Highly extensile approach for comminuted ulna coronoid process fractures with mini-plate fixation: a case series of 31 patients.

BACKGROUND: For the treatment of coronoid process fractures, medial, lateral, anterior, anteromedial, and posterior approaches have been increasingly reported; however, there is no general consensus on the method of fixation of coronal fractures. Here, we present a highly-extensile minimally invasive approach to treat coronoid process fractures using a mini-plate that can achieve anatomic reduction, stable fixation, and anterior capsular repair. Further, the study aimed to determine the complication rate of the anterior minimally invasive approach and to evaluate functional and clinical patient-reported outcomes during follow-up. METHODS: Thirty-one patients diagnosed with coronoid fractures accompanied with a "terrible triad" or posteromedial rotational instability between April 2012 and October 2018 were included in the analysis. Anatomical reduction and mini-plate fixation of coronoid fractures were performed using an anterior minimally invasive approach. Patient-reported outcomes were evaluated using the Mayo Elbow Performance Index (MEPI) score, range of motion (ROM), and the visual analog score (VAS). The time of fracture healing and complications were recorded. RESULTS: The mean follow-up time was 26.7 months (range, 14-60 months). The average time to radiological union was 3.6 ± 1.3 months. During the follow-up period, the average elbow extension was 6.8 ± 2.9° while the average flexion was 129.6 ± 4.6°. According to Morrey's criteria, 26 (81%) elbows achieved a normal desired ROM. At the last follow-up, the mean MEPI score was 98 ± 3.3 points. There were no instances of elbow instability, elbow joint stiffness, subluxation or dislocation, infection, blood vessel complications, or nerve palsy. Overall, 10 elbows (31%) experienced heterotopic ossification. CONCLUSION: An anterior minimally invasive approach allows satisfactory fixation of coronoid fractures while reducing incision complications due to over-dissection of soft tissue injuries. In addition, this incision does not compromise the soft tissue stability of the elbow joint and allows the patient a more rapid return to rehabilitation exercises.

Primary Breast Natural Killer/T-cell lymphoma with Cutaneous Involvement: A Case Report.

Objective: Extranodal natural killer/T-cell lymphoma comprises less than 1% of all non-Hodgkin lymphomas. It is rare in Western countries but is common in East Asia and Central and South America. The pathological features are angiocentricity /angioinvasion and significant tissue necrosis. Case Presentation: A 72-year-old woman was diagnosed with primary breast extranodal natural killer/T-cell lymphoma. The patient presented with a painless right breast tumor and had uneven internal echo and strip blood flow signal on breast ultrasonography. After right breast tumor resection, the pathological diagnosis was extranodal natural killer/T-cell lymphoma. Despite receiving CHOP chemotherapy, the patient died of lymphoma and multiple organ dysfunction syndrome 27 months after diagnosis. Conclusion: Extranodal natural killer/T-cell lymphoma with breast tissue as the primary site is very rare. The disease is prone to misdiagnosis and missed diagnosis, and diagnosis by ultrasound is difficult, so pathological examination after biopsy is particularly important.

Extracellular vesicles derived from hypoxia-preconditioned olfactory mucosa mesenchymal stem cells enhance angiogenesis via miR-612.

Mesenchymal stem cells (MSCs) play important roles in tissue repair and regeneration, such as the induction of angiogenesis, particularly under hypoxic conditions. However, the molecular mechanisms underlying hypoxic MSC activation remain largely unknown. MSC-derived extracellular vesicles (EVs) are vital mediators of cell-to-cell communication and can be directly utilized as therapeutic agents for tissue repair and regeneration. Here, we explored the effects of EVs from human hypoxic olfactory mucosa MSCs (OM-MSCs) on angiogenesis and its underlying mechanism. EVs were isolated from normoxic (N) OM-MSCs (N-EVs) and hypoxic (H) OM-MSCs (H-EVs) using differential centrifugation and identified by transmission electron microscopy and flow cytometry. In vitro and in vivo, both types of OM-MSC-EVs promoted the proliferation, migration, and angiogenic activities of human brain microvascular endothelial cells (HBMECs). In addition, angiogenesis-stimulatory activity in the H-EV group was significantly enhanced compared to the N-EV group. MicroRNA profiling revealed a higher abundance of miR-612 in H-EVs than in N-EVs, while miR-612 inactivation abolished the N-EV treatment benefit. To explore the roles of miR-612, overexpression and knock-down experiments were performed using a mimic and inhibitor or agomir and antagomir of miR-612. The miR-612 target genes were confirmed using the luciferase reporter assay. Gain- and loss-of-function studies allowed the validation of miR-612 (enriched in hypoxic OM-MSC-EVs) as a functional messenger that stimulates angiogenesis and represses the expression of TP53 by targeting its 3'-untranslated region. Further functional assays showed that hypoxic OM-MSC-EVs promote paracrine Hypoxia-inducible factor 1-alpha (HIF-1α)-Vascular endothelial growth factor (VEGF) signaling in HBMECs via the exosomal miR-612-TP53-HIF-1α-VEGF axis. These findings suggest that hypoxic OM-MSC-EVs may represent a promising strategy for ischemic disease by promoting angiogenesis via miR-612 transfer.

