Compare the efficacy of antifungal agents as primary therapy for invasive aspergillosis: a network meta-analysis.

BACKGROUND: Several antifungal agents are available for primary therapy in patients with invasive aspergillosis (IA). Although a few studies have compared the effectiveness of different antifungal agents in treating IA, there has yet to be a definitive agreement on the best choice. Herein, we perform a network meta-analysis comparing the efficacy of different antifungal agents in IA. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Clinical Trials databases to find studies (both randomized controlled trials [RCTs] and observational) that reported on treatment outcomes with antifungal agents for patients with IA. The study quality was assessed using the revised tool for risk of bias and the Newcastle Ottawa scale, respectively. We performed a network meta-analysis (NMA) to summarize the evidence on antifungal agents' efficacy (favourable response and mortality). RESULTS: We found 12 studies (2428 patients) investigating 11 antifungal agents in the primary therapy of IA. There were 5 RCTs and 7 observational studies. When treated with monotherapy, isavuconazole was associated with the best probability of favourable response (SUCRA, 77.9%; mean rank, 3.2) and the best reduction mortality against IA (SUCRA, 69.1%; mean rank, 4.1), followed by voriconazole and posaconazole. When treated with combination therapy, Liposomal amphotericin B plus caspofungin was the therapy associated with the best probability of favourable response (SUCRA, 84.1%; mean rank, 2.6) and the best reduction mortality (SUCRA, 88.2%; mean rank, 2.2) against IA. CONCLUSION: These findings suggest that isavuconazole, voriconazole, and posaconazole may be the best antifungal agents as the primary therapy for IA. Liposomal amphotericin B plus caspofungin could be an alternative option.

Catalytic Enantioselective Synthesis of 2,3'-Bis(indolyl)methanes Bearing All-Carbon Quaternary Stereocenters via 2-Indole Imine Methides.

An organocatalytic enantioselective formal hydroarylation of 2-vinyl indoles for the preparation of enantioenriched 2,3'-bis(indolyl)methanes bearing an all-carbon quaternary stereocenter is described. This reaction features mild conditions, low catalyst loading, excellent efficiency and enantioselectivity. The obtained products showed promising anticancer activity.

Recent Advances in Silica-Nanomaterial-Assisted Lateral Flow Assay.

Lateral flow assays (LFAs) have attracted much attention as rapid and affordable point-of-care devices for medical diagnostics. The global SARS-CoV-2 pandemic has further highlighted the importance of LFAs. Many efforts have been made to enhance the sensitivity of LFAs. In recent years, silica nanomaterials have been used to either amplify the signal of label materials or provide stability, resulting in better detection performance. In this review, the recent progress of silica-nanomaterial-assisted LFAs is summarized. The impact of the structure of silica nanomaterials on LFA performance, the challenges and prospects in this research area are also discussed.

Is the future of peer review automated?

The rising rate of preprints and publications, combined with persistent inadequate reporting practices and problems with study design and execution, have strained the traditional peer review system. Automated screening tools could potentially enhance peer review by helping authors, journal editors, and reviewers to identify beneficial practices and common problems in preprints or submitted manuscripts. Tools can screen many papers quickly, and may be particularly helpful in assessing compliance with journal policies and with straightforward items in reporting guidelines. However, existing tools cannot understand or interpret the paper in the context of the scientific literature. Tools cannot yet determine whether the methods used are suitable to answer the research question, or whether the data support the authors' conclusions. Editors and peer reviewers are essential for assessing journal fit and the overall quality of a paper, including the experimental design, the soundness of the study's conclusions, potential impact and innovation. Automated screening tools cannot replace peer review, but may aid authors, reviewers, and editors in improving scientific papers. Strategies for responsible use of automated tools in peer review may include setting performance criteria for tools, transparently reporting tool performance and use, and training users to interpret reports.

Catalytic Asymmetric Allylic Substitution/Isomerization with Central Chirality Transposition.

