Ring-Contracted Artemisinin Derivatives as Novel CDK 4/6 Inhibitors: Synthesis and Anti-Breast Cancer Evaluation.

The endoperoxide group of artemisinins is universally accepted an essential group for their anti-cancer effects. In this study, a series of D-ring-contracted artemisinin derivatives were constructed by combining ring-contracted artemisinin core with fragments of functional heterocyclic molecules or classical CDK4/6 inhibitors to identify more efficacious breast cancer treatment agents. Twenty-six novel hybridized molecules were synthesized and characterized by HRMS, IR, 1H-NMR and 13C NMR. In antiproliferative activities and kinase inhibitory effects assays, we found that the antiproliferative effects of B01 were close to those of the positive control Palbociclib, with GI50 values of 4.87±0.23 µM and 9.97±1.44 µM towards T47D cells and MDA-MB-436 cells respectively. In addition, the results showed that B01 was the most potent compound against CDK6/cyclin D3 kinase, with an IC50 value of 0.135±0.041 µM, and its activity was approximately 1/3 of the positive control Palbociclib.

Development and validation of a deep-learning model for the detection of non-displaced femoral neck fractures with anteroposterior and lateral hip radiographs.

Background: Hip fractures, including femoral neck fractures, are a significant cause of morbidity and mortality in the elderly population and are typically diagnosed using plain radiography. However, diagnosing non-displaced femoral neck fractures can be challenging due to their subtle appearance on hip radiographs. Previous deep-learning models have shown low accuracy in identifying these fractures on anteroposterior (AP) radiographs; however, no studies have used lateral radiographs. This study aimed to evaluate the potential of using deep-learning with both AP and lateral hip radiographs to automatically identify non-displaced femoral neck fractures. Methods: We conducted a retrospective analysis of patients with femoral neck fractures at The First Affiliated Hospital of Xiamen University. All the hip radiographs were reviewed, and cases of non-displaced femoral neck fractures were included in the study. Additionally, 439 participants with normal hip radiographs were also included in the study. A vision transformer (Vit) model was developed using 1,536 AP and lateral hip radiograph. The model's performance was compared to the performance of two groups of human observers: an expert group comprising orthopedic surgeons and radiologists, and a non-expert group, including emergency physicians and general practice doctors. We also carried out the external validation using two additional data sets to assess the generalizability of the model. Results: The Vit model showed exceptional performance in detecting non-displaced femoral neck fractures on paired AP and lateral hip radiographs, achieving a binary accuracy of 95.8% [95% confidence interval (CI): 94.9%, 96.8%] and an area under the curve (AUC) of 0.988. Compared to the human observers, the model had a higher accuracy of 96.7% (95% CI: 93.9%, 99.5%) on the paired AP and lateral hip radiographs, while the accuracy of the expert group was 90.5% (95% CI: 85.7%, 95.2%). Further, the model maintained good performance during the external validation, with an AUC of 0.959 on the paired AP and lateral views. Conclusions: Our Vit model showed expert-level performance in identifying non-displaced femoral neck fractures on paired AP and lateral hip radiographs. This model has the potential to enhance diagnosis accuracy and improve patient outcomes by reducing the need for additional examinations and preoperative time.

Ethyl cellulose/gelatin-carboxymethyl chitosan bilayer films doped with Euryale ferox seed shell polyphenol for cooked meat preservation.