Cementless total hip arthroplasty for failed treatment of subtrochanteric fracture.

BACKGROUND: Failed treatment of subtrochanteric fractures commonly leads to pain, limping, and poor limb function. Cementless total hip arthroplasty (THA) could serve as an efficient salvage procedure in such cases. This study aimed to evaluate the outcomes and complications of salvage THA in failed subtrochanteric fracture fixation cases. METHODS: From January 2001 to December 2017, cementless THA for failed treatment of subtrochanteric fractures was performed in 18 hips of 11 men and 7 women (average age, 74 years; age range, 57.0-89.0 years). Patients were followed up for clinical and radiological assessments in terms of implant survival and complications after a minimum follow-up of 2 years. The Wagner femoral stems (Zimmer, Warsaw, USA) were used in all 18 patients (100%), with the long-length stem (Wagner SL stem) and standard-length stem (Wagner cone stem) used in 11 and 7 patients, respectively. RESULTS: The mean follow-up period was 5.2 years (range: 2.2-10.8 years). The mean Harris hip score (HHS) was 38.2 (range: 24-56) preoperatively and 85.4 (range: 79-92) at the last follow-up. The mean postoperative limb length discrepancy was 6.4 mm (range: 4-9 mm). Only one patient underwent revision due to bone in-growth failure of the femoral stem. One patient had an episode of postoperative dislocation and was treated with closed reduction without reoccurrence. Delayed union of the fracture site occurred in one patient. Patients who were previously treated with an intramedullary nail had a significantly shorter surgical duration, lesser intraoperative blood loss, and fewer blood transfusions than those who were previously treated with plate and screws. Kaplan-Meier survival rate with an endpoint of revision was 94.4% (95% confidence interval 72.7-99.9) at 5 years. CONCLUSION: Our results indicate that cementless THA is a beneficial and effective procedure for salvaging the failed treatment of subtrochanteric fractures. The Wagner conical prosthesis has shown satisfactory function outcomes, stable fixation, and survival rate for these complex situations. However, attention should be paid to increased operation time, blood loss, and complications when performing THA for subtrochanteric fractures with failed fixation devices especially, plates and screws.

Mid-term results of total hip arthroplasty with modified trochanteric osteotomy in Crowe type IV developmental dysplasia of the hip.

BACKGROUND: This study aimed to explore mid-term clinical results of cementless total hip arthroplasty (THA) with modified trochanteric osteotomy in Crowe type IV developmental dysplasia of the hip (DDH). METHODS: Thirteen patients (13 hips) with Crowe type IV DDH who underwent THA with modified trochanteric osteotomy between May 2013 and October 2015 were retrospectively analyzed. The mean follow-up duration was 5.2 years (range, 4.9-6.1 years). RESULTS: The mean Harris Hip Score (HHS) significantly (p < 0.05) improved from 30.7 (range, 22-38) to 87.5 (range, 83-93). The mean leg length discrepancy (LLD) was 53.4 mm (range, 42.1-68.5 mm) preoperatively. The final LLD was 5.6 mm (range, 2.4-9.1 mm; p < 0.05). The mean leg length after surgery was 47.4 mm (range, 33.6-67.2 mm) and the femur shortening distance was 43.8 mm (range, 31.2-53.4 mm). The average duration of bone union for the greater trochanter (GT) was 2.5 months (range, 1.5-3.6 months). There was no infection, GT non-union, or loosening (septic or aseptic) of the stem or cup in any case. CONCLUSIONS: THA with modified trochanteric osteotomy with a cementless cup is an effective treatment for Crowe type IV DDH. It can rebuild complex biomechanics and biology of hip dysplasia without increasing complications.

