MDM2 inhibitor APG-115 synergizes with ABT-199 to induce cell apoptosis in chronic lymphocytic leukemia.

Although clinical outcomes in chronic lymphocytic leukemia (CLL) have greatly improved with several approved small molecular inhibitors, acquired resistance does occur, leading to disease progression and eventual death. Thus, the effort to explore novel inhibitors and combination therapeutic regimens is needed. The inhibition of MDM2-p53 interaction to restore p53 function has been regarded as a potential strategy for treating different cancers. We investigated the effects of novel MDM2 inhibitor APG-115 in CLL. We found that APG-115 treatment upregulated the expression of p53, MDM2, and p21 at the mRNA and protein level. APG-115 inhibited cell proliferation, induced apoptosis, and arrested the cell cycle at G0/G1 stage. Moreover, APG-115 inhibited the expression of BCL-2, BCL-xL, and MCL-1, and suppressed the activation of AKT and ERK signaling pathways. APG-115 combined with the BCL2 inhibitor, ABT-199 (venetoclax), led to further inhibition of the expression of BCL-2 family anti-apoptotic proteins and consequently enhanced cell death. Collectively, this study demonstrates that APG-115 activates p53 and thus inhibits multiple pro-survival mechanisms, which provides a rational explanation for APG-115 efficiency in inducing cell apoptosis in CLL. The synergistic effect of APG-115 with ABT-199 suggested a potential combination application in CLL therapy.

Water bridges as the trigger in an amino functionalized Zn-MOF for highly selective and sensitive fluorescent sensing of water.

Water is a fundamental element for life. The highly selective and sensitive sensing of water is always attractive for mankind in activities such as physiological processes study and extraterrestrial life exploration. Fluorescent MOFs with precise channels and functional groups might specifically recognize water molecules with hydrogen-bond interaction or coordination effects and work as water sensors. As a proof of concept, herein, an amino functionalized Zn-MOF (named as complex 1) with pores that just right for water molecules to form hydrogen bond bridges is revealed for highly selective and sensitive fluorescent sensing of water. The single-crystal X-ray diffraction analysis indicates that the 3D framework of complex 1 is functionalized with free amino groups in the channels. Hydrogen bonds formed in the channel along b-axis as water bridges to connect two adjacent NH2bdc ligands and result in the restriction of intramolecular motions (RIM) which could responsible for the selective turn-on fluorescence response to water. Complex 1 exhibits high sensitive to trace amount of water in organic solvents and could be used for water detection in a wide range water contents. Take advantages of complex 1, portable sensors (complex 1@PMMA) were prepared and used in the highly sensitive water sensing.

Pathoanatomy and Injury Mechanism of Typical Maisonneuve Fracture.

OBJECTIVE: Maisonneuve fracture is a special type of injury which are rare in clinic. The manifestation of such fractures is variable. The aim of this study is to describe the pathoanatomical features of typical Maisonneuve fracture on the basis of radiographs, computed tomography (CT) scans, magnetic resonance imaging (MRI), and intraoperative exploration findings, and to investigate the injury mechanism of this variety. METHODS: The data of 41 patients with Maisonneuve fracture from April 2014 to September 2019 were retrospectively analyzed. There were 32 males and nine females, the average age was 37.9 years (range, 18 to 61 years), the fractures occurred on the left side in 20 patients and on the right side in 21 patients. The cause of injuries were traffic accident in five patients, sprain injury in 20 patients, and falling injury from height in 16 patients. All patients underwent posteroanterior and lateral X-ray examinations of the ankle and calf. CT scan of the ankle was performed in 38 patients, including three-dimensional reconstruction in 33 patients. MRI examination of the ankle and calf was performed in 28 and five patients, respectively. Forty patients were treated with open reduction and internal fixation. The features of proximal fibular fracture, injuries of the medial and posterior structures of the ankle, injuries of the anterior inferior tibiofibular ligament and the interosseous membrane were recorded and analyzed. RESULTS: Forty-one patients had proximal one-third fractures of the fibula including six patients with fracture involving the fibular neck, 30 with proximal one-third fractures of the fibular shaft, and five with proximal-medial one-third junction fracture of the fibular shaft. Thirty-five patients (35/41, 85.37%) with injury of posterior structures, 34 patients had posterior malleolar fracture (34/41, 82.93%), and one patient had posterior inferior tibiofibular ligament rupture (1/41, 2.44%). There were 20 patients with type I fracture, four patients with type II fracture, and 10 patients with type III fracture according to the Haraguchi classification of posterior malleolus fracture. The fracture of the medial malleolus was in 30 patients (30/41, 73.17%), rupture of the deltoid ligament was in 10 patients (10/41, 24.39%), and medial structures intact were in one patient (1/41, 2.44%). All 41 patients had injury of the anterior inferior tibiofibular ligament. CONCLUSIONS: Maisonneuve fracture is characterized by fractures of the proximal fibula and the complete rupture of the anterior inferior tibiofibular ligament. Pronation-external rotation is the main injury mechanism. The manifestations of typical Maisonneuve fracture including that the fibular fracture located in proximal one-third diaphysis and the fracture line was from anterosuperior to posteroinferior.