This study evaluated the effects of an edible bilayer containing polyphenols from the Euryale ferox seed shell on ready-to-eat cooked beef products, including the physical, mechanical, antioxidant, and antibacterial capabilities. Here, the bilayer films were prepared by layer-by-layer solution pouring using hydrophobic ethyl cellulose (EC) as the outer layer, and hydrophilic gelatin/carboxymethyl chitosan (GC) as the inner layer. By adjusting the proportion of gelatin to carboxymethyl chitosan, the optical, mechanical, and barrier characteristics of bilayer films were markedly enhanced. Extracted polyphenol (EP) from shell of the Euryale ferox seed performed potent antibacterial property against Listeria monocytogenes (L. monocytogenes). The addition of EP to the inner layer of the optimized bilayer film further improved the mechanical and barrier properties of films, and as expected, the film exhibited antioxidant and antibacterial abilities. Additionally, cooked beef and cooked chicken preservation tests indicated that the active bilayer film showed good inhibition of L. monocytogenes and delayed lipid oxidation in ready-to-eat meat products, and significantly delayed the pH, moisture loss, color and texture changes. This study developed multifunctional bilayer active edible films, which has a great potential in the preservation ready-to-eat cooked meat products.

Stereoselective (4 + 3) cycloadditions of allenyl ethers-furans by chiral auxiliaries inducing and evaluation of anti-breast cancer activity.

The medicinal plants were wildly library of natural products in drug discovery. The most active molecules with seven-membered rings skeleton represent a challenge for construction. A stereoselectivity (4 + 3) cycloadditions between allenyl ethers and substituted furans induced by chiral auxiliaries has been investigated. And the results showed significant stereoselectivities and regioselectivities. The optical cycloadducts with an oxygen-substituted seven-membered ring framework were generated by removing chiral auxiliaries under acidic conditions. The antiproliferative activity of the novel compounds displayed moderate antiproliferative effects toward T47D cells.

An advanced sol-gel strategy for enhancing interfacial reactivity of iron oxide nanoparticles on rosin biochar substrate to remove Cr(VI).

The application of iron oxide nanoparticles (IONs) is often limited by agglomeration and low loading. Here, we presented a facile phase change material (PCM) -based sol-gel strategy for the fabrication of α-Fe2O3 nanoparticles. Rosin was used as the PCM in the sol-gel process and the carbon-based substrate of α-Fe2O3 nanoparticles in the thermal process. The α-Fe2O3 nanoparticle embedded rosin-derived biochar(α-Fe2O3@HrBc)were highly dispersed. The dispersity of α-Fe2O3 nanoparticle could be regulated by the weight ratios of rosin to FeCl3·6H2O during the preparation, as evidenced by the scanning electron microscope (SEM) spectrum and the sorption capacity results. Among a series of α-Fe2O3@HrBc nanocomposites, the one with the weight ratios of 1/1.5 rosin/FeCl3·6H2O had the highest capacity for hexavalent chromium (Cr(VI)) sorption. This phenomenon can be ascribed to a remarkably enhanced interfacial reactivity due to an increase in the dispersity of α-Fe2O3 nanoparticle. In addition, SEM showed that the majority of α-Fe2O3 nanoparticles was dispersed on and inside the biochar substrate. Batch adsorption experiments revealed that the α-Fe2O3@HrBc adsorbed 90% Cr(VI) within one minute, and the maximum capacity was up to 166 mg·g-1 based on the Langmuir model. The FTIR and XPS spectra revealed that the adsorbed Cr(VI) species were partially reduced to less toxic Cr(III). Considering that α-Fe2O3 nanoparticles provided important sorption sites, the newly formed Cr(III) and the remaining Cr(VI) ions could be adsorbed on α-Fe2O3@HrBc via the formation of FeCr coprecipitation.

[Design, synthesis and antiproliferative activity in cancer cells of novel dihydropyrazolyl and pyrazolyl artemisinin-phenyl ethers].

To explore potent anticancer agent based on artemisinin scaffold, a series of 10-O-phenyl ethers derivatives containing dihydropyrazolyl or pyrazolyl moiety have been designed and synthesized. Their structures were determined by LC-MS and ¹H-NMR date. Inhibitory effects of the target compounds in human breast cancer MCF-7, MCF/Adr, MDA-MB-231 cells and prostate cell line PC-3 were determined by MTT assay. Those derivatives displayed good antiproliferative activity against the tested cancer cells. Particularly, target compounds exhibited significant cytotoxicity against drug-resistance cells MCF/Adr, which was worthy for further investigation.