We have developed a catalytic asymmetric allylic substitution/isomerization process with central chirality transposition. This process takes advantage of the ambident reactivity of the 2-indole imine methide generated in situ from racemic tertiary indolylmethanols. The use of a suitable chiral phosphoric acid catalyst and an ortho-directing group allowed regioselective formation a C-C bond at the 3 position but enantiocontrolled construction of a stereogenic center at the 2-benzylic position.

Vertebrae Labeling via End-to-End Integral Regression Localization and Multi-Label Classification Network.

Accurate identification and localization of the vertebrae in CT scans is a critical and standard pre-processing step for clinical spinal diagnosis and treatment. Existing methods are mainly based on the integration of multiple neural networks, and most of them use heatmaps to locate the vertebrae's centroid. However, the process of obtaining vertebrae's centroid coordinates using heatmaps is non-differentiable, so it is impossible to train the network to label the vertebrae directly. Therefore, for end-to-end differential training of vertebrae coordinates on CT scans, a robust and accurate automatic vertebral labeling algorithm is proposed in this study. First, a novel end-to-end integral regression localization and multi-label classification network is developed, which can capture multi-scale features and also utilize the residual module and skip connection to fuse the multi-level features. Second, to solve the problem that the process of finding coordinates is non-differentiable and the spatial structure of location being destroyed, an integral regression module is used in the localization network. It combines the advantages of heatmaps representation and direct regression coordinates to achieve end-to-end training and can be compatible with any key point detection methods of medical images based on heatmaps. Finally, multi-label classification of vertebrae is carried out to improve the identification rate, which uses bidirectional long short-term memory (Bi-LSTM) online to enhance the learning of long contextual information of vertebrae. The proposed method is evaluated on a challenging data set, and the results are significantly better than state-of-the-art methods (identification rate is 91.1% and the mean localization error is 2.2 mm). The method is evaluated on a new CT data set, and the results show that our method has good generalization.

CLINICAL APPLICATION OF RT-PCR IN TUBERCULOSIS DNA DETECTION COMBINED WITH TB-IGRA IN THE DIAGNOSIS OF SPUTUM SMEAR-NEGATIVE PULMONARY TUBERCULOSIS.

The aim was to investigate detection of pulmonary alveolar lavage fluid tuberculosis DNA by real-time fluorescent polymerase chain reaction (RT-PCR) combined with clinical application of the sputum smear-negative pulmonary tuberculosis diagnosis with TB interferon-γ release assay (TB-IGRA). From October 2014 to October 2015, 632 outpatients and inpatients treated in our hospital were randomly selected, of which 459 patients as the research group managed with RT-PCR detection combined with TB-IGRA and 173 patients as the control group undergoing electronic bronchoscopy alveolar lavage fluid detection, with detection results statistically evaluated. The positive rate in the research group was 96.51%, i.e. significantly higher than that in the control group (66.47%), yielding a statistically significant difference (χ2=109.68, p=0.00). The true positive rate was 97.7% in the research group and 67.92% in the control group; the true positive rate was significantly higher in the research group patients as compared with the control group, yielding a statistically significant difference (χ2=112.04, p=0.00). The sensitivity and specificity, as well as Youden index were significantly higher in the research group as compared with the control group. In conclusion, TB DNA detection by RT-PCR combined with TB-IGRA is a very good method of diagnosing tuberculosis, and it can be implemented in clinical diagnosis of pulmonary tuberculosis.

Catalytic Enantioselective Synthesis of 2,3-Dihydrobenzo[b]oxepines via Asymmetric Oxetane Opening by Internal Carbon Nucleophiles.

An intramolecular C-C formation process based on catalytic asymmetric oxetane opening by carbon nucleophiles has been developed, which provides rapid access to a range of valuable enantioenriched 2,3-dihydrobenzo[b]oxepines. With the combination of Sc(OTf)3 and a Box ligand, good chemical efficiency and enantioselectivity were achieved under mild conditions. The products are also useful precursors to other valuable structures, such as the bicyclo[3.2.2]nonane derivatives.