[Progress of total ankle arthroplasty for end-stage ankle osteoarthritis].

Objective: To review the progress of total ankle arthroplasty (TAA) in treatment of end-stage ankle osteoarthritis (AOA). Methods: The domestic and foreign literatures about TAA in recent years were reviewed. The current status and progress of TAA were summarized from the results of traditional and computer-assisted TAA clinical outcomes. Results: End-stage AOA often leads to severe pain and dysfunction, and arthrodesis is still the main selective treatment option. In recent years, with the advancement of surgical techniques and prosthesis design, TAA which can remain joint mobility has increased gradually, and the surgical results also have significant progress. Accurate prosthesis implant and mechanical alignment restoration are critical factors for TAA, and surgery-related malalignment is correlative to the prosthesis failure. Computer assisted patient-specific guide can simplify the TAA procedures and obtain the accuracy of tibia and talus osteotomy. Conclusion: The clinical efficiency of preoperative CT based patient-specific guide technology for TAA needs further clinical follow-up. Meanwhile, it is necessary to further develop intraoperative navigation and robotic surgery system suitable for TAA.

[Study on sustentaculum tali screw placement for constant fragment of calcaneal fracture].

Objective: To investigate the anatomical characters of the sustentaculum tali (ST), accurate entry point and direction for the placement of ST screw from posterior subtalar joint facet to the constant fragment (CF) in calcaneal fractures. Methods: A total of 100 patients with calcaneal fractures performed ankle CT scans were enrolled between January 2016 and April 2016. According to the inclusion criteria, the clinical data of 33 patients were analyzed, including 18 males and 15 females, with a median age of 41.0 years (range, 18-60 years). There were 16 cases on left side and 17 cases on the right side. Three-dimensional (3D) calcaneal model was reconstructed by Mimics 17.0 software, and the ST anatomical references were measured, including the length of upper and lower edge, the length and height of the midline, the horizontal angle between the midline and foot plantar surface. The parameters of the optimal entry point position (P' point) and placement angle of the ST screw were determined. The length of ST screw was also measured. The differences between males and females or left and right sides were compared. Results: The length of upper edge of the ST was (16.60±2.23) mm, lower edge (20.65±2.90) mm, midline (20.56±2.62) mm, and the height of midline was (9.61±1.36) mm. The horizontal angle between the midline and foot plantar surface was (23.43±3.36)°. The vertical distance from P' point to the lowest point of the tarsal sinus was (3.09±1.65) mm, while the horizontal distance was (14.29±2.75) mm. The distance from P' point to the apex of the lateral talus, subchondral bone of subtalar joint, calcaneocuboid joint was (11.41±3.22), (6.59±2.22), (34.58±3.75) mm, respectively. The horizontal angle between the ST screw and foot plantar surface was (-1.17±2.07)°. The anteversion angle of ST screw was (16.18±2.05)° and the length was (41.64 ± 3.09) mm. There were significant differences in the length of upper and lower edge, the length and height of the midline, the distance from P' point to the apex of the lateral talus, subchondral bone of subtalar joint, and calcaneocuboid joint, and the anteversion angle and length of the ST screw between males and females ( P<0.05). There was no significant difference in above all parameters between left and right sides ( P>0.05). Conclusion: After appropriate reduction of the calcaneal fractures, the entry point of ST screw was recommended at about 14 mm posterior and about 3 mm upper related to the foot horizontal line through the lowest tarsal sinus point; and the direction of ST screw placement was about 17° anteversion for males and 15° anteversion for females.

