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BackgroundHaemorrhages of brainstem cavernous malformations (CMs) can lead to neurological deficits, the natural history of which is uncertain. The study aimed to evaluate the neurological outcomes of untreated brainstem CMs and to identify the adverse factors associated with worsened outcomes.MethodsFrom 2009 to 2015, 698 patients (321 women) with brainstem CMs were entered into the prospective cohort after excluding patients lost to follow-up (n=43). All patients were registered, clinical data were collected and scheduled follow-up was performed.ResultsAfter a median follow-up of 60.9 months, prospective haemorrhages occurred in 167 patients (23.9%). The mean modified Rankin Scale scores at enrolment and at censoring time were 1.6 and 1.2. Neurological status was improved, unchanged and worsened in 334 (47.9%), 293 (42.0%) and 71 (10.2%) patients, respectively; 233 (33.4%) recovered to normal levels. Lesions crossing the axial midpoint (relative risk (RR) 2.325, p=0.003) and developmental venous anomaly (DVA) (RR 1.776, p=0.036) were independently significantly related to worsened outcomes. The percentage of worsened outcomes was 5.3% (18 of 337) in low-risk patients (neither DVA nor crossing the axial point) and increased to 26.0% (13 of 50) in high-risk patients (with both DVA and crossing the axial point). The percentage of worsened outcomes significantly increased as the number of prospective haemorrhages increased (from 1.5% (8 of 531, if 0 prospective ictus) to 37.5% (48 of 128, if 1 ictus) and 38.5% (15 of 39, if >1 ictus)).ConclusionsThe neurological outcomes of untreated brainstem CMs were improved/unchanged in majority of patients (89.8%) with a fatality rate of 1.7% in our cohort, which seemed to be favourable. Radiological features significantly predicted worsened outcomes. Our results provide evidence for clinical consultation and individualised treatment. The referral bias of our cohort was underlined.

There was a lack of natural history of incidental brainstem cavernous malformations (CMs), hemorrhage of which would lead to severe neuropathies. The study aimed to evaluate the prospective hemorrhage rate and neurological outcome of the disease. This prospective cohort included patients with incidental brainstem CMs referred to our institute from 2009 to 2015. The diagnosis was confirmed based on the patients' complain, physical examination, and radiographic evidence. Clinical data were collected, scheduled follow-up was performed, and the independent risk factors were identified by multivariate analysis. This cohort included 48 patients (22 female, 45.8%). The median follow-up duration was 60.7 months, and 13 prospective hemorrhages occurred within 244.0 patient-years yielding an annual hemorrhage rate of 5.3%. The hemorrhage-free survival at 1 and 5 years was 91.6% and 80.6%. Age ≥ 55 years (hazard ratio (HR) = 8.59, p = 0.003), lesion size (per 1-mm increase) (HR = 3.55, p = 0.041), developmental venous anomaly (HR = 10.28, p = 0.017), and perilesional edema (HR = 4.90, p = 0.043) were independent risk factors for hemorrhage. Seven patients (14.6%) received surgical resection, and the other 41 patients remained under observation. Neurological function was improved in 22 patients (45.8%), unchanged in 19 (39.6%), and worsened in 7 (14.6%). Prospective hemorrhage (odds ratio = 14.95, p = 0.037) was the only independent risk factor for worsened outcomes. The natural history of incidental brainstem CMs seemed to be acceptable with improved/unchanged outcomes in most patients (85.4%). These results improved our understanding of the disease, and the future study of a large cohort was required to verify our findings.

PURPOSE The extranodal natural killer (NK)/T-cell lymphoma (NKTCL) of non-upper aerodigestive tract (NUAT) was found to have clinical heterogeneity compared with NKTCL of the upper aerodigestive tract (UAT) in small scale studies. We conducted this study in a much larger cohort to analyze the clinical characteristics, prognostic factors, treatment modality, and clinical outcomes of patients with NUAT-NKTCL. Materials and Methods From January 2001 to December 2017, a total of 757 NKTCL patients were identified and included in this study, including 92 NUAT-NKTCL patients (12.2%) and 665 UAT-NKTCL patients (87.8%). RESULTS NUAT-NKTCL patients had relatively poorer performance status, more unfavorable prognostic factors, and more advanced stage, compared with UAT-NKTCL patients. The 5-year overall survival (OS) was 34.7% for NUAT-NKTCL, which was significantly worse than UAT-NKTCL (64.2%, p