Graphical integrity issues in open access publications: Detection and patterns of proportional ink violations.

Academic graphs are essential for communicating complex scientific ideas and results. To ensure that these graphs truthfully reflect underlying data and relationships, visualization researchers have proposed several principles to guide the graph creation process. However, the extent of violations of these principles in academic publications is unknown. In this work, we develop a deep learning-based method to accurately measure violations of the proportional ink principle (AUC = 0.917), which states that the size of shaded areas in graphs should be consistent with their corresponding quantities. We apply our method to analyze a large sample of bar charts contained in 300K figures from open access publications. Our results estimate that 5% of bar charts contain proportional ink violations. Further analysis reveals that these graphical integrity issues are significantly more prevalent in some research fields, such as psychology and computer science, and some regions of the globe. Additionally, we find no temporal and seniority trends in violations. Finally, apart from openly releasing our large annotated dataset and method, we discuss how computational research integrity could be part of peer-review and the publication processes.

Short-echo-time magnitude image derived from quantitative susceptibility mapping could resemble neuromelanin-sensitive MRI image in substantia nigra.

BACKGROUND: In this study, we explored whether the proposed short-echo-time magnitude (setMag) image derived from quantitative susceptibility mapping (QSM) could resemble NM-MRI image in substantia nigra (SN), by quantitatively comparing the spatial similarity and diagnosis performances for Parkinson's disease (PD). METHODS: QSM and NM-MRI were performed in 18 PD patients and 15 healthy controls (HCs). The setMag images were calculated using the short-echo-time magnitude images. Bilateral hyperintensity areas of SN (SNhyper) were manually segmented on setMag and NM-MRI images by two raters in a blinded manner. The inter-rater reliability was evaluated by the intraclass correlation coefficients (ICC) and the Dice similarity coefficient (DSC). Then the inter-modality (i.e. setMag and NM-MRI) spatial similarity was quantitatively assessed using DSC and volume of the consensual voxels identified by both of two raters. The performances of mean SNhyper volume for PD diagnosis on setMag and NM-MRI images were evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The SNhyper segmented by two raters showed substantial to excellent inter-rater reliability for both setMag and NM-MRI images. The DSCs of SNhyper between setMag and NM-MRI images showed substantial to excellent voxel-wise overlap in HCs (0.80 ~ 0.83) and PD (0.73 ~ 0.76), and no significant difference was found between the SNhyper volumes of setMag and NM-MRI images in either HCs or PD (p > 0.05). The mean SNhyper volume was significantly decreased in PD patients in comparison with HCs on both setMag images (77.61 mm3 vs 95.99 mm3, p < 0.0001) and NM-MRI images (79.06 mm3 vs 96.00 mm3, p < 0.0001). Areas under the curve (AUCs) of mean SNhyper volume for PD diagnosis were 0.904 on setMag and 0.906 on NM-MRI images. No significant difference was found between the two curves (p = 0.96). CONCLUSIONS: SNhyper on setMag derived from QSM demonstrated substantial spatial overlap with that on NM-MRI and provided comparable PD diagnostic performance, providing a new QSM-based multi-contrast imaging strategy for future PD studies.

Spigelian hernia in the right upper abdominal wall: a case report.