Long non-coding RNA ZFAS1 sponges miR-486 to promote osteosarcoma cells progression and metastasis in vitro and vivo.

Long noncoding RNAs (lncRNAs) have been wildly demonstrated to participate in the osteosarcoma tumorigenesis. ZFAS1 is a novel identified lncRNA, however, its role in osteosarcoma is still unclear. In present study, we utilize lncRNA microarray assay to screen the lncRNA expression profile in osteosarcoma tissue, and investigate the regulatory function of ZFAS1 in osteosarcoma. LncRNA microarray assay revealed that lncRNA ZFAS1 was significantly up-regulated in 3 pairs of osteosarcoma and adjacent non-tumor tissue, which was confirmed by RT-PCR. Furthermore, in 53 pairs of osteosarcoma patient samples, the up-regulated expression of ZFAS1 was closely related to poor prognosis. In vitro, loss-of-function experiments showed that ZFAS1 knockdown significantly suppressed the proliferation, induced cycle arrest at G0/G1 phase and enhance apoptosis. In vivo, ZFAS1 knockdown inhibited the tumor growth. Bioinformatics online programs predicted that ZFAS1 sponge miR-486 at 3'-UTR with complementary binding sites, which was validated using luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Rescue experiments confirmed that miR-486 could reverse the functions of ZFAS1 on osteosarcoma genesis. In conclusion, our results demonstrate that ZFAS1 act as competing endogenous RNA (ceRNA) for miR-486, and act as oncogene in osteosarcoma tumorigenesis, and discover the functional regulatory pathway of ZFAS1 sponging miR-486.

Three-dimensional Computer-assisted Modeling of Talus Morphology in Chinese Patients.

OBJECTIVE: To provide more accurate reference data for the assessment and treatment of talar injuries by constructing 3-D computer-assisted models of the talus and comparing them with reference data obtained from measurements on cadaver specimens. METHODS: Three-dimensional talus models were constructed from CT data recorded for healthy Chinese volunteers using SuperImage Orthopedics software. Structural variables such as length, width, height and volume of talus were compared using the Fisher least significant difference test to determine the significance of bilateral or sex-specific differences in the study cohort. RESULTS: Measurement data were normally distributed. No significant difference between the left and right talus in either men or women was identified for any measurement (P > 0.05). The bilateral mean volume of the talus in men (37.87 ± 6.69 mm) was significantly larger than that in women (26.95 ± 5.73 mm; P < 0.05). Although the dimensions of most of the structural features and articular surfaces of the talus were significantly larger in men than in women (P < 0.05), no significant differences in the angles of the talar neck and head were observed between men and women in our cohort (P > 0.05). CONCLUSION: Our method of 3-D model construction provided precise measurements of the structural features of the talus. The talar dimensions in our Chinese study cohort differ from those previously reported for people of different ethnic groups. Our models should provide accurate reference data for constructing models based on CT images for the assessment and treatment of talar injuries in Chinese patients.

Short-Term Hypoxia Accelerates Bone Loss in Ovariectomized Rats by Suppressing Osteoblastogenesis but Enhancing Osteoclastogenesis.

BACKGROUND Although it has been reported that hypoxic exposure can attenuate hypertension, heart disease, diabetes, and some other diseases, effects of hypoxia on osteoporosis are still unknown. MATERIAL AND METHODS The current study investigated whether short-term hypoxic exposure (in comparison with normoxic conditions) affects bone metabolism in normal or ovariectomized (OVX) adult female rats in an vivo study. Micro-computed tomography bone volume/structural analyses, histological examination, and serum bone turnover biochemical assays were used. In addition, the expressions of some associated major regulatory molecules were measured in osteoblastic cultures. RESULTS While the 14-day hypoxic exposure did not change the bone-remodeling process in normal adult female rats, it decreased bone volume, osteoclast density, and serum bone formation marker (alkaline phosphatase) level, but increased osteoclast density and serum bone resorption marker (C-telopeptide of collagen) level in OVX rats. The bone marrow adipocyte number and serum fatty acid binding protein-4 level were increased in OVX-hypoxic rats compared with OVX-normoxic rats. Consistently, in human MG-63 osteoblastic cultures, the hypoxic condition suppressed protein expression of osteogenic transcriptional factors Runx2 and osterix, elevated protein expression of osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand, but reduced that of osteoclastogenic inhibitor osteoprotegerin. CONCLUSIONS Our results suggest that, although no change occurred in the bone-remodeling process in normal adult female rats after hypoxic exposure, under the estrogen-deficient osteoporotic condition, the hypoxic condition can alter the bone microenvironment so that it may further impair osteoblastic differentiation and enhance osteoclastic formation, and thus reduce bone formation, enhance bone resorption, and accelerate bone loss.