SARS-CoV-2 is the etiologic agent of COVID-19, which has led to a dramatic loss of human life and presents an unprecedented challenge to public health worldwide. The gold standard assay for SARS-CoV-2 identification is real-time polymerase chain reaction; however, this assay depends on highly trained personnel and sophisticated equipment and may suffer from false results. Thus, a serological antibody test is a supplement to the diagnosis or screening of SARS-CoV-2. Here, we develop and evaluate the diagnostic performance of an IgM/IgG indirect ELISA method for antibodies against SARS-CoV-2 in COVID-19. The ELISA was constructed by coating with a recombinant nucleocapsid protein of SARS-CoV-2 on an enzyme immunoassay plate, and its sensitivity and specificity for clinical diagnosis of SARS-CoV-2 infection was assessed by detecting the SARS-CoV-2-specific IgM and IgG antibodies in COVID-19 patient's sera or healthy person's sera. The SARS-CoV-2 positive serum samples (n = 168) were collected from confirmed COVID-19 patients. A commercial nucleocapsid protein-based chemiluminescent immunoassay (CLIA) kit and a colloidal gold immunochromatography kit were compared with those of the ELISA assay. The specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of IgM were 100, 95.24, 100, and 91.84%, whereas those of IgG were 100, 97.02, 100, and 94.74%, respectively. We developed a highly sensitive and specific SARS-CoV-2 nucleocapsid protein-based ELISA method for the diagnosis and epidemiologic investigation of COVID-19 by SARS-CoV-2 IgM and IgG antibody detection.

Osteosarcoma is a malignant primary bone tumor commonly occurring in children and adolescents. The treatment of local osteosarcoma is mainly based on surgical resection and chemotherapy, whereas the improvement of overall survival remains stagnant, especially in recurrent or metastatic cases. Tumor microenvironment (TME) is closely related to the occurrence and development of tumors, and macrophages are among the most abundant immune cells in the TME. Due to their vital roles in tumor progression, macrophages have gained increasing attention as the new target of tumor immunotherapy. In this review, we present a brief overview of macrophages in the TME and highlight the clinical significance of macrophages and their roles in the initiation and progression of osteosarcoma. Finally, we summarize the therapeutic approaches targeting macrophage, which represent a promising strategy in osteosarcoma therapies.

E2F transcription factors (E2Fs) are a family of transcription factors involved in cell proliferation, differentiation, and apoptosis. Their important roles in the development and metastasis of breast carcinoma (BC) have been discovered by previous in vitro and in vivo studies. Yet, expressions and distinct prognostic values of these eight E2Fs in human BC remain unclear in many respects. In this study, we aimed to reveal their roles in BC through analyzing the transcription and survival data of the E2Fs in BC patients from four online databases including ONCOMINE, Breast Cancer Gene-Expression Miner v4.1, cBioPortal for Cancer Genomics, and Kaplan-Meier Plotter. We found the overexpression of E2Fs in BC tissues compared with normal breast tissues, except for E2F4. Higher expression levels of E2Fs, except for E2F4 and E2F6, were associated with higher levels of Scarff-Bloom-Richardson grade of BC. Alterations of E2Fs were found to be significantly correlated with poorer overall survival of BC patients. Through plotting the survival curve in the Kaplan-Meier Plotter, it was found that higher mRNA levels of E2F1, E2F3, E2F7, and E2F8 were associated with poorer relapse-free survival in all BC patients, indicating that they are potential targets for individualized treatments of BC patients. Conversely, higher mRNA expression level of E2F4 predicted better RFS in BC patients, suggesting E2F4 as a new biomarker for BC prognosis. Considering currently available limited evidence, further studies need to be performed to investigate the roles of E2Fs in BC.