Survival Analysis of Total Hip Arthroplasty for High Hip Dislocation Secondary to Developmental Dysplasia or Septic Arthritis of the Hip.

BACKGROUND: This retrospective study was conducted to know clinical and radiographic outcomes, complication rate, and survival of THA in patients with high hip dislocation secondary to developmental dysplasia(DDH) or septic arthritis of the hip(SSH). METHODS: Between March 2005 and September 2014, there were consecutive series of 53 THAs in patients with a highly dislocated hip secondary to DDH or SSH. Of these, 48 hips (DDH 24 and SSH 24) were reviewed at a mean follow-up of 7.9 years(range, 5.0-14.3 years). The mean age at the time of THA was 39.1 years(range, 18.0-59.0 years). RESULTS: Intraoperative blood loss, total drainage and blood transfusion amounts, and mean time to greater trochanter union were significantly lower in the DDH group than in the SSH group (P = .001, P = .039 and P = .014, and P = .015, respectively). No significant difference in Kaplan-Meier survivorship was observed between groups (log-rank, P = .343). The survival rates with an endpoint of cup aseptic loosening in cases with a cemented cup at 7.9 and 10 years (68.1% and 60.5%, respectively) were significantly lower than those in cementless cup cases (100%) at the same checkpoints (P = .019).. CONCLUSION: We found similar clinical outcomes between the DDH and SSH groups. However, due to poor bone quality and a lack of containment, cementless acetabular cups could not be performed in more than 50% of patients. Our experience shows that revision cementless fixation cup was possible due to reconstitution of the acetabulum in cases with failed cemented fixation.

Reinvestigation of Disulfide-bonded Oligomeric Forms of the Unfolded Protein Response Transducer ATF6.

ATF6α is an endoplasmic reticulum (ER)-embedded transcription factor which is rapidly activated by ER stress, and a major regulator of ER chaperone levels in vertebrates. We previously suggested that ATF6α occurs as a monomer, dimer and oligomer in the unstressed ER of Chinese hamster ovary cells due to the presence of two evolutionarily conserved cysteine residues in its luminal region (C467 and C618), and showed that ATF6α is reduced upon ER stress, such that only reduced monomer ATF6α is translocated to the Golgi apparatus for activation by proteolysis. However, mutagenesis analysis (C467A and C618A) revealed that the C618A mutant behaves in an unexpected manner (monomer and oligomer) during non-reducing SDS-PAGE, for reasons which remained unclear. Here, we used human colorectal carcinoma-derived HCT116 cells deficient in ATF6α and its relevant ATF6ß, and found that ATF6α dimer and oligomer are both dimers, which we designated C618-dimer and C467-dimer, respectively. We demonstrated that C467-dimer (previously considered an oligomer) behaved bigger than C618-dimer (previously considered a dimer) during non-reducing SDS-PAGE, based on their disulfide-bonded structures. Furthermore, ATF6α monomer physically associates with another ATF6α monomer in the absence of disulfide bonding, which renders two C467 residues in close proximity so that formation of C467-dimer is much easier than that of C618-dimer. In contrast, C618-dimer is more easily reduced upon ER stress. Thus, our analysis revealed that all forms of ATF6α, namely monomer, C618-dimer and C467-dimer, are activated by single reduction of a disulfide bond in response to ER stress, ensuring the rapidity of ATF6α activation.Key words: disulfide-bonded structure, endoplasmic reticulum, membrane-bound transcription factor, non-reducing SDS-PAGE, unfolded protein response.

Nanoscale Laser Metallurgy and Patterning in Air Using MOFs.