A novel synthesized 3', 5'-diprenylated chalcone mediates the proliferation of human leukemia cells by regulating apoptosis and autophagy pathways.

Leukemia is a hematologic malignancy with poor prognosis in humans and chemotherapy is the main strategy for treating leukemia patients. Novel drugs with better selectivity and lower toxicity are required for the treatment of patients. A novel 3',5'-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3- pyridinyl)-propene-1-one (C10) is a potential new anti-leukemia agent. In this study, we investigated the molecular mechanisms of the anti-leukemia effects of C10 on different leukemia cells in vitro. C10 showed strong inhibition of proliferation of the human erythroleukemia cell line HEL and human myeloid leukemia cell line K562, and several cell and flow cytometer assays showed that inhibition by C10 was due to the regulation of gene expression or phosphorylation in the apoptosis and autophagy pathways. The results showed that C10 regulated the expression of Bax, c-Myc, Bcl-2, P38/AMPK and ERK 1/2, activated the expression of Caspase-3, -8, and PARP at the protein level in the apoptosis pathway of the two leukemia cell types, and inhibited the expression of erythroleukemia carcinogene Fli-1 in the human erythroleukemia cell line HEL. Additionally,treatment with the compound induced a time-dependent increase in expression of LC 3A/B via inhibiting the AKT-mTOR pathway, which is associated with cell autophagy. Taken together, the above results suggest that the novel synthesized 3',5'-diprenylated chalcone can prevent the growth of leukemia cells by inducing apoptosis and autophagy.

The Effectiveness of Medial Femoral Epicondyle Up-Sliding Osteotomy to Correct Severe Valgus Deformity in Primary Total Knee Arthroplasty.

BACKGROUND: While many surgical techniques can achieve neutral limb alignment and soft tissue balance in severe valgus deformity during total knee arthroplasty (TKA), few published reports concern medial femoral epicondyle up-sliding osteotomy. METHODS: A prospective investigation was conducted of patients with severe valgus deformities who underwent medial femoral epicondyle up-sliding osteotomy. Clinical measurements, radiological evaluation, and complication data were recorded. RESULTS: Using posterior-stabilized prostheses, 26 patients underwent 28 TKAs performed by the same surgeon using medial femoral epicondyle up-sliding osteotomy to balance the soft tissue. On average, the follow-up was 54 ± 18 months, and the patient age was 63 ± 11 years. All knees were type II according to Krackow's classification. Varus-valgus knee motion was prohibited with the protection of long-leg knee brace for 3 months. At the last follow-up, the Knee Society function score, Hospital for Special Surgery knee-rating scale, and range of motion were 94 ± 6, 91 ± 4, and 116° ± 8°, respectively. All knees were stable laterally, whereas 2 knees had mild medial laxity and the others were stable. The hip-knee-ankle angle, femorotibial angle, condylar-hip angle, plateau-ankle angle, and valgus angle were 179.9° ± 3.4°, 172.9° ± 3.6°, 89.8° ± 2.5°, 90.2° ± 1.1°, and 7.3° ± 3.5°, respectively. CONCLUSION: Medial femoral epicondyle up-sliding osteotomy during TKA in patients with severe valgus deformities facilitates the restoration of lower limb alignment, soft tissue balance, and knee stability.

[Mid-term effectiveness of total hip arthroplasty with subtrochanteric shortening osteotomy in treatment of Crowe type â £ developmental dysplasia of hip].