Primary breast diffuse large B‐cell lymphoma (PB‐DLBCL) is an uncommon extranodal non‐Hodgkin's lymphoma (NHL), which was traditionally treated with anthracycline‐containing regimens followed by consolidative radiation therapy (RT) to add therapeutic benefits. The introduction of anti‐CD20 antibody rituximab for the treatment of B‐cell NHLs has significantly improved the clinical outcome of these malignant diseases. It is unclear, however, whether consolidative RT could still add therapeutic benefits for PB‐DLBCL patients treated with rituximab. To answer this important question, we used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the impact of RT on the clinical outcomes of PB‐DLBCL patients in the rituximab era. Information on patient age, year of diagnosis, stage, race, laterality, and RT status for PB‐DLBCL patients diagnosed between 2001 and 2014 were extracted. Kaplan–Meier survival curves were plotted, and log‐rank test was used to compare the potential survival difference. Multivariate analysis using Cox proportional hazards model was employed to determine the impact of RT and other factors such as age, race, tumor laterality, stage, and year of diagnosis on survival. Among the 386 patients identified, the median follow‐up time was 45 months (range, 0–167 months); the median age was 64 years (range, 19–93 years); 33.9% of the patients were younger than 60 years of age; 69.9% of the patients were stage I; 79.0% were white; 51.8% received RT. The 5‐year OS and cause‐specific survival (CSS) for the whole cohort were 72.3% and 82.5%, respectively. The 5‐year OS was significantly superior for patients who received RT compared to those who did not receive RT (78.1% vs. 66.0%, P = 0.031). In multivariable analysis, RT remained significantly associated with improved OS (P = 0.026). In summary, our study suggests that RT still adds significant therapeutic benefits for patients with PB‐DLCBL in the rituximab era.

Cancer side-population (SP) represents a sub-population of stem-like cancer cells that have an important role in drug resistance due to their high expression of the ATP-binding cassette transporter ABCG2 involved in drug export. Auranofin (AF), a clinical drug of gold complex that is used in treatment of rheumatoid arthritis, has been reported inducing tumor antiproliferation. However, whether AF can impact SP cells remains unclear. Our study showed that AF caused a depletion of SP cells and a downregulation of stem cell markers, and impaired their ability to form tumor colonies in vitro and incidence to develop tumors in vivo of lung cancer cells. Reactive oxygen species (ROS) had an important role in mediating AF-induced depletion of SP cells, which could be reversed by antioxidant NAC. Further study revealed that AF could also cause ATP depletion by inhibition of glycolysis. The depletion of cellular ATP might impair the function of ABCG2 pump, leading to increased drug accumulation within the cells and thus enhancing anticancer activity of chemotherapeutic agents such as adriamycin. Synergistic effect of AF and adriamycin was demonstrated both in vitro and in vivo. Simultaneous increase of ROS and inhibition of glycolysis is a novel strategy to eliminate stem-like cancer cells. Combination of AF with adriamycin seems to be promising to enhance therapeutic effectiveness.

Two new sandwich-type heterometallic ZnII-LnIII clusters based on a methoxy substituted salicylamide Salen-like ligand, [Zn2Er3(HL)2(H2L)2(OH)2(NO3)3](NO3)2·2CH3OH (Zn2Er3), [Zn2Yb3(HL)2(H2L)2(OH)2 (NO3)3](NO3)2·2CH3OH (Zn2Yb3), H3L = 1-(2-hydroxy-4-methoxy-benzamido)-2-(2-hydroxy-3-methoxy-benzylideneamino)-ethane, were prepared and structurally characterized. Single-crystal structure analyses reveal that both compounds are pentanuclear clusters with a hydroxyl bridged trinuclear LnIII3 core swaddled by two ZnII ions, two singly deprotoned H2L− ligands, two doubly deprotoned HL− ligands and three nitrate anions. Photophysical determination indicates that the two ZnII-LnIII compounds display both ligand-centered and near-infrared emission. The magnetic susceptibility measurements reveal that Zn2Er3 displays antiferromagnetic interactions with zero field slow magnetization relaxation diagnostic of single-molecule-magnet (SMM).