Analysis of complications of intertrochanteric fracture treated with Gamma 3 intramedullary nail.

UNLABELLED: Whether Gamma 3 fixation system is suitable for all intertrochanteric fractures is inconclusive. This paper analyzed the surgical complications of Gamma 3 intramedullary nail in the treatment of intertrochanteric fractures. METHODS: A total of 186 cases were enrolled in the study including 115 males and 71 females. The surgical operations were performed in all cases and Gamma 3 intramedullary nail was inserted in medullary cavity. RESULTS: Anti-rotation screw displacement into the intermuscular space of inner thigh occurred in 1 case, lateral femoral wall defect in 3 cases; refracture of proximal femur shaft during the Gamma 3 nail inserting into the medullary cavity occurred in 5 cases and fractures with a gap or malalignment in closed reduction of A3 type in occurred 6 cases. Fracture union occurred in 3-4 months postoperative. Recovery situations of all patients were evaluated based on Harris scoring system 6 with an average of 87 points. There are indications and shortcomings in the treatment of intertrochanteric fracture with Gamma 3 intramedullary nail. CONCLUSION: Understanding the surgical indications, standardizing the operation and upgrading skills are the key points to ensure operation successful, reduce complications and improve clinical outcomes.

[Extorsion traction and pushing manipulation with fingers for the treatment of anterior shoulder dislocation in elderly].

OBJECTIVE: To investigate a manipulating therapy for treatment of anterior shoulder dislocation in elderly. METHODS: From October 2011 to June 2012,27 elderly patients with anterior shoulder dislocation were treated by extorsion traction and pushing manipulation with fingers, including 7 males and 20 females aged from 65 to 86 years old with an average of 77. The course of disease ranged from 1 h to 1 d. The shoulder manifested square deformity, Dugus signs showed positive, and X-ray displayed anterior shoulder dislocation. Dugus fixation was applied for and removed external fixation at 3 weeks after operation and carried out shoulder functional exercise. Functional evaluation standard on shoulder joint injuries was used for evaluate clinical outcomes. RESULTS: All patients were gained reduction for the first time, and followed up at 3 months after operation, no dislocation occurred. According to functional evaluation standard on shoulder joint injuries, 22 cases got an excellent result,2 cases good,and 1 case moderate. CONCLUSION: Extorsion traction and pushing manipulating therapy for treatment of anterior shoulder dislocation in elderly, which has advantages of simple, convenient, less painful, and can avoid iatrogenic injury, is feasible to widespread.

[Clinical features in the diagnosis and treatment of ankle fracture with Wagsaffe fragment].