We report metallurgy on the nanoscale to generate metal nanoparticles and their simultaneous patterning in a single step. This is achieved by the self-reduction of porous metal-organic framework crystals using nanosecond pulsed laser irradiation. Metal nanoparticles of Fe, Co, Ni, Cu, Zn, Cd, In, Bi, and Pb with uniform sizes (controllable between 3 to 200 nm) and gaps (as narrow as 2 nm) are produced by nine different metal-organic frameworks, where atomically dispersed non-noble metal ions are reduced and gathered across the pores. The instant light absorption and cooling at local positions by a laser allows for precise and efficient patterning of metal nanoparticles. This new method is suitable for device fabrication at a speed of 15 mm2 s-1 on glass, consuming only 1.5 W of power. A large variety of metal nanoparticle three-dimensional architectures are demonstrated, among which one architecture exhibits an enhanced plasmonic effect homogeneously across the entire pattern for the detection of molecules at an extremely low concentration (10-12 M). These architectures are extremely stable under air and humidity during production, use, and storage, without altering the oxidation state, for 6 months.

Scalable Nanoshaping of Hierarchical Metallic Patterns with Multiplex Laser Shock Imprinting Using Soft Optical Disks.

Large-area patterning of metals in nanoscale has always been a challenge. Traditional microfabrication processes involve many high-cost steps, including etching and high-vacuum deposit, which limit the development of functional nanostructures, especially multiscale metallic patterns. Here, multiplex laser shock imprinting (MLSI) process is introduced to directly manufacture hierarchical micro/nanopatterns at a high strain rate on metallic surfaces using soft optical disks with 1D periodic trenches as molds. The unique metal/polymer layered structures in inexpensive soft optical disks make them strong candidates of molds for MLSI processes. The feasibility of MLSI on hard metals toward soft molds is studied using theoretical simulation. In addition, various types of hierarchical structures are fabricated via MLSI, and their optical reflectance can be modulated via a combination of depth (laser power density), width (types of molds), and angles (rotation between molds). The optical properties have been studied with surface plasmon polariton modes theory. This work opens a new way of manufacturing hierarchical micro/nanopatterns on metals, which is promising for future applications in fields of plasmonics and metasurfaces.

Observation of Optical and Electrical In-Plane Anisotropy in High-Mobility Few-Layer ZrTe5.

Transition metal pentatelluride ZrTe5 is a versatile material in condensed-matter physics and has been intensively studied since the 1980s. The most fascinating feature of ZrTe5 is that it is a 3D Dirac semimetal which has linear energy dispersion in all three dimensions in momentum space. Structure-wise, ZrTe5 is a layered material held together by weak interlayer van der Waals force. The combination of its unique band structure and 2D atomic structure provides a fertile ground for more potential exotic physical phenomena in ZrTe5 related to 3D Dirac semimentals. However, the physical properties of its few-layer form have yet to be thoroughly explored. Here we report strong optical and electrical in-plane anisotropy of mechanically exfoliated few-layer ZrTe5. Raman spectroscopy shows a significant intensity change with sample orientations, and the behavior of angle-resolved phonon modes at the Γ point is explained by theoretical calculations. DC conductance measurement indicates a 50% of difference along different in-plane directions. The diminishing of resistivity anomaly in few-layer samples indicates the evolution of band structure with a reduced thickness. A low-temperature Hall experiment sheds light on more intrinsic anisotropic electrical transport, with a hole mobility of 3000 and 1500 cm2/V·s along the a-axis and c-axis, respectively. Pronounced quantum oscillations in magnetoresistance are observed at low temperatures with the highest electron mobility up to 44 000 cm2/V·s.

AAV-mediated expression of an ADAMTS13 variant prevents shigatoxin-induced thrombotic thrombocytopenic purpura.

Severe deficiency of plasma ADAMTS13 activity causes thrombotic thrombocytopenic purpura (TTP), a life-threatening syndrome for which plasma is the only effective therapy currently available. As much as 5% of TTP cases are hereditary, resulting from mutations of the ADAMTS13 gene. Here, we report the efficacy and safety of recombinant adeno-associated virus serotype 8 (AAV8)-mediated expression of a murine ADAMTS13 variant (MDTCS), truncated after the spacer domain, in a murine model of TTP. Administration of AAV8-hAAT-mdtcs at doses greater than 2.6 × 10(11) vg/kg body weight resulted in sustained expression of plasma ADAMTS13 activity at therapeutic levels. Expression of the truncated ADAMTS13 variant eliminated circulating ultralarge von Willebrand factor multimers, prevented severe thrombocytopenia, and reduced mortality in Adamts13(-/-) disease-prone mice triggered by shigatoxin-2. These data support AAV vector-mediated expression of a comparable truncated ADAMTS13 variant as a novel therapeutic approach for hereditary TTP in humans.