Objective: To explore the mid-term effectiveness of total hip arthroplasty (THA) with subtrochanteric shortening osteotomy in treatment of Crowe type Ⅳ developmental dysplasia of the hip (DDH). Methods: Between September 2009 and March 2014, a total of 49 patients (57 hips) who were diagnosed with Crowe type Ⅳ DDH were treated with THA and subtrochanteric shortening osteotomy. Of the 49 patients, 7 were male and 42 were female with an average age of 44.6 years (range, 20-73 years). The preoperative Harris score was 44.68±3.39 and the preoperative leg length discrepancy was (5.27±0.55) cm. Results: All incisions healed primarily. All patients were followed up 32-87 months (mean, 52.1 months). At last follow-up, the Harris score was 85.67±2.89 and the leg length discrepancy was (1.12±0.48) cm, showing significant differences when compared with the preoperative values ( t=-69.53, P=0.00; t=42.94, P=0.00). X-ray films showed that bone union of the femoral osteotomy end at 6 months after operation. There was no loosening and subsidence of prosthesis at last follow-up. Conclusion: The subtrochanteric shortening osteotomy with THA in treatment of Crowe type Ⅳ DDH can obtain satisfactory mid-term effectiveness with low risk of peripheral vascular and nerve traction injuries.

[Effectiveness of autologous femoral head bone graft in total hip arthroplasty for Crowe type â ¢ developmental dysplasia of hip with acetabular bone defect].

Objective: To explore the surgical technique and effectiveness of autologous femoral head bone graft in total hip arthroplasty (THA) for Crowe type Ⅲ developmental dysplasia of the hip (DDH) with acetabular bone defect. Methods: Between July 2012 and September 2015, 12 cases (12 hips) of Crowe type Ⅲ DDH with acetabular bone defect were included. Of the 12 patients, 2 were male and 10 were female, with an average age of 54.3 years (range, 37-75 years). The Harris score before operation was 41.08±7.90. The preoperative leg length discrepancy was 0.53-4.28 cm, with an average of 2.47 cm. Autologous femoral head bone graft and cancellous screw fixation were used in all cases to reconstruct acetabula in THA. Four cases were performed with subtrochanteric shortening osteotomy at the same time. Results: All incisions healed by first intention. Twelve cases were followed up 1 year and 10 months to 5 years, with an average of 3.0 years. X-ray films showed that bone healing was observed in all cases at 6 months to 1 year after operation. There was no bone graft osteolysis, absorption, bone graft collapse, and acetabular prosthesis loosening. At last follow-up, the Harris score was 89.50±2.78, showing significant difference when compared with preoperative value ( t=-25.743, P=0.003). The length discrepancy was 0-1.81 cm at last follow-up with an average of 0.76 cm. Conclusion: Autologous femoral head bone graft is effective for Crowe type Ⅲ DDH with acetabular bone defect, which has advantages of restoring pelvic bone stock, obtaining satisfied prosthetic stability and mid-term effectiveness.

[Research on Relationship of HIF-1 Signaling Pathway and Postmenstrual Osteoporosis].

