Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.

Advances on treatment of periprosthetic infection and antibiotic delivery system after total hip arthroplasty / 中国骨伤

Periprosthetic infection after hip replacement is a clinical catastrophic disease, which often leads to the failure of the prosthesis. It needs the combination of systemic antibiotics to cure the infection, which brings huge burden to doctors and patients. There are strict indications for debridement and one-stage revision of the prosthesis, and few cases meet the requirements. The second revision is still the gold standard for the treatment of periprosthetic infection. It is suitable for all infection conditions and has a high success rate. On the second phase of renovation, the antibiotic sustained release system plays a key role, and the carrier of antibiotic sustained-release system is the focus of current research, including classic bone cement and absorbable biomaterials. Bone cement has strong mechanical strength, but the antibiotic release shows a sharp decline trend; the absorbable biomaterials can continuously release antibiotics with high concentration, but the mechanical strength is poor, so it could not use alone. The combination of bone cement and absorbable biomaterials will be an ideal antibiotic carrier. PMMA is the most commonly used antibiotic carrier, but the antibiotic release concentration is decreased sharply after 24 hours. It will be difficult to control the infection and increase the risk of bacterial resistance if it is lower than the minimum inhibitory concentration. The biodegradable materials can release antibiotics completely, with long release time and high concentration, but low mechanical strength. Antibiotic spacer plays an important role in the control of infection. In the future, how to further extend the antibiotic release time of antibiotic sustained-release system, increase the amount of antibiotic release and maintain the mechanical strength of the material will be studied.

Procalcitonin as a sensitive index of chronic infection after artificial joint replacement:a retrospective analysis / 中国骨伤

OBJECTIVE@#To study the predictive value of procalcitonin as a serum biomarker in diagnosis of late periprosthetic joint infection(PJI) for providing theoretical reference basis for diagnosis of PJI.@*METHODS@#A total of 77 cases were retrospective included from January 2015 to December 2017 for revision of total hip arthroplasty and total knee arthroplasty, according to the diagnostic criteria of Musculoskeletal Infection Society(MISI). All cases were divided into infection group and non-infection group. Infection group included 21 cases, 7 cases for male and 14 cases for female, with an average age of (60.70±8.75) years old (ranged 43 to 75 years old). Non-infection group 56 included cases, 24 cases for male and 32 cases for female, with an average age (64.40±12.14) years old (ranged 43 to 85 years old). Concentration of preoperative serum procalcitonin was examined and the chi-square test was used to compare positive rate between the two groups.@*RESULTS@#Two cases in the infection group had positive serum procalcitonin, 0.06 ng/L and 0.10 ng/L respectively, with the positive rate of 9.52%; 4 cases in non-infected group had positive serum procalcitonin, 0.05 ng/L, 0.06 ng/L, 0.06 ng/L, 0.16 ng/L respectively, with the positive rate of 7.14%. No statistically significant difference was observed between the two groups (=0.662).@*CONCLUSIONS@#Most of PJI were low toxicity infection with little systemic inflammatory response, so the concentration of serum procalcitonin was normal or slightly higher level, had little clinical significance for diagnosis of PJI. But the cases of this retrospective study are not enough, more cases are needed for further study.

Does serum calcium relate to different types of hip fracture? A retrospective study / 中华创伤杂志(英文版)

<p><b>PURPOSE</b>To investigate the potential correlation between two different types of hip fractures and serum calcium levels.</p><p><b>METHODS</b>We consecutively studied 101 cases of femoral neck fracture and 95 cases of femoral inter- trochanteric fracture between January 2011 and December 2013. Fasting blood samples were taken and serum calcium measurements were performed respectively in three periods: the time of admission, postoperation, and discharge. Creatinine, alkaline phosphatase and albumin were also analyzed.</p><p><b>RESULTS</b>Considering the levels of serum calcium between two groups at the time of admission, post- operation and discharge, there was significant difference at admission and discharge (p <0.05), while there was no significant difference at the time of postoperation (p > 0.05). The magnitude of serum calcium fluctuation was larger in femoral neck group than femoral intertrochanteric group. Concerning alkaline phosphatase and albumin levels at admission, there was no significant difference between two groups (p > 0.05).</p><p><b>CONCLUSION</b>The capability of reservation and restoration of serum calcium in patients with femoral neck fracture is better than that in patients with femoral intertrochanteric fracture. A low serum calcium level may be susceptible to femoral intertrochanteric fracture.</p>

Experimental study of directional differentiation of bone mesenchymal stem cells (BMSCs) to osteoblasts guided by serum containing cistanche deserticola / 中国骨伤

<p><b>OBJECTIVE</b>To study directional differentiation of BMSCs guided by Desert living Cistanche (Herba Cistanches) which invigorates the kidney.</p><p><b>METHODS</b>Primary BMSCs were obtained by whole bone marrow culture and subcultured to the fourth generation by trypsin digestion, and than inoculated into two six-well plates at 5 x 10(6) cells per milliliter, all the plates were divided into three groups as blank group, Dexamethasone (DXM) group and Herba Cistanches group, three wells in each group, medium were changed at day 2. The blank group were changed with L-DMEM containing 10% FBS. The DXM group were changed with medium containing 10 mmol/L beta-sodium glycerophosphate, 0.1 micromol/L DXM and 50 mg/L vitamin C. The Herba Cistanches group were changed with medium containing 10% blood serum containing Herba Cistanches and L-DMEM. One of the six-well plates was stained by alkaline phosphatase (AKP) at the tenth day,the other one was stained by alizarin Bordeaux at the twentieth day.</p><p><b>RESULTS</b>At the tenth day DXM group and Herba Cistanches group were ALKP stained positive; from the 12th day,white calcium nodus could be seen at the surface of the wells; which alizarin stained positive by the twentyth day.</p><p><b>CONCLUSION</b>The medium containing Herba Cistanches can guide BMSCs to differentiate into osteoblast, which promises a favorable prospect for the treatment of osteoporosis and bone fracture disunion.</p>