3D stereolithography printing of graphene oxide reinforced complex architectures.

Properties of polymer based nanocomposites reply on distribution, concentration, geometry and property of nanofillers in polymer matrix. Increasing the concentration of carbon based nanomaterials, such as CNTs, in polymer matrix often results in stronger but more brittle material. Here, we demonstrated the first three-dimensional (3D) printed graphene oxide complex structures by stereolithography with good combination of strength and ductility. With only 0.2% GOs, the tensile strength is increased by 62.2% and elongation increased by 12.8%. Transmission electron microscope results show that the GOs were randomly aligned in the cross section of polymer. We investigated the strengthening mechanism of the 3D printed structure in terms of tensile strength and Young's modulus. It is found that an increase in ductility of the 3D printed nanocomposites is related to increase in crystallinity of GOs reinforced polymer. Compression test of 3D GOs structure reveals the metal-like failure model of GOs nanocomposites.

Gain-of-function ADAMTS13 variants that are resistant to autoantibodies against ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is primarily caused by immunoglobulin G (IgG) autoantibodies against A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, 13 (ADAMTS13). Nearly all adult idiopathic TTP patients harbor IgGs, which bind the spacer domain of ADAMTS13, a region critical for recognition and proteolysis of von Willebrand factor (VWF). We hypothesize that a modification of an exosite in the spacer domain may generate ADAMTS13 variants with reduced autoantibody binding while preserving or enhancing specific activity. Site-directed mutagenesis was used to generate a series of ADAMTS13 variants, and their functional properties were assessed. Of 24 novel ADAMTS13 variants, 2 (ie, M4, R660K/F592Y/R568K/Y661F and M5, R660K/F592Y/R568K/Y661F/Y665F) exhibited increased specific activity approximately 4- to 5-fold and approximately 10- to 12-fold cleaving a peptide VWF73 substrate and multimeric VWF, respectively. More interestingly, the gain-of-function ADAMTS13 variants were more resistant to inhibition by anti-ADAMTS13 autoantibodies from patients with acquired idiopathic TTP because of reduced binding by anti-ADAMTS13 IgGs. These results shed more light on the critical role of the exosite in the spacer domain in substrate recognition. Our findings also help understand the pathogenesis of acquired autoimmune TTP. The autoantibody-resistant ADAMTS13 variants may be further developed as a novel therapeutic for acquired TTP with inhibitors.

Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice.

Development of neutralizing Abs to blood coagulation factor VIII (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endocytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and retained its activity as measured by chromogenic assay. FVIII-R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4(+) T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A.

[ADAMTS13-Mediated Proteolytic Cleavage of Unusually Large von Willebrand Factor Polymers on Endothelial Cells in the Absence of Fluid Shear Stress].

OBJECTIVE: To investigate the molecular mechanism of proteolytic cleavage of unusually large von Willebrand Factor(ULVWF) on endothelial cells by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) in the absence of fluid shear stress, so as to provide a theoretical basis for the pathogenesis of thrombotic thrombocytopenic purpura (TTP) and other thrombotic disorders. METHODS: The ADAMTS13-mediated proteolysis of ULVWF on the surface of endothelial cells in the absence of fluid shear stress was observed through immunofluorescence microscopy. The variation in VWF antigen levels in the conditioned media were determined by ELISA assay. The levels of VWF and the proteolytic fragments released into the conditioned media were determined by ELISA assay and Western blot in the absence and presence of fluid shear stress or FVIII. The effect of ADAMTS13-mediated ULVWF cleavage on the normal distribution of plasma VWF multimers was evaluated by multimer analysis. Histamine stimulated human umbilical vein endothelial cells (HUVECs) were incubated with ADAMTS13 and various N- and C-terminally truncated mutants. Then the ULVWF that maintained binding to the cells were observed through immunofluorescence microscopy and the soluble ULVWF released from endothelial cells was determined by ELISA, so as to demonstrate the domains of ADAMTS13 required for proteolysis of ULVWF on endothelial cells. RESULTS: The ULVWF strings on the endothelial cell surface were rapidly proteolyzed by recombinant and plasma ADAMTS13 in the absence of fluid shear stress. This proteolytic processing of ULVWF depended on incubation time and ADAMTS13 concentration, but not shear stress and FVIII. The distribution of VWF releaseded by ADAMTS13-mediated proteolysis was quite similar to that secreted by endothelial cells under histamine stimulation, suggesting the ULVWF cleavage occured at the cell surface. The proteolysis of the ULVWF on endothelial cells required the Cys-rich(CysR) and spacer domains, but not the TSP1 2-8 and CUB domains of ADAMTS13. CONCLUSION: The ULVWF polymers on endothelial cells are sensitive to ADAMTS13-mediated cleavage even in the absence of fluid shear stress. The findings provide novel insight into the molecular mechanism of ADAMTS13-mediated ULVWF cleavage at the cellular level and may contribute to understanding of the pathogenesis of TTP and other thrombotic disorders.