OBJECTIVE: To explore the methods in the diagnosis and treatment of ankle fracture with Wagsaffe fragment. METHODS: Among 1 201 patients, there were 18 cases of concurrent Wagstaffe fractures at our hospital between January 2009 to January 2012. There were 11 males and 7 females with an average of 37.4 (17-54) years. The causes of injuries were fall (n = 10), sports-related injury (n = 4), traffic injury (n = 3) and high-altitude fall (n = 1). All of them had lateral malleolar fracture. Other injuries included internal malleolar fracture (n = 16), posterior malleolar fracture (n = 8) and disruption of medial deltoid ligament (n = 3). According to the Lauge-Hansen system, all fractures were of supination-external rotation type. The fractures of fibula and Wagstaffe were explored through an anterolateral approach. The lateral malleolar fracture was fixed with plate While Wagstaffe fragment secured with lag screw or thread. Disrupted anterior tibiofibular ligament was restored. Other treatments included open reduction and internal fixation of medial and posterior malleolus, repair of medial deltoid ligament and screw fixation of disrupted tibiofibular syndesmosis. Ankle function was evaluated by the Baird-Jackson criteria. RESULTS: Wagstaffe fracture occurred at a rate of 1.5% in ankle fractures. Wagstaffe fracture was found in 4.4% of ankle fracture of supination-external rotation type. Seventeen patients were followed up over an average follow-up period of 16.8 (12-25) months. All radiographs showed union of all fractures and normal mortise. Baird-Jackson ankle functional score was from 81 to 99. In all 17 patients, 9 were rated as excellent, 5 as good and 3 as fair. The excellent and good rate was 87.4%. At the latest follow-up, 14 patients resumed their preinjury activities. CONCLUSION: As an easily misdiagnosed condition, Wagstaffe fracture is associated with ankle diastase and prone to occur in ankle fracture of supination-external rotation type. Accurate reduction and stable fixation facilitate the restoration of stable syndesmosis in the treatment of ankle fracture with concurrent Wagsaffe fragment.

Overexpression of suppressors of cytokine signaling 1 promotes the neuronal differentiation of C17.2 neural stem cells.

OBJECTIVE: To investigate the role and mechanism of suppressor of cytokine signaling 1 (SOCS1) in the regulation and differentiation of C17.2 neural stem cells (NSCs). METHODS: In this study, lentiviral (LV)-SOCS1-enhanced green fluorescent protein (EGFP) was constructed and transfected into C17.2 NSCs. There were three groups of C17.2 NSCs: LV-SOCS1-EGFP, LV-EGFP, and phosphate-buffered saline (PBS). The expression levels of microtubule-associated protein 2 (MAP2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), nestin, and ß-tubulin III in C17.2 NSCs were analyzed by reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry, and western blot. In addition, the phosphorylation level of Jaks/Stats family members in C17.2 NSCs were analyzed by western blot. Moreover, the morphological changes of C17.2 NSCs after transfection were observed by light microscopy. RESULTS: The gene expression of MAP2 increased significantly and the gene expression of nestin decreased significantly in C17.2 NSCs transfected with LV-SOCS1-EGFP. Some C17.2 NSCs underwent prominent neuronal morphological changes and expressed ß-tubulin III after LV-SOCS1-EGFP transfection. The number of positive cells for ß-tubulin III immunocytochemical staining and ß-tubulin III protein expression in C17.2 NSCs after LV-SOCS1-EGFP transfection were both more than those after LV-EGFP transfection or PBS treatment. The phosphorylation levels of Jak2 and Stat3 but not Jak3 in C17.2 NSCs were inhibited by SOCS1 overexpression. CONCLUSION: Overexpression of SOCS1 in C17.2 NSCs promotes the generation of neurons, which is likely mediated by the negative feedback inhibition of Jak2 and Stat3. This study is the first to provide evidence that SOCS1 is involved in the regulation of neurogenesis.

[Treatment of anterior cruciate ligament injury with peroneus longus tendon].

OBJECTIVE: To evaluate the effects of anterior cruciate ligament reconstruction with peroneus longus tendon and observe the clinical outcomes of ankle joint after the resection of peroneus longus tendon. METHODS: From January 2006 to December 2009, 35 patients with anterior cruciate ligament injuries were recruited to undergo surgical procedures. There were 30 males and 5 females with an average age of 31.8 years (range: 21 - 56). All anterior cruciate ligament reconstructions underwent arthroscopy. All ligaments were reconstructed with peroneus longus tendon and fixed with absorb screw. The post-operative assessments included the followings:clinical evaluations, Lysholm knee score, KT-3000 arthrometer evaluation and the American Orthopedic Foot and Ankle Society ankle-hindfoot scale AOFAS). RESULTS: All cases were followed up for an average follow-up period of 15 months (range: 12 - 24). The healing time was 6 - 15 weeks.according to the Lysholm knee score, their outcomes were excellent (n = 25), good (n = 6), fair (n = 3) and poor (n = 1). The average score was 97.2 (range: 60 - 100). The rate of excellent and good was 88.6%; according to the KT-3000 arthrometer evaluations, the outcomes were normal (n = 28), nearly normal (n = 4), abnormal (n = 2) and poor (n = 1). Preoperatively, the average anterior displacement was 11.59 ± 1.25 mm and the average anterior displacement at final follow-up 1.76 ± 1.83 mm. The average AOFAS score was 96.3 (range: 84 - 100). Lysholm knee score and KT-3000 arthrometer evaluation had statistical differences (P < 0.05) while AOFAS score showed no difference (P > 0.05). CONCLUSION: Peroneus longus tendon can be a good substitute of anterior cruciate ligament reconstruction. And its resection has no major influence for ankle joint.

