The PARP1 Inhibitor Niraparib Represses DNA Damage Repair and Synergizes with Temozolomide for Antimyeloma Effects.

Purpose: Poly(ADP-ribose) polymerase 1 (PARP1) is necessary for single-strand break (SSB) repair by sensing DNA breaks and facilitating DNA repair through poly ADP-ribosylation of several DNA-binding and repair proteins. Inhibition of PARP1 results in collapsed DNA replication fork and double-strand breaks (DSBs). Accumulation of DSBs goes beyond the capacity of DNA repair response, ultimately resulting in cell death. This work is aimed at assessing the synergistic effects of the DNA-damaging agent temozolomide (TMZ) and the PARP inhibitor niraparib (Nira) in human multiple myeloma (MM) cells. Materials and Methods: MM RPMI8226 and NCI-H929 cells were administered TMZ and/or Nira for 48 hours. CCK-8 was utilized for cell viability assessment. Cell proliferation and apoptosis were detected flow-cytometrically. Immunofluorescence was performed for detecting γH2A.X expression. Soft-agar colony formation assay was applied to evaluate the antiproliferative effect. The amounts of related proteins were obtained by immunoblot. The combination index was calculated with the CompuSyn software. A human plasmacytoma xenograft model was established to assess the anti-MM effects in vivo. The anti-MM activities of TMZ and/or Nira were evaluated by H&E staining, IHC, and the TUNEL assay. Results: The results demonstrated that cotreatment with TMZ and Nira promoted DNA damage, cell cycle arrest, and apoptotic death in cultured cells but also reduced MM xenograft growth in nude mice, yielding highly synergistic effects. Immunoblot revealed that TMZ and Nira cotreatment markedly increased the expression of p-ATM, p-CHK2, RAD51, and γH2A.X, indicating the suppression of DNA damage response (DDR) and elevated DSB accumulation. Conclusion: Inhibition of PARP1 sensitizes genotoxic agents and represents an important therapeutic approach for MM. These findings provide preliminary evidence for combining PARP1 inhibitors with TMZ for MM treatment.

Clinical Significance of a Novel Knee Joint Stability Assessment System for Evaluating Anterior Cruciate Ligament Deficient Knees.

OBJECTIVE: To investigate the six degrees of freedom (6DOF) kinematics of anterior cruciate ligament (ACL) deficient knees during gait and to explore the clinical significance of a novel knee joint stability assessment system (Opti_Knee, Innomotion, Shanghai, China) in comparison with imaging and arthroscopic examination. METHODS: Three subjects diagnosed with ACL deficient knees on the basis of preoperative MRI and CT findings were subjected to treadmill gait analysis. Motion of both knees in 6DOF was measured and analyzed with an optical joint kinematics measurement system. Arthroscopic examination, the gold standard, was performed to confirm the final diagnosis and the clinical diagnosis of ACL deficiency by imaging and motion marker techniques compared with this gold standard. RESULTS: Only two of the three subjects diagnosed with ACL deficiency by imaging techniques were later confirmed to have this condition by arthroscopic examination; the third was found to have an intact ACL. When the kinematics of their injured and contralateral knees were compared, abnormalities were found in the two subjects confirmed by arthroscopy to be ACL deficient However, no kinematic difference between the two knees was found in the ACL intact subject. CONCLUSIONS: Opti_Knee (Innomotion) can detect abnormal kinematics in ACL deficient knees and thus provides an effective way of assisting the diagnosis of this condition and has potential for clinical application.

Direct comparison of the diagnostic accuracy between blood and cerebrospinal fluid procalcitonin levels in patients with meningitis.

OBJECTIVE: To compare the clinical utility of serum and cerebrospinal fluid (CSF) procalcitonin (PCT) for the diagnosis of bacterial meningitis (BM) among patients with suspected meningitis. METHODS: Patients with meningitis-like symptoms (n=120), admitted to the Second People's Hospital of Wuxi or the Changhai Hospital of Shanghai between January 2011 and December 2013, were prospectively and consecutively enrolled in this study. BM was finally diagnosed by CSF culture, Gram staining, quantitative polymerase chain reaction (qPCR), and treatment response. The diagnostic accuracy of the serum and CSF PCT was assessed by receiver operator characteristic (ROC) curve analysis. The relationship between CSF and serum PCT levels as well as the CSF leukocyte count and protein level was analyzed by Spearman's correlation analysis. RESULTS: PCT level in both the serum and CSF was significantly increased in the BM patients. The area under ROC curve of serum PCT for the diagnosis of BM was 0.96 (95% confidence interval (CI): 0.93-1.00), significantly higher than that of CSF PCT (0.90, 95% CI: 0.83-0.96). Using 0.88ng/mL as the threshold, the diagnostic sensitivity, specificity, and accuracy of serum PCT for the diagnosis of BM were 0.87 (95% CI, 0.73-0.95), 1.00 (95% CI, 0.95-1.00), and 95%, respectively. The serum PCT level was positively correlated with the CSF PCT level, leukocyte count, and protein level. CONCLUSION: Both the serum and CSF PCT had a high diagnostic value for BM among suspected meningitis patients, and serum PCT demonstrated a superior diagnostic value compared to CSF PCT.

Biomechanics of single-tunnel double-bundle anterior cruciate ligament reconstruction using fixation with a unique expandable interference screw.