BACKGROUND: Spigelian hernia (SH) is rare and constitutes less than 2% of all hernias. It is reported that more than 90% of SHs lie in the "Spigelian belt", but SH in the upper abdominal wall is extremely uncommon. Here, we report a case of SH in the right upper quadrant of abdomen. CASE PRESENTATION: A 38-year-old female was admitted to hospital with complaints of abdominal pain and right upper quadrant mass for 10 days. Contrast-enhanced computed tomography (CECT) of abdomen revealed the dilated small intestine between the swelling ventral muscles in the right upper abdominal wall which suggested a ventral hernia. The surgeons considered it was a spontaneous hernia because there was no history of surgery or trauma in the upper abdomen. About two hours later, the patient underwent emergency surgery. According to laparotomy, a diagnosis of SH with ileum herniation in the right upper abdominal wall was confirmed. The necrotic ileum segment was resected. Meanwhile the abdominal wall defect was repaired by suturing the internal oblique and transverse muscles to the rectus sheath. The patient had a favorable outcome for 1 year without recurrence. CONCLUSION: A mass and pain in the upper abdominal wall may suggest an atypical SH. SH occurring in the upper abdominal wall is a rare condition with possibility of dire outcome if not managed early.

Fabrication of acellular nerve allograft through chemical extraction and efficacy with the use of the graft in repair of rat sciatic nerve defect / 中华创伤杂志

Objective To evaluate regenerative nerve and functional recovery of target muscle in rats with sciatic nerve defect bridged by acellular nerve allograft made through chemical extraction.Methods Sciatic nerve of SD rats was processed in a volume fraction of 3％ Triton X-lO0 solution and 40 g/L sodium deoxycholate solution.Morphology of myelin sheath,axons and basal lamina tubes of sciatic nerve segments was observed under the light microscopy before and after the chemical processing.Twenty-five Wistar rats were divided into acellular nerve allograft group (n =10),autograft group (n =10) and normal control group(n =5) according to the random number table.A 1 cm sciatic nerve defect was created in acellular nerve allograft group and autograft group,and was respectively bridged by acellular nerve allograft and autograft.Sciatic nerve function index (SFI) was measured every two weeks.Twelve weeks after surgery,nerve conduction velocity (NCV),recovery rate of compound muscle action potential (CMAP) and recovery rate of muscle force were measured in each group.Results Cellular components including myelin sheath and axons were removed thoroughly,but the basal lamina tubes were preserved completely.At postoperative 2,4,6,8,10 and 12 weeks,SFI in normal control group (-1.7±5.9,-0.3 ±2.5,0.8 ±4.1,-1.4±3.6,-2.5 ±5.7 and-2.1±3.2) was superior over autograft group (-94.3±3.7,-90.1±4.1,-63.7±7.8,-51.9±8.2,-48.8±8.6 and -44.3 ± 10.5) and acellular nerve allograft group (-97.1 ± 5.3,-91.2 ± 6.1,-70.6 ± 5.5,-60.4±6.2,-58.2 ±10.2 and-56.4 ±8.0) (P ＜0.01).At postoperative 6,8,10 and 12 weeks,SFI in autograft group were better than those in acellular nerve allograft group (P ＜0.05).NCV [(61.6 ± 8.1) m/s],recovery rate of CMAP[(98.7 ± 5.9) ％] and recovery rate of muscle force [(101.8 ± 6.6) ％] in normal control group were higher than those in acellular nerve allograft group [(22.3 ± 4.7) m/s,(40.3 ± 9.2) ％ and (43.8 ± 9.3) ％] and those in autograft group [(29.0 ±5.5) m/s,(52.5 ± 10.6) ％ and (54.3 ± 10.5) ％] (P ＜ 0.01).NCV,recovery rate of CMAP and recovery rate of muscle force in autograft group were better than those in acellular nerve allograft group (P ＜ 0.05).Conclusions Acellular nerve segments are harvested satisfactorily by chemical extraction.Sciatic nerve defect in rats can be cured with the acellular nerve allograft,but the repair effect of autograft is relatively better.