Comparison of Short Curved Stems and Standard-length Single Wedged Stems for Cementless Total Hip Arthroplasty.

Purpose: The purpose of this study was to compare the clinical and radiographic outcomes with use of short-curved stems versus standard-length single wedged stems over a minimum follow-up period of five years. Materials and Methods: A retrospective study of primary total hip arthroplasties performed using the Fitmore® stem (127 hips, 122 patients) and the M/L taper® stem (195 hips, 187 patients) between October 2012 and June 2014 was conducted. The clinical and radiographic outcomes were obtained for evaluation over a minimum follow-up period of five years. Results: In both the Fitmore® and M/L taper® groups, the mean Harris hip score improved from 52.4 and 48.9 preoperatively to 93.3 and 94.5 at the final follow-up, respectively (P=0.980). The mean Western Ontario and McMaster Universities Osteoarthritis Index scores also improved from 73.3 and 76.8 preoperatively to 22.9 and 25.6 at the final follow-up, respectively (P=0.465). Fifteen hips (Fitmore®: 14 hips; M/L taper®: one hip, P<0.001) developed intraoperative cracks and were treated simultaneously with cerclage wiring. Radiography showed a radiolucent line in 24 hips in the Fitmore® group and 12 hips in the M/L taper® group (P=0.125). Cortical hypertrophy was detected in 29 hips (Fitmore® group: 28 hips; M/L taper® group: one hip, P<0.001). Conclusion: Similarly favorable clinical and radiographic outcomes were achieved with use of both short-curved stems and standard-length single wedged stems. However, higher cortical hypertrophy and a higher rate of femoral crack were observed with use of Fitmore® stems.

Decorating PtCo bimetallic alloy nanoparticles on graphene as sensors for glucose detection by catalyzing luminol chemiluminescence.

A new type of PtCo(x) @graphene nanocomposite is prepared by a simple chemical solution method, which can dramatically enhance the chemiluminescence (CL) intensity of luminol-H(2)O(2) system, making it possible for the detection of glucose through measuring the H(2)O(2) produced from its catalytic oxidation.

Genetic ablation of Adamts13 gene dramatically accelerates the formation of early atherosclerosis in a murine model.

OBJECTIVE: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) cleaves von Willebrand factor, thereby modulating thrombosis and inflammation. Low plasma ADAMTS13 activity is associated with cardiovascular events, including myocardial and cerebral infarction. Here, we investigated the role of ADAMTS13 in the development of early atherosclerosis in a murine model. METHODS AND RESULTS: Apolipoprotein E-null (ApoE(-/-)) and Adamts13-null (Adamts13(-/-)) ApoE(-/-) mice were fed with a high-fat Western diet for 12 weeks. Atherosclerotic lesions in the aorta and aortic roots were quantified after staining. Leukocyte rolling and adhesion onto cremaster venules after oxidative injury were determined by intravital microscopy. Although plasma cholesterol levels were largely similar in both groups, the extent of atherosclerotic lesions in the aorta en face and in the aortic roots in the Adamts13(-/-)ApoE(-/-) mice increased ≈ 5.5-fold (P=0.0017) and ≈ 6.1-fold (P=0.0037), respectively. In addition, the ratio of plasma high- to low-molecular-weight von Willebrand factor multimers increased ≈ 3-fold. The leukocyte rolling velocities were significantly reduced (P<0.001), with an increased number of leukocyte rolling (P=0.0026) and macrophage infiltration into the atherosclerotic lesions in the Adamts13(-/-)ApoE(-/-) mice. CONCLUSIONS: Our results suggest that ADAMTS13 plays a critical role in modulating the development of early atherosclerosis, likely through the proteolytic cleavage of ultra-large von Willebrand factor multimers, thereby inhibiting platelet deposition and inflammation.