BACKGROUND: Single-tunnel double-bundle (STDB) anterior cruciate ligament (ACL) reconstruction can restore biomechanical function and anatomic structure, but existing methods of graft fixation are not adequate. The aims of this study are to examine knee biomechanics after STDB reconstruction using a unique expandable interference screw for fixation. METHODS: The biomechanical parameters of six pairs of human cadaveric knee specimens were measured with the ACL intact, after ACL removal, and after STDB reconstruction using the interference screw or single-tunnel single-bundle (STSB) reconstruction. Anterior tibial translation under 134 N anterior tibial load in a neutral position as well as in 15° and 30° internal and external knee rotation and the internal tibial rotation angle under the rotatory load (5 N·m internal tibial rotation) were measured. RESULTS: Anterior tibial translations at each degree of knee flexion in the STDB group were significantly less than in the STSB group (all, P<0.05). The internal rotation angles in the STSB group at five flexion angles were significantly higher than in the ACL intact group, whereas there were significantly less than those of the ACL absent group (P<0.05). Under rotatory loads in the neutral position, the tibial internal rotation angles of the STDB group were significantly lower than in the STSB group at all flexion angles (all, P<0.05). CONCLUSIONS: STDB ACL reconstruction with the expandable interference screw provides better anteroposterior and rotational stability than STSB reconstruction. CLINICAL RELEVANCE: The technique provides the advantages of double-bundle reconstruction using a single-tunnel technique.

[Changes of red cell immune function and T-lymphocyte subsets in children with bronchiolitis].

OBJECTIVE: To study the changes of red cell immune function and T-lymphocyte subsets in children with bronchiolitis and their possible roles in the pathogenesis of bronchiolitis. METHODS: Forty-five children with bronchiolitis and 30 healthy controls were enrolled. Red cell immune complex rosette (RBC-ICR) and red cell C3b receptor rosette (RBC-C3bRR) were detected. The percentages of CD3+, CD4+ and CD8+ cells were assayed by flow cytometry. RESULTS: RBC-C3bRRï¼»(13.6 ± 6.2)% vs (18.0 ± 7.4)%] and the percentage of CD8+ cells [(21.6 ± 4.4)% vs (25.6 ± 5.2) %ï¼½ in the bronchiolitis group were lower than those in the control group (P<0.01). The percentage of CD3+ cells ï¼»(59.9 ± 6.7)% vs (52.1 ± 8.3)%ï¼½ and CD4+ cells [(53.5 ± 6.2)% vs (46.8 ± 4.9)%] and RBC-ICR [(8.3 ± 3.5)% vs (6.1 ± 2.5)%] in the bronchiolitis group were higher than those in the control group (P<0.01). The percentage of CD4+ cells was positively correlated with RBC-ICR (r=0.63,P<0.05) and negatively correlated with RBC-C3bRR (r=-0.82,P<0.01). CONCLUSIONS: There are dysfunctions of red cell immune and T-lymphocyte subsets in children with brochiolitis, which may play a role in the pathogenesis of brochiolitis.

[Impact of muscle strength on knee joint stability in static loading].

OBJECTIVE: To study the in vivo stability of normal and anterior cruciate ligament (ACL)-injured knee joint before and after epidural anesthesia under 134 N pre-loading and evaluate the influence of muscular tension on the knee stability. METHODS: Eight volunteers with unilateral ACL rupture and normal contralateral knee were enrolled in this study. CT (3D) images and 2 orthogonal images of the knee were captured at 0°, 30°, 60°, and 90° under 134 N pre-loading. The orthogonal images were used to recreate the in vivo knee positions at each of the targeted flexion angles by 2D/3D registration to analyze the tibial translation data. RESULTS: The anterior tibia translation of both the intact and ACL-injured knees after anesthesia was significantly different from that before anesthesia at all the angles (P<0.05). The anterior tibial translation of the intact knee after anesthesia increased by 1.7 mm at 0°, 2.7 mm at 30°, 2.6 mm at 60°, and 2.3 mm at 90°, as compare to the increase of ACL-injured knee by 4.2 mm, 2.6 mm, 1.2 mm, and 1.6 mm, respectively. CONCLUSION: The muscular tension has evident influence on the knee stability in static loading.

Sellmeier's equation and the expression of the thermal refractive-index coefficient for a Nd0.007Gd0.993VO4 crystal.

The principal refractive indices of a Nd0.007Gd0.993VO4 crystal for wavelengths of 0.488, 0.6328, 1.064, 1.0795, and 1.3414 microm under the temperature range of 20-170 degrees C are measured by the autocollimation method, and the Sellmeier's equation and the expression of the thermal refractive-index coefficient are then obtained. The reliability of these results is checked by comparing the calculated values with the measured values for the measured wavelengths and the temperature region, as well as with the published values by Studenikin et al. [Quantum Electron. 25, 1162-1165 (1995)] for wavelengths of 0.491, 0.546, 0.578, 0.632, 0.808, and 1.062 microm at 20 degrees C. In addition, the birefringence and the thermal coefficient of the birefringence were obtained by measured results. The results show that the birefringence is larger than that of a YVO4 crystal and that the thermal coefficient of birefringence is less than that of a YVO4 crystal. Therefore it can be expected that the GdVO4 crystal is not only an excellent laser crystal but also an excellent birefringent crystal used in a modern optical transmission system as a passive fiber-optic component.