OBJECTIVE: Exploring the role of hypoxia-induceibal factor-1 (HIF-1) signaling pathway in postmenstrual osteoporosis (PMOP) and how to play a role in PMOP. METHODS: Sixty C57BL/6J female mouse were randomly divided into 4 groups: sham-operation group (A group),ovariectomized PMOP group (B group),HIF-1 alpha inhibitor 2-methoxy estradiol (2ME2) treatment group(D group) and solvent control group(C group),15 mice in each group. There months after modeling,the metabolism product of mouse bone tissue including serum propeptide of typeⅠ procollagen (PINP),C-terminal telopeptide-Ⅰ (CTX-1) and serum estrogen were quantified by enzyme-linked immunosorbent assay (ELISA). Changes of bone structure were observed on HE stained tissue sections. Regulation products of HIF-1 signaling pathway including HIF-1α,HIF-1ß,specific prolyl hydroxylases (PHD),Hipple-Lindau tumor suppressor protein (VHL),and factor inhibiting HIF (FIH) were measured by immuno-histochenmistry staining. Osteoclasts derived from OVX-mice were treated with inhibitors of extracellular regulated protein kinases (ERK),protein kinase B (Akt) and nuclear factor kappa B (NF-κB) signaling pathways. HIF-1α expression were detected by Western blot to obtain a rudimentary knowledge of possible mechanism of up-regulation of HIF-1α in osteoclasts of postmenospausal osteoporosis. RESULTS: Metabolism product of mouse bone tissue of B group were higher than A group ( P<0.001). The positive expression of HIF-1-alpha protein was found in osteoclasts,and the expression of HIF-1-alpha protein in bone marrow region was higher than that in A group ( P<0.001), while the change od HIF-1ß,PHD,VHL,and FIH were not obviously. After the HIF-1α inhibitor treatment,markers of bone resorption of bone metabolism in ovariectomized mice reduced and the osteoporosis get greatly relieved ( P<0.001). HIF-1α expression was down-regulated in osteoclasts of OVX-mice after treated with inhibitors of ERK,Akt and NF-κB signaling pathways ( P<0.05). CONCLUSION: HIF-1 signaling pathway get involved in the pathological evolution of osteoporosis after menopause,and inhibition of HIF-1 can significantly improve the severity of osteoporosis after menopause. ERK,Akt and NF-κB signaling pathways may involve in the up-regulation of HIF-1 signaling pathway in osteoclasts of PMOP.

Synthesis, anticancer evaluation and pharmacokinetic study of novel 10-O-phenyl ethers of dihydroartemisinin.

Twenty hybrid compounds, tethering dihydroartemisinin (DHA) with diaryl-pyrazoline/diaryl-pyrazole through ether linkage, were synthesized based on hybridization strategy and assessed for their anticancer activity. The representative compound 6f exhibited significantly elevated antiproliferative activity compared with DHA against a panel of cancer cell lines. Unexpected sensitivity of 6f in Adriamycin-resistant MCF-7 cells (MCF-7/Adr) inspired subsequent research on anticancer activity of these DHA derivatives against breast cancer cell lines. All the novel compounds exhibited potent activity in three breast cancer cells including MDA-MB-231, MCF-7 and MCF-7/Adr. Most of them exerted almost 10-fold higher potency in MCF-7/Adr than in MCF-7 and MDA-MB-231 cells. Compound 5f, the most potent compound against MCF-7/Adr (GI50 = 18 nM), was used for mechanism research which revealed that compound 5f arrested MCF-7 and MCF-7/Adr cells in G0/G1 phase with decreased levels of cyclin D1 and increased levels of p27. Preliminary pharmacokinetic properties of 5f and 6f were investigated in rats after a single intravenous administration. The high sensitivity of MCF-7/Adr indicates that these compounds have potential to be developed as therapeutic agents to treat drug-resistant cancer.

[Effect on time of temporarily-closed wound drainage on blood loss of primary total knee arthroplasty after intravenous and intra-articular injection of tranexamic acid].