[Operative treatment of displaced intra-calcaneal fractures].

OBJECTIVE: To explore the clinical efficacies of displaced intra-calcaneal fractures with operative treatment. METHODS: From January 2005 to December 2010, 103 calcaneal patients (92 males, 11 females) were recruited. The mean age was 45.8 years old (range: 23 - 65). All received operative treatment. They included left calcaneal fractures (n = 51), right calcaneal fractures (n = 40) and bilateral calcaneal fractures (n = 12). All patients were of closed fractures. According to the Sanders classification, there were type II (n = 15), type III (n = 75) and type IV (n = 13). A modified lateral approach with profiled plate fixation was adopted for all. Partial weight-bearing occurred at 6 weeks and full weight-bearing at 12 weeks. Function assessment was made with the American Orthopedic Foot and Ankle Society ankle-hindfoot scale (AOFAS). RESULTS: The mean follow-up period was 18 months (range: 6 - 30) and the mean healing duration 12 weeks (range: 8 - 15). Two cases had incision dehiscence. After the removal of plate, the skin healed. Eight cases were associated with subtalus arthritis and painful walking. Three cases of caved calcaneal surface appeared after weight-bearing. According to the AOFAS foot score, the outcomes were excellent (n = 83), good (n = 13), fair (n = 5) and poor (n = 2). And the excellent and good rate was 93.2%. CONCLUSION: With a modified lateral approach, displaced intra-calcaneal fracture may be treated with a satisfactory clinical efficacy.But an orthopedic surgeon should master skillful surgical techniques.

[Therapeutic efficacies of bone grafing for calcaneal intra-calcaneal fractures].

OBJECTIVE: To evaluate the efficacies of treating intra-calcaneal fractures with bone grafting. METHODS: From January 2005 to October 2011, a total of 182 calcaneal patients underwent operations for closed fractures. There were 159 males and 23 females with an average age of 41.2 years old. The fractures were of the following types: left calcaneal (n = 68), right calcaneal (n = 86) and bilateral (n = 28). According to the Sander's classification, there were type II (n = 27), type III (n = 109) and type IV (n = 46). And they were divided into bone graft (n = 94) and non-bone graft (n = 88) groups. All of them underwent a profiled plate fixation via a lateral approach. No external fixation was necessary and early ankle functional exercises started postoperatively. They handled partial weight-bearing at Week 6 and full weight-bearing at Week 12. Their outcomes were assessed by the American Orthopedic Foot and Ankle Society ankle-hindfoot scale (AOFAS) while classification comparison affected the prognosis (P < 0.05). RESULTS: The follow-ups of 10 patients were lost at Month 3. And 172 cases were followed up for an average period of 14.2 months (range: 9 - 16). The average healing duration was 12 weeks (range: 6 - 15). None of follow-up cases had any complication, such as vascular and nerve injury and osteomyelitis. Twenty-nine cases in the non-bone graft group had articular cave-in after weight bearing. And 21 cases were associated with subtalar arthritis. And in the bone graft group, there was no articular cave-in and only 1 case was associated with subtalar arthritis. The outcomes of bone graft and non-graft groups were as follows: excellent (n = 68), good (n = 20), fair (n = 5) and poor (n = 1) vs. excellent (n = 44), good (n = 26), fair (n = 7) and poor (n = 9). The rate of excellent and good was 87.9%. And the post-operative AOFAS scores had statistical differences between 2 groups (P < 0.05). CONCLUSION: Bone grafting is important for improving the therapeutic efficacies for intra-calcaneal fractures.