Meta-analysis of the efficacy and safety of daratumumab in the treatment of multiple myeloma.

BACKGROUND: The treatment of multiple myeloma has significantly progressed over the past half-century. The purpose of this study was to perform a systematic review and meta-analysis in order to explore the efficacy and safety of daratumumab in treating multiple myeloma. AIM: To explore the efficacy and safety of daratumumab in treating multiple myeloma. METHODS: A systematic literature search was performed using Chinese and English databases, including the China National Knowledge Infrastructure, Wanfang, China Biology Medicine, VIP, the Cochrane Library, Embase, and PubMed. The search encompassed studies in treating multiple myeloma with daratumumab, spanning from the inception of the database to June 2023. Revman 5.1 software was used for analysis. RESULTS: Our analysis included eight English articles and one Chinese article of high quality. The meta-analysis results indicated that compared to other therapies, daratumumab could improve the overall response rate (ORR) [odds ratio (OR) = 2.67, 95% confidence interval (CI) = 2.01, 3.53, Z = 6.85, P < 0.00001], complete remission (CR) (OR = 2.87, 95%CI = 2.16, 3.83, Z = 7.23, P < 0.00001) and progression-free survival (PFS) time (hazard ratio = 0.48, 95%CI = 0.38,0.60, Z = 6.54, P < 0.00001) in patients with multiple myeloma. These differences were statistically significant. Additionally, these results suggested that daratumumab increases the risk of neutropenia and thrombocytopenia with minimal effect on the incidences of anemia and upper respiratory tract infections. CONCLUSION: Daratumumab can improve ORR, CR rate, and PFS in patients with multiple myeloma. It also increases the risk of neutropenia and thrombocytopenia, necessitating careful monitoring during its clinical application.

Circ_0088194 Regulates Proliferation, Migration, Apoptosis, and Inflammation by miR-30a-3p/ADAM10 Axis in Rheumatoid Arthritis Fibroblastic Synovial Cells.

Dysregulation of circular RNAs (circRNAs) has been observed in multiple diseases including rheumatoid arthritis (RA), and we investigated the role of the circ_0088194/microRNA (miR)-30a-3p/a disintegrin and metalloproteinase 10 (ADAM10) axis in RA. Circ_0088194, miR-30a-3p, and ADAM10 contents in RA tissues and RA-fibroblast-like synoviocytes (RA-FLSs) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Cell proliferation, migration, apoptosis, and inflammatory factor secretion of RA-FLSs were detected using 5-ethynyl-2'-deoxyuridine (EdU), wound healing assay, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). Targeting relationship between miR-30a-3p and circ_0088194 or ADAM10 was validated by luciferase reporter system, RNA immunoprecipitation (RIP), and RNA pull-down assays. Circ_0088194 and ADAM10 levels were increased, while miR-30a-3p was decreased in RA tissues and RA-FLSs. Circ_0088194 knockdown suppressed the growth, migration, and inflammation of RA-FLSs, while the upregulation of circ_0088194 showed opposite effects. Circ_0088194 directly targeted miR-30a-3p, ADAM10 was a target of miR-30a-3p, and circ_0088194 regulated the expression of ADAM10 by sponging miR-30a-3p. MiR-30a-3p inhibition restored the inhibition effects of circ_0088194 knockdown or RA-FLSs. Moreover, miR-30a-3p re-expression repressed growth, migration, and inflammatory response in RA-FLSs, which were reversed by ADAM10 overexpression. Circ_0088194 acted on miR-30a-3p/ADAM10 axis to promote the proliferation, migration, and inflammatory response, and inhibit apoptosis in RA-FLSs.