Objective: To investigate the effect and safety of time of temporarily-closed wound drainage on blood loss of primary total knee arthroplasty (TKA) after intravenous and intra-articular injection of tranexamic acid (TXA). Methods: Eighty female patients were selected from 102 patients who underwent primary TKA between September 2015 and July 2016, who were randomly divided into 4 groups: control group (group A), 30 minutes group (group B), 60 minutes group (group C), and 90 minutes group (group D), 20 patients each group. No significant difference was found in age, body mass index, side, pathogen, duration, and preoperative hemoglobin, albumin, and hematocrit between 4 groups ( P>0.05). All the patients received intravenous injection of 1 g TXA at 10 minutes before removing the tourniquet. The patients in group A were injected with 60 mL normal saline into the articular cavity and closed drainage after surgery, while the patients in groups B, C, and D were injected with 60 mL TXA into the articular cavity and closed drainage for 30, 60, and 90 minutes respectively. The volume of drainage at 24 hours after operation, the total blood loss, the postoperative hemoglobin level, maximum hemoglobin loss, albumin loss, the volume and frequency of blood transfusion, venous thrombo embolism rate, and pulmonary embolism rate were recorded and compared between groups. Results: The volume of drainage and total blood loss in groups B, C, and D were less than those of group A, showing significant difference between groups C, D and group A ( P<0.05), but no significant difference between group B and group A ( P>0.05). The volume of drainage at 24 hours after operation in group B was higher than that in groups C and D, showing significant difference between groups B and D ( P<0.05), but no significant difference was found between groups C and D ( P>0.05). There was no significant difference in the total blood loss between groups B, C, and D ( P>0.05). The hemoglobin loss and albumin loss gradually decreased from groups A to D, but no significant difference was found between groups ( P>0.05). No venous thrombo embolism and pulmonary embolism occurred. The hemoglobin value decreased to 28 g/L at 3 days after operation in 1 patient of group D, who received venous transfusion of 20 g human albumin. Conclusion: Intravenous and topical application of TXA in TKA can significantly decrease postoperative bleeding. Topical TXA combined with 60 minutes temporarily-closed wound drainage may reduce postoperative blood loss to the greatest extent without increasing the risk of venous thrombo and pulmonary embolism event after TKA．.

Activin A/Smads signaling pathway negatively regulates Oxygen Glucose Deprivation-induced autophagy via suppression of JNK and p38 MAPK pathways in neuronal PC12 cells.

Activin A (Act A), a member of the transforming growth factor-beta (TGF-ß), reduces neuronal apoptosis during cerebral ischemia through Act A/Smads signaling pathway. However, little is known about the effect of Act A/Smads pathway on autophagy in neurons. Here, we found that oxygen-glucose deprivation (OGD)-induced autophagy was suppressed by exogenous Act A in a concentration-dependent manner and enhanced by Act A/Smads pathway inhibitor (ActRIIA-Ab) in neuronal PC12 cells. These results indicate that Act A/Smads pathway negatively regulates autophagy in OGD-treated PC12 cells. In addition, we found that c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways are involved in the OGD-induced autophagy. The activation of JNK and p38 MAPK pathways in OGD-treated PC12 cells was suppressed by exogenous Act A and enhanced by ActRIIA-Ab. Together, our results suggest that Act A/Smads signaling pathway negatively regulates OGD-induced autophagy via suppression of JNK and p38 MAPK pathways in neuronal PC12 cells.

Molecular Basis of the Antioxidant Capability of Glutathione Unraveled via Aerosol VUV Photoelectron Spectroscopy.

Glutathione (GSH), the most abundant nonenzymatic antioxidant in living systems, actively scavenges various exogenous/endogenous oxidizing species, defending important biomolecules against oxidative damages. Although it is well established that the antioxidant activity of GSH originates from the cysteinyl thiol (-SH) group, the molecular origin that makes the thiol group of GSH a stronger reducing agent than other thiol-containing proteins is unclear. To gain insights into the molecular basis underlying GSH's superior antioxidant capability, here we report, for the first time, the valence electronic structures of solvated GSH in the aqueous aerosol form via the aerosol vacuum ultraviolet photoelectron spectroscopy technique. The pH-dependent electronic evolution of GSH is obtained, and the possible correlations between GSH and its constituting amino acids are interrogated. The valence band maxima (VBMs) for GSH aqueous aerosols are found at 7.81, 7.61, 7.52, and 5.51 ± 0.10 eV at a pH of 1.00, 2.74, 7.00, and 12.00, respectively, which appear to be lower than the values of their corresponding hybrid counterparts collectively contributed from the three isolated constituting amino acids of GSH. An additional photoelectron feature is observed for GSH aqueous aerosols at pH = 12.00, where the thiol group on its Cys residue becomes deprotonated and the relatively well-separated feature allows its vertical ionization energy (VIE) to be determined as 6.70 ± 0.05 eV. Compared to a VIE of 6.97 ± 0.05 eV obtained for a similar thiolate feature observed previously for isolated Cys aqueous aerosols ( Su et al. VUV Photoelectron Spectroscopy of Cysteine Aqueous Aerosols: A Microscopic View of Its Nucleophilicity at Varying pH Conditions . J. Phys. Chem. Lett. 2015 , 6 , 817 - 823 ), a 0.27 eV reduction in the VIE is found for GSH, indicating that the outermost electron corresponding to the nonbonding electron on the thiolate group can be removed more readily from the GSH tripeptide than that from Cys alone. The possible origins underlying the decrease in the VBM of GSH with respect to that of each corresponding hybrid counterpart and the decrease in the VIE of the thiolate feature of GSH with respect to that of the isolated Cys are discussed, providing hints to understand the superior antioxidant capability of GSH from a molecular level.