Background: Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive lymphoma with a dismal prognosis, and novel therapeutic targets are urgently needed. Programmed death-ligand 1 (PD-L1) has become a promising therapeutic target for various cancers, but most of the studies have focused on expression of PD-L1 on tumor cells. Expression of PD-L1 on tumor-infiltrating non-malignant cells, especially monocytes, has not been studied in NKTCL, and its prognostic value remains unknown. Materials and Methods: Expression of PD-L1 on tumor-infiltrating stromal cells was measured in NKTert and HS5 cells when cultured alone or co-cultured with NKTCL cell lines. Clinical samples were collected from 42 patients with newly diagnosed NKTCL. Expression of PD-L1 on monocytes was analyzed in patients' peripheral blood and tumor tissues using flow cytometry and immunofluorescent staining, respectively. Survival data were retrospectively collected and the prognostic significance of PD-L1 expression on monocytes was analyzed. Results: PD-L1 expression on tumor-infiltrating stromal cells was remarkably elevated when co-cultured with NKTCL cells. The percentage of PD-L1+ monocytes among all monocytes in peripheral blood was significantly higher in NKTCL patients than that in healthy individuals. Among NKTCL patients, percentage of PD-L1+ monocytes in blood positively correlated with that in tumor tissues. Patients with a higher percentage (≥78.2%) of PD-L1+ monocytes in blood or with a higher percentage (≥24.2%) of PD-L1+ monocytes in tumor tissues exhibited a significantly inferior survival, compared with their counterparts. A higher percentage of PD-L1+ monocytes in blood or tumor tissues was an independent adverse prognostic factor. Conclusions: Expression of PD-L1 on monocytes is up-regulated and has significant prognostic value in patients with NKTCL.

Compelling evidences from recent studies suggest that leukemia stem cells (LSCs), a small subpopulation of malignant cells with long-term self-renewal capacity, play a key role in leukemia development, drug resistance, and disease relapse and recurrence (1). It has also been known for some time that tumor microenvironment or tissue niches may exert profound effect on the fates and viability of LSCs. A recent study by Ye et al . revealed a metabolic interaction between LSCs and adipose tissues, and showed that LSCs could be segregated into two metabolically and functionally distinct subgroups by their expression of the fatty acid (FA) transporter CD36 (2). The authors also suggested that gonadal adipose tissue (GAT) might provide a preferred niche to support CD36 + LSCs and promote drug resistance in a mouse model of blast crisis chronic myeloid leukemia (CML).

Here we report five cases of NDM-7-producing Escherichia coli from patients with bacteriuria in a teaching hospital in mainland China. Two isolates belonged to sequence type 131 (ST131), simultaneously carrying blaCTX-M-15, blaSHV-11, blaTEM-1 and qnrS1. The blaNDM-7 gene was located on a conjugative IncX3-type plasmid bearing blaTEM-1 and qnrS1. These findings indicate the spread of NDM-7 metallo-β-lactamase in a highly resistant and virulent E. coli sequence type in China.

Diffuse large B-cell lymphoma (DLBCL) patients with high Ki-67 expression receive limited benefits from R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. This study aims to compare the R-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and R-CHOP regimens as first-line therapy in DLBCL patients with high Ki-67 expression. Data from 44 untreated DLBCL patients with high Ki-67 expression receiving R-EPOCH therapy were matched with those from 132 untreated DLBCL patients with high Ki-67 expression receiving R-CHOP therapy based on the International Prognostic Index (IPI: age, Ann Arbor stage, performance status, LDH level, number of extranodal sites), gender, and Ki-67 expression. In the R-EPOCH group, 42/44 patients were eligible for response evaluation. A total of 35 patients (83.3%) achieved complete remission (CR); 6 patients (14.3%) achieved partial remission (PR); and one patient (2.4%) exhibited progressive disease (PD) after 2 cycles of therapy. Patients in the R-EPOCH group presented better survival outcomes than those in the R-CHOP group (3-year overall survival [OS]: 89.9% vs. 70.2%, p = 0.041; 3-year progression-free survival [PFS]: 86.6% vs. 59.7%, p = 0.024). The survival superiority of the R-EPOCH over the R-CHOP regimen persisted when considering only patients of low-to-intermediate IPI risk, but it was not observed in those of high IPI risk. Our data suggest that R-EPOCH could be superior to R-CHOP as a first-line regimen in DLBCL patients with high Ki-67 expression, especially in those of low-to-intermediate IPI risk.