Mutation analysis of the PTPN11 gene in a family with LEOPARD syndrome / 中华皮肤科杂志

Objective To detect mutations in the PTPN11 gene in a family with LEOPARD syndrome (LS).Methods Clinical data were collected from a 7-year-old boy patient with LS.Peripheral blood was obtained from the patient,both of his parents,and 50 healthy controls.All the exons and their flanking sequences of the PTPN11 gene were amplified by PCR followed by direct DNA sequencing.Results A heterozygous missense mutation c.836A ＞ G,which resulted in a substitution of TAT by TGT at codon 279,was found in exon 7 of the PTPN11 gene in the patient.No mutation was detected in the unaffected parents or healthy controls.Conclusion The missense mutation c.836A ＞ G may be the cause of the phenotype of LS in this family.

[Association between hepatitis B virus infection and risk of pancreatic cancer: a meta-analysis].

OBJECTIVE: To investigate the relationship between hepatitis B virus (HBV) infection and risk of pancreatic cancer. METHODS: Various English and Chinese language literature databases, including PubMed, Web of Knowledge, Embase, Cochrane Library and the Chinese National Knowledge Infrastructure, were searched for case-control studies comparing rates of HBV infection and pancreatic cancer. The RevMan meta analysis software, version 5.0, was used to perform the meta-analysis of the 6 included studies. RESULTS: Compared with the control group, the pancreatic cancer group had a significantly higher rate of positivity for hepatitis B surface antigen (HBsAg) (8.87% vs.5.86%, odds ratio (OR) =1.24, 95% confidence interval (CI):1.06 to 1.47, P =0.009) and a lower rate of patients never exposed to HBV (defined as HBsAg(-)/hepatitis B core antibody (anti-HBc)(-) (69.4% vs.77.1%, OR =0.68, 95% CI:0.51 to 0.92, P =0.01). There was no significant difference between the two groups in the rate of hepatitis B e antigen positivity (P =0.55). CONCLUSION: HBV-infected patients with HBsAg(+) status are at greater risk of developing pancreatic cancer; however, since most of the research studies evaluated were conducted in Asians, the generalizability of this conclusion is unknown.

A noncontact resonance frequency detection technique for the assessment of the interfacial bone defect around a dental implant.

This study employed a noncontact resonance frequency (RF) detection technique that was developed by our group to evaluate the interfacial bone in in vitro implant-bone models. Based on our method, the implant-bone structure was excited by the acoustic energy of a loudspeaker, and its vibration response was acquired with a capacitance sensor. The spectral analysis was used to characterize the first RF value. Two types of in vitro defect models, Buccal-Lingual (BL) and Mesial-Distal (MD), were constructed for the verification. The measurements of the RF for a defect model clamped at four different heights (9, 10, 11, and 12 mm) were performed in two sensing directions (BL and MD). Moreover, each model was also analyzed using an Osstell Mentor. The obtained two parameters, RF and ISQ (Implant Stability Quotient), were statistically analyzed through one-way analysis of variance (ANOVA) and linear regression analysis for comparisons. The RF and the ISQ values obtained for all of the defect models at the four clamp heights decreased significantly (p < 0.05) with an increase in the severity of the defect. The two parameters for each imperfection increase significantly (p < 0.05) with an increase in the clamp height. Additionally, the RFs of all of the defect models are linearly correlated with their corresponding ISQs for the four clamp heights and the two measuring orientations. Therefore, our developed technique is feasible for the assessment of the postoperative healing around a dental implant.

[Effects of Notch signaling pathway and vascular endothelial growth factor gene on the functions of endothelial cells derived from rat bone marrow mesenchymal stem cells].