[EFFECTIVENESS OF SLIDING OSTEOTOMY FOR CORRECTING SEVERE VALGUS DEFORMITY IN TOTAL KNEE ARTHROPLASTY].

OBJECTIVE: To explore the surgical technique and effectiveness of sliding osteotomy of medial femur condyle in handling soft tissue balance of severe valgus deformity in total knee arthroplasty (TKA). METHODS: Between June 2008 and February 2014, 18 cases (19 knees) of severe valgus knees undergoing sliding osteotomy of medial femur condyle in primary TKA were included, Of the 18 patients, 6 were male and 12 were female with an average age of 52.3 years (range, 29-72 years), including 3 cases (3 knees) of osteoarthritis, 11 cases (12 knees) of rheumatoid arthritis, 3 cases (3 knees) of post-traumatic arthritis, and 1 case (1 knee) of deformities in skeletal dysplasia. Before surgery, the tibial femur angle (TFA) was (33.0 +/- 2.9) degrees; the Hospital for Special Surgery (HSS) score was 41.6 +/- 7.7; the Knee Society Score (KSS) lateral stability score was 6.0 +/- 5.4. All cases wererated as type II according to Krackow classification of valgus knee. During primary TKA, sliding osteotomy of medial femur condyle was performed via a medial parapatellar approach. RESULTS: Incision healed by first intention in all cases. Peroneal nerve palsy occurred in 1 patient, which was cured after 6 months of conservative treatment. Eighteen cases were followed up 19 months to 7 years, with an average of 5.7 years. All patients had no complications of deep vein thrombosis, deep infection, and prosthesis loosening. X-ray films showed that bone healing was achieved in all cases at 6 months. At last follow-up, the TFA was (4.8 +/- 1.8) degrees, showing significant difference when compared with preoperative value (t=62.61, P=0.00). The HSS score was 87.2 +/- 10.5 and the KSS lateral stability score was 12.4 +/- 3.1, all showing significant differences when compared with preoperative scores (t = -33.35, P=0.00; t = -6.83, P=0.00). CONCLUSION: Sliding osteotomy of medial femur condyle is effective for correcting severe valgus knee deformity during TKA. Satisfactory joint function and stability may be achieved

Combating P-glycoprotein-mediated multidrug resistance with 10-O-phenyl dihydroartemisinin ethers in MCF-7 cells.

A series of 10-ß-phenyl ethers of dihydroartemisinin (DHA) with piperazine substitutions were synthesized with the goal of overcoming multidrug resistance in cancer therapy. These novel compounds exerted significant antiproliferative activities in breast cancer MCF-7 and MCF-7/Adr cell lines at the submicromolar level and were shown to be approximately 100- to 300-times more potent than the lead compound DHA. Remarkably, the P-gp-overexpressed MCF-7/Adr cell line showed collateral sensitivity towards these derivatives. Furthermore, compounds 3d and 5c, with the highest selectivity for MCF-7/Adr towards MCF-7 cells, were free from P-gp efflux in a MDCK-MDR1 assay. Flow cytometry and western blot assays suggested that the antiproliferative effects of 5c were associated with cell cycle arrest at G1 phase through the downregulation of Cyclin D1 and Cyclin B1.