// Xi Zhang 1, * , Jia-Jia Huang 1, * , Yi Xia 1, * , Chao-Feng Li 2 , Yu Wang 1 , Pan-Pan Liu 1 , Xi-Wen Bi 1 , Peng Sun 1 , Tong-Yu Lin 1 , Wen-Qi Jiang 1 , Zhi-Ming Li 1 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China 2 Department of Information, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China * These authors contributed equally to this work Correspondence to: Zhi-Ming Li, email: lzmsysu@sysucc.org.cn Keywords: peripherally inserted central venous catheter (PICC), thrombosis, lymphoma Received: February 17, 2016 Accepted: March 28, 2016 Published: April 07, 2016 ABSTRACT Peripherally inserted central venous catheters (PICCs) are widely used in cancer patients. Although PICC is a convenient tool, its use is associated with an obvious increase in the incidence of venous thrombosis. The risk factors for deep vein thrombosis associated with the use of PICCs in cancer patients are largely unexplored. This study aimed to investigate the incidence of PICC-associated thrombosis in lymphoma compared with its incidences in other types of cancer. A total of 8028 adult cancer patients inserted with PICC between June 2007 and June 2015 were included in this study. A total of 249 of the 8028 included patients (3.1%) inserted with PICC developed upper extremity deep vein thrombosis (PICC-UEDVT). Patients with lymphoma were more likely to have PICC-UEDVT than those with other types of malignancies (7.1% vs. 2.80%; P < 0.001). Logistic analysis revealed that a lymphoma diagnosis was a risk factor for UEDVT in cancer patients inserted with PICC (OR: 3.849, 95% CI: 2.334–6.347). Patients with lymphoma may be more predisposed to developing PICC-UEDVT than those with other types of malignancies. Identifying the mechanism underlying the relationship between PICC-UEDVT and lymphoma requires further study.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries and is currently incurable due, in part, to difficulty in eliminating the leukemia cells protected by stromal microenvironment. Based on previous observations that CLL cells exhibit mitochondrial dysfunction and altered lipid metabolism and that carnitine palmitoyltransferases (CPT) have a major role in transporting fatty acid into mitochondria to support cancer cell metabolism, we tested several clinically relevant inhibitors of lipid metabolism for their ability to eliminate primary CLL cells. We discovered that perhexiline, an antiangina agent that inhibits CPT, was highly effective in killing CLL cells in stromal microenvironment at clinically achievable concentrations. These effective concentrations caused low toxicity to normal lymphocytes and normal stromal cells. Mechanistic study revealed that CLL cells expressed high levels of CPT1 and CPT2. Suppression of fatty acid transport into mitochondria by inhibiting CPT using perhexiline resulted in a depletion of cardiolipin, a key component of mitochondrial membranes, and compromised mitochondrial integrity, leading to rapid depolarization and massive CLL cell death. The therapeutic activity of perhexiline was further demonstrated in vivo using a CLL transgenic mouse model. Perhexiline significantly prolonged the overall animal survival by only four drug injections. Our study suggests that targeting CPT using an antiangina drug is able to effectively eliminate leukemia cells in vivo, and is a novel therapeutic strategy for potential clinical treatment of CLL.

Background: Malignant lymphomas are a group of distinct lymphoid neoplasms, exhibiting marked diversity in biological behaviors and clinical outcomes. Liquid biopsy, such as circulating cell-free DNA (cfDNA), has recently been attempted to be used for mutation profiling of lymphomas using next-generation sequencing (NGS). However, only limited data about cfDNA are restricted in Hodgkin's lymphoma and B cell lymphoma, and there is no report in the T cell lymphoma so far. Patient and Methods: Medical records of a total of 50 lymphoma patients were retrospectively reviewed, and cfDNA samples were analyzed by capture-based NGS targeting 390 lymphoma- and cancer- relevant genes. We sought to explore the clinical utility of cfDNA in establishing the mutation profiles of different lymphoma subtypes and analyze the correlation between cfDNA concentration and other clinical indices such as serum LDH and IPI. Results: Somatic alterations were identified in cfDNA samples with a median of 64 variants per sample. The concentration of cfDNA in the plasma was found to be significantly correlated with the clinical indices in diffuse large B cell lymphoma (DLBCL). The genetic heterogeneity of different lymphoma subtypes was clearly observed in cfDNAs from germinal center B-cell (GCB) DLBCL, non-GCB DLBCL and natural killer/T-cell lymphoma (NKTCL), confirming that distinct molecular mechanisms are involved in the pathogenesis of different lymphomas. Conclusion: Our findings demonstrate that NGS-based cfDNA mutation profiling reveals genetic heterogeneity across lymphoma subtypes, with potential implications for the discovery of therapeutic targets, the exploration of genome evolution and the development of risk-adapted treatment.

