HK2 cells was investigated by immunofluorescence and Western blotting after being treated with recombinant C5a or C5a combined with C5aR antagonist (C5aRA).Results As compared with WT group,the severity of kidney injury was obviously reduced in C5aRKO group (P＜0.05).After ischemia-reperfusion,the expression of autophagy-related protein LC3 gradually increased with the reperfusion time prolonged.The level of autophagy induced by ischemia-reperfusion was significantly reduced in C5aRKO group as compared with WT group (P＜0.05).In addition,the expression of autophagy-related protein LC3 Ⅱ in HK2 cells was increased with the augment of C5a stimulation concentration in vitro.Blockage of C5aR pathway by C5aRA led to a significant decrease in autophagy (P ＜ 0.05).Conclusion Complement C5a/C5aR pathway promotes renal IRI-induced autophagy.

BACKGROUND:Tumor stem cels are found to be involved in the recurrence, metastasis and drug resistance of the tumor.
OBJECTIVE:To explore the relationship between cel activity and multidrug resistance of CD44+CD24-/low breast cancer stem cels.
METHODS:CD44+CD24-/low breast cancer stem cels sorted from multidrug resistant breast cancer cel line MCF-7/ADR were detected as percentage using flow cytometry. P-gp fluorescence intensity of the cel membrane and MDR mRNA expression in sorted cels and MCF-7/ADR were detected using flow cytometry and RT-PCR, respectively.
RESULTS AND CONCLUSION: After sorting by flow cytometry, the proportion of CD44+CD24-/low breast cancer stem cels was more than 90%, indicating that the sorted cels could meet the needs of the subsequent experiment. CD44+CD24-/low cel subsets exhibited stronger ability to form microspheres than non- CD44+CD24-/low cel subsets. The P-gp fluorescence intensity and MDR mRNA expression of CD44+CD24-/low cels were significantly higher than those of MFC-7/ADR cel line (P < 0.05). These experimental findings suggest that CD44+CD24-/low breast cancer stem cels sorted from MCF-7/ADR cel lines have a strong ability to form cel microspheresin vitro, and significantly raise the level of P-gp protein and MDR mRNA expression, which may be one of the causes of multidrug resistance.

Objective:To investigate the role of alloreactive T cell in clonal deletion and regulatory T cells ( Treg) in transplant tolerance.Methods:F1 mice were bred by crossing female BALB/c mice and male C57BL/6 mice.Within 24 h,newborn C57BL/6 mice were inoculated with F1 spleen cells via the orbital branch of the anterior facial vein.Six weeks later,the mice were subjected to F1 skin grafting to evaluate their tolerance.Proliferation,flow cytometry and adoptive transfer assay were used to analyze clonal deletion of alloreactive T cells and the expression of CD4+Foxp3+T cells in neonatal treated mice.Results: Newborn C57BL/6 mice injected with F1 splenic cells could induce transplantation tolerance,the level of tolerance was associated with the dose of splenic cells.3×107 splenic cells from F1 mice could induce long-term skin graft acceptance in C57BL/6 mice ,1×107splenic cells significantly prolonged the survival of F1 skin grafts,but the grafts completely rejected within 50 days.The mixed lymphocyte reaction ( MLR) experiment in vivo showed that alloreactive T cell in long-term tolerant mice was deleted completely,but a certain amount of reactive T cells existed in the low-dose group mice.Flow cytometry ( FCM) analysis showed that the expression of CD4+Foxp3+T cell in the high-dose group and low-dose group mice had no obvious difference compared with the naive mice.When alloreactive T-cells were injected into tolerant mice,the skin graft rejection was observed,and Treg cells upregulated in graft-rejected mice.Conclusion:The degree of transplantation tolerance depended on the clonal deletion of alloreactive T cells,instead of on the expression of CD4+Foxp3+Treg cells.CD4+Foxp3+regulatory T cells upregulated in graft rejected mice,which may be served as a negative feedback mechanism to control the intensity of rejection.

Adenocarcinoma ; blood ; diagnosis ; pathology ; Biopsy, Needle ; Humans ; Male ; Neoplasm Invasiveness ; Neoplasm Staging ; methods ; Prostate-Specific Antigen ; blood ; Prostatic Intraepithelial Neoplasia ; blood ; diagnosis ; pathology ; Prostatic Neoplasms ; blood ; diagnosis ; pathology

Arthrography ; Bone Neoplasms ; diagnosis ; diagnostic imaging ; pathology ; Bone and Bones ; diagnostic imaging ; pathology ; Diagnosis, Differential ; Diagnostic Errors ; Humans ; Immunohistochemistry ; Joint Diseases ; diagnosis ; diagnostic imaging ; pathology ; Joints ; diagnostic imaging ; pathology ; Radionuclide Imaging