[Design, synthesis and antiproliferative activities of artemisinin derivatives substituted by N-heterocycles].

Increasing attention has been focused on the antitumor activity of artemisinin derivatives in recent years, for artemisinin had been reported to have cytotoxic effects against HL-60, P388 and MCF-7 tumor cells. We report here the synthesis and evaluation for antitumor activity of a series of artemisinin-ether derivatives bearing tetrahydropyrrole, morpholine, piperidine, substituted piperidines and azoles with various linkers. Sixteen 10-O-substituted dihydroartemisinin derivatives were designed and synthesized, all of which have never been reported in literatures and whose antiproliferative effects on human breast cancer MCF-7, MCF-7/Adr and HL-60 cells were determined by MTT assay or direct cell counting. Each of these artemisinin derivatives possessed better effects than dihydroartemisinin evidently against HL-60 and MCF-7 cells growth, while less potent than doxorubicin. All target compounds exhibited significantly improved potency compared to DHA and doxorubicin on the doxorubicin-resistant MCF-7/Adr cells, so did they in their sensitive counterparts MCF-7 cells. Among them, compounds GF02, GH04 and ZH04 showed strong activity against these three cell lines growth. Further research is undergoing.

Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety.

Anti-apoptotic protein Mcl-1 plays an important role in protecting cell from death in acute myeloid leukemia (AML). The apoptosis blocking activity of Mcl-1 is inhibited by BH3-only protein Noxa. We found that dihydroartemisinin (DHA) and its derivative X-11 are potent apoptosis inducers in AML cells and act through a Noxa-mediate pathway; X-11 is four-fold more active than DHA. DHA and X-11-induced apoptosis is associated with induction of Noxa; apoptosis is blocked by silencing Noxa. DHA and X-11 induce Noxa expression by upregulating the transcription factor FOXO3a in a reactive oxygen species-mediated pathway. Interfering with the integrity of the endoperoxide moiety of DHA and X-11, as well as chelating intracellular iron with deferoxamine, diminish apoptosis and Noxa induction. AML cells expressing Bcl-xL, or with overexpression of Bcl-2, have decreased sensitivity to DHA and X-11-induced apoptosis which could be overcome by addition of Bcl-2/Bcl-xL inhibitor ABT-737. DHA and X-11 represent a new group of AML cells-apoptosis inducing compounds which work through Noxa up-regulation utilizing the specific endoperoxide moiety and intracellular iron.

E-cadherin interactome complexity and robustness resolved by quantitative proteomics.

E-cadherin-mediated cell-cell adhesion and signaling plays an essential role in development and maintenance of healthy epithelial tissues. Adhesiveness mediated by E-cadherin is conferred by its extracellular cadherin domains and is regulated by an assembly of intracellular adaptors and enzymes associated with its cytoplasmic tail. We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin. In addition, we used proteomics to identify proteins associated with E-cadherin-containing adhesion plaques from a cell-glass interface, which enabled the assignment of cellular localization to putative E-cadherin-interacting proteins. Moreover, by tagging identified proteins with GFP (green fluorescent protein), we determined the subcellular localization of 83 putative E-cadherin-proximal proteins and identified 24 proteins that were previously uncharacterized as part of adherens junctions. We constructed and characterized a comprehensive E-cadherin interaction network of 79 published and 394 previously uncharacterized proteins using a structure-informed database of protein-protein interactions. Finally, we found that calcium chelation, which disrupts the interaction of the extracellular E-cadherin domains, did not disrupt most intracellular protein interactions with E-cadherin, suggesting that the E-cadherin intracellular interactome is predominantly independent of cell-cell adhesion.