Coxsackievirus A6 (CV-A6) is an emerging pathogen associated with hand, foot, and mouth disease (HFMD). Its genetic characterization and pathogenic properties are largely unknown. Here, we report 39 circulating CV-A6 strains isolated in 2013 from HFMD patients in northeast China. Three major clusters of CV-A6 were identified and related to CV-A6, mostly from Shanghai, indicating that domestic CV-A6 strains were responsible for HFMD emerging in northeast China. Four full-length CV-A6 genomes representing each cluster were sequenced and analyzed further. Bootscanning tests indicated that all four CV-A6-Changchun strains were most likely recombinants between the CV-A6 prototype Gdula and prototype CV-A4 or CV-A4-related viruses, while the recombination pattern was related to, yet distinct from, the strains isolated from other regions of China. Furthermore, different CV-A6 strains showed different capabilities of viral replication, release, and pathogenesis in a mouse model. Further analyses indicated that viral protein 2C contributed to the diverse pathogenic abilities of CV-A6 by causing autophagy and inducing cell death. To our knowledge, this study is the first to report lethal and nonlethal strains of CV-A6 associated with HFMD. The 2C protein region may play a key role in the pathogenicity of CV-A6 strains. IMPORTANCE Hand, foot, and mouth disease (HFMD) is a major and persistent threat to infants and children. Besides the most common pathogens, such as enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16), other enteroviruses are increasingly contributing to HFMD. The present study focused on the recently emerged CV-A6 strain. We found that CV-A6 strains isolated in Changchun City in northeast China were associated with domestic origins. These Changchun viruses were novel recombinants of the CV-A6 prototype Gdula and CV-A4. Our results imply that measures to control CV-A6 transmission are urgently needed. Further analyses revealed differing pathogenicities in strains isolated in a neonatal mouse model. One of the possible causes has been narrowed down to the viral protein 2C, using phylogenetic studies, viral sequences, and direct tests on cultured human cells. Thus, the viral 2C protein is a promising target for antiviral drugs to prevent CV-A6-induced tissue damage.

Staphylococcus aureus is known to be a predominant pathogen causing bloodstream infection (BSI) from burn units. Our study aimed to perform the clinical epidemiological analysis and virulence features of S. aureus strains isolated from the burn patients with BSI from a burn center in southeastern China during 2012-2016. A collection of 112 S. aureus isolates causing BSI from burn center of a tertiary care hospital in China was carried out. Antimicrobial susceptibility testing was conducted in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines. Toxin gene profiles, multilocus sequence typing, staphylococcal protein A (spa) typing, accessory gene regulator (agr) locus typing, staphylococcal cassette chromosome mec (SCCmec) typing, and dendrographic analysis were used to characterize and analyze these isolates. Of 112 S. aureus isolates, 52 (46.4%) were methicillin-resistant S. aureus (MRSA) and 60 (53.6%) were methicillin-susceptible S. aureus (MSSA). ST239-SCCmec III-t030-agr I was the major prevalent clone (26 from MRSA and 6 from MSSA), which was followed by ST239-SCCmec III-t037-agr I (12, 10.0%) and ST5-SCCmec II-t002-agr I (11, 9.2%). The genotyping results showed high genetic diversity in molecular characterization and toxin gene profiles of the strains. Carriage of tsst-1 was mainly associated with ST239-SCCmec III-t030-agr I and ST30-SCCmec IV-t062-agr III, whereas lukS/F-PV was distributed in different clones. In conclusion, ST239-SCCmec III-t030-agr I is the commonest clone causing BSI among burn patients in eastern regions of China. In contrast to MRSA, polyclonality was statistically significantly higher among MSSA isolated from burn patients with BSI.