OBJECTIVE: To explore the effects of Notch signaling pathway and the vascular endothelial growth factor [VEGF(165)] gene on the functions of endothelial cells derived from rat bone marrow mesenchymal stem cells (MSCs). METHODS: Isolated and cultivated rat bone marrow MSCs in vitro, then the cells were treated by VEGF165 and basic fibroblast growth factor (bFGF) for 2 weeks to induce them to differentiate into endothelial cells. The gene of VEGF165 was transfected into differentiated endothelial cells to promote the functions of the cells. The receptor Notch1 and the ligand Jagged1 of the Notch signaling were detected by reverse transcription-polymerase chain reaction (RT-PCR) before and after the transfection. γ-secretase inhibitor L-685458 was used to block Notch pathway. Migration ability of cells was detected by scarification test. Cells were inoculated on semisolid gel to study their ability of forming capillary-like structure. RESULTS: After transfection, VEGF165 mRNA could be detected on the differentiated endothelial cells. The expression of Jagged1 mRNA was up regulated(1.08 ± 0.01 vs. 1.01 ± 0.02,P < 0.01) and there was no change in Notch1 mRNA(0.60 ± 0.02 vs. 0.59 ± 0.01,P > 0.05). The ability of migration was enhanced (number of cells on the scratched area:46.45 ± 4.46 vs. 41.61 ± 1.42,P < 0.05), and the ability of forming capillary-like structure on semisolid gel showed no change (cells classification: 3.00 ± 0.89 vs. 2.00 ± 0.89,P > 0.05). After the transfection, using the γ-secretase inhibitor L-685458 to block the Notch signaling transduction, the ability of migration of the differentiated endothelial cells (number of cells on the scratched area: 51.72 ± 3.47 vs. 46.45 ± 4.46,P < 0.05), and that of forming capillary--like structure (cells classification: 4.17 ± 0.75 vs. 3.00 ± 0.89, P < 0.05), was also further enhanced. CONCLUSION: Transfection of the gene of VEGF165 into the differentiated endothelial cells can reinforce the function of these cells, and when Notch signaling was blocked, this effect can be further amplified.

Biomechanical study on the edge shapes for penetrating keratoplasty.

A parametric study to investigate the compressive and the shear stress distributions for various edge shapes created during penetrating keratoplasty (PK) using femtosecond laser is reported. The finite element analysis has been implemented using ABAQUS to study the cornea with various edge shapes, namely the standard edge shape, the zigzag edge shape, the top hat edge shape and the mushroom edge shape for PK. The ratio of maximum compressive stress to maximum shear stress is used as the main factor to assess the relative merits of wound healing rate for different edge shapes. For the typical values of tissue mechanical properties, the zigzag edge shape has the highest ratio of maximum compressive stress to maximum shear stress (11.1 in the xy-direction and 3.7 in the yz-direction), followed by the mushroom edge shape (7.7 in the xy-direction and 3.2 in the yz-direction). The ratios for the top hat and the standard edge shapes are even lower in both directions. A sensitivity analysis of the model has been done to demonstrate that the zigzag edge shape always results in the highest ratios of stresses regardless of the difference in the tissue mechanical properties. The zigzag edge shape also gives the lowest dioptric power D = 45.4. The present results imply that the zigzag edge shape provides the best wound healing rate and optical outcome among the four edge shapes models for PK.

[The role of Notch signaling during the differentiation of rat bone marrow mesenchymal stem cells into endothelial cells].

OBJECTIVE: To research the role of Notch signaling during the differentiation of bone marrow mesenchymal stem cells (MSCs) into endothelial cells and its effect on the functions of the differentiated cells. METHODS: Rat bone marrow MSCs were isolated and cultured in vitro, then the cells were treated with vascular endothelial growth factor (VEGF165) and basic fibroblast growth factor (bFGF) for 2 weeks to induce it to differentiate into endothelial cells. The differentiated cells were identified by fluorescence immunoassay. The receptors and ligands of the Notch signaling were detected by reverse transcription-polymerase chain reaction (RT-PCR) before and after the differentiation. γ-secretase inhibitor was used to block Notch pathway. Migration ability of cells were assessed by scarification test. Cells were inoculated on semisolid gel to study their ability of forming the capillary-like structure. RESULTS: After inducing MSCs to differentiate into endothelial cells by VEGF165 and bFGF, MSCs gained the characteristics of the endothelial cells with expression of CD31 and Flk1. There were Notch1 mRNA and Jagged1 mRNA expressions in rat bone marrow MSCs. The expression changes in the receptor Notch1 were not statistically significant on the differentiated cells (0.59±0.01 vs. 0.59±0.01, P>0.05), but there was a trend towards an increase of Jagged1 mRNA (1.01±0.02 vs. 0.99±0.03, P>0.05). When Notch pathway was blocked, the differentiated cells' migration ability was increased (number of cells on the scratched area: 44.61±4.34 vs. 40.06±2.43, P<0.05), and the ability of forming capillary-like structure was also increased (cells classification: 3.67±0.82 vs. 2.00±0.89, P<0.01). CONCLUSION: Notch signaling may have an important role during the differentiation of MSCs into endothelial cells. The function of differentiated cells were strengthened when Notch pathway was blocked.