// Hang Yang 1, 2, * , Yu Wang 1, 2, * , Jing Zhan 1, 3 , Yi Xia 1, 2 , Peng Sun 1, 2 , Xi-Wen Bi 1, 2 , Pan-Pan Liu 1, 2 , Zhi-Ming Li 1, 2 , Su Li 1, 3 , Ben-Yan Zou 1, 4 , Wen-Qi Jiang 1, 2 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China 2 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China 3 Clinical Trial Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China 4 Nursing Department, Sun Yat-sen University Cancer Center, Guangzhou 510060, China * These authors have contributed equally to this work Correspondence to: Wen-Qi Jiang, e-mail: jiangwq_sysuucc@163.com Ben-Yan Zou, e-mail: zouby@sysucc.org.cn Keywords: XC-302, PI3K pathway, non-Hodgkin lymphoma, safety and efficacy, pharmacokinetics Received: July 20, 2015 Accepted: September 24, 2015 Published: October 17, 2015 ABSTRACT Objectives: To determine the safety of Puquitinib Mesylate (XC-302), an oral inhibitor of phosphatidylinositol 3-kinase, in treating relapsed or refractory non-Hodgkin’s lymphoma (NHL). Methods: Between October 2013 and July 2015, 21 patients from Sun Yat-sen University Cancer Center were treated twice daily on each day of a 28-day cycle (median number of cycles, 2; maximum, 20) with XC-302 at a post prandial dose of 25 mg, 37.5 mg, or 50 mg. Adverse events (AEs), AUC last and C max , response rates, and overall survival were assessed. Results: Patients had received a median (range) of 1 (1 to 3) previous cancer treatments. At the latest follow-up, two patients were still benefitting from the study. The most common drug-related AEs were elevations in alanine transaminase (ALT, 14 of 21 patients) and aspartate transaminase (AST, 7 of 21 patients). Four patients, both in the-50-mg group, had dose-limiting toxicities, and therapy was discontinued in a fifth because of persistent abnormal liver function. The overall response rate was 2 of19. Serum concentrations of XC-302 increased in a dose-dependent pattern. Median progression-free survival in all patients was 1.9 (95% CI, 1.7 to 2.0) months. Conclusion: XC-302 has an acceptable safety profile and offers potential therapeutic value to patients with relapsed or refractory non-Hodgkin lymphoma.

Zuota is regarded as the king of Tibetan medicine. However, the major starting material of Zuota is mercury, which is one very toxic heavy metal. This has aroused serious doubts on the biosafety of Zuota containing drugs. In this study, we quantified the Hg contents in four Zuota samples, monitored the release of Hg in simulated gastric/intestinal juice and evaluated their cytotoxicity to Caco-2 cells. Our results showed that the Hg contents in Zuota samples were in the range of 566-676 mg/g. Fortunately, the release of Hg from Zuota samples was very low in simulated gastric juice, and much lower in simulated intestinal juice. Direct contact of Zuota with Caco-2 cells led to dose-dependent cytotoxicity, including activity loss and membrane leakage. The toxicity was closely related to apoptosis, because the caspase 3/7 levels of Caco-2 cells increased after the exposure to Zuota. Interestingly, Zuota samples inhibited the oxidative stress at low concentrations, but the toxicity could be relived by antioxidants. The possible toxicity should be attributed to the cellular uptake of Zuota particulates. Beyond the cytotoxicity, significant differences among Zuota samples from different institutions were observed, suggesting that the preparation process of Zuota had meaningful influence of its biosafety. The implications to the safety and clinical applications of Zuota are discussed.

The optimal treatment strategy for elderly patients with natural killer/T-cell lymphoma (NKTCL) remains to be established. A total of 63 elderly patients with newly diagnosed NKTCL were retrospectively reviewed. Among the patients with stage I-II disease, 58.3 % received radiotherapy (RT) ± chemotherapy, and 41.7 % received chemotherapy alone. Compared with chemotherapy alone, RT ± chemotherapy elicited a significantly higher overall response rate (ORR) (100 vs. 57.1 %, P

Two new structure-related pyrazolone-type Salen ligands, N,N′-ethylamine bis[1-(4-methoxy-phenyl)-3-methyl-4-benzoylimino-2-pyrazoline-5-ol](H2LI) and N,N′-ethylamine bis[1-(4-methoxy-phenyl)-3-methyl-4-acetylimino-2-pyrazoline-5-ol](H2LII) have been designed and synthesized with the ultimate aim of self-assembling novel Zn(II) compounds with interesting fluorescence properties. Reactions of Zn(OAc)2 with the two ligands led to the formation of two new Zn(II) complexes with the formulae of [ZnLI(CH3OH)] (1) and [Zn2LII2] (2), which have been characterized by single-crystal X-ray diffraction, powder X-ray diffraction, elemental analysis, IR spectroscopy and thermal gravimetric analysis. Mononuclear complex 1 with the pentacoordinated zinc(II) ion hosted into the N2O3 compartment crystallized in the monoclinic space group P21/c, while the hydroxyl-bridged dinuclear [Zn2LII2] complex (2) with the pentacoordinated zinc(II) ion hosted into the N2O2 compartment crystallized in