Different clinical characteristics between polymicrobial and monomicrobial Aeromonas bacteremia--a study of 216 cases.

BACKGROUND: Part of Aeromonas bacteremia is polymicrobial infection. However, a clinical comparison of monomicrobial and polymicrobial Aeromonas bacteremia has not hitherto been reported. METHODS: A retrospective analysis of medical records of patients with Aeromonas bacteremia at three large referral hospitals in Taiwan for an 8-year period (2001-2008) was conducted. RESULTS: There were 154 patients with monomicrobial Aeromonas bacteremia and 62 patients with polymicrobial Aeromonas bacteremia. In the polymicrobial infections, E. coli was the most common combined pathogen (42%), followed by Klebsiella spp. (24%) and Enterobacter spp. (16%). Multivariate logistic regression analysis revealed solid cancer as the risk factor for polymicrobial Aeromonas bacteremia, with male gender and cirrhosis as risk factors for monomicrobial Aeromonas bacteremia. However, of all types of solid cancer, hepatoma was associated with monomicrobial Aeromonas bacteremia. APACHE II score was the most important prognostic factor in both groups. CONCLUSION: Aeromonas bacteremia in patients with cirrhosis or male gender tended to be monomicrobial. Polymicrobial Aeromonas bacteremia was associated with solid cancers. In either polymicrobial or monomicrobial Aeromonas bacteremia, prognosis could be predicted according to disease severity measured by APACHE II score.

Synergistic mitosis-arresting effects of arsenic trioxide and paclitaxel on human malignant lymphocytes.

The treatment outcome of acute lymphoblastic leukemia (ALL) has improved steadily over the last 50 years. However, the cure rates are unlikely to be raised further with current therapies. Since increasing the dosage of chemotherapeutic agents could also elevate toxicity, a solution to how one could achieve maximum therapeutic effect with the minimum dosage possible is imminent. One possibility is the employment of combination drug therapies. Arsenic trioxide (ATO) is a widely used drug for acute promyelocytic leukemia (APL). Its combination with other drugs presented therapeutic activities in malignant cancers other than APL. Considering the fact that ATO induces mitotic arrest prior to apoptosis induction, we attempted to investigate the potential anti-cancer effects of ATO in combination with the microtubule-stabilizing agent, paclitaxel (PTX), using malignant lymphocytes as in vitro models. Three malignant lymphocytic cell lines and primary cells were treated with ATO and/or PTX. Using the Chou-Talalay analysis for evaluation of combined effect of ATO and PTX, we found a synergistic effect of the two drugs in the inhibition of cell growth. We also found that the combination of ATO and PTX at low concentrations synergistically induced mitotic arrest followed by apoptosis in malignant lymphocytes, which increased phosphorylated cyclin-dependent kinase 1 (Cdk1) on Thr(161) and promoted the dysregulated activation of Cdk1. The ATO/PTX combination also significantly enhanced the activation of spindle checkpoint by inducing the formation of the inhibitory checkpoint complex BubR1/Cdc20. Our study provided the first in vitro demonstration that low concentrations of ATO and PTX synergistically induce mitotic arrest in malignant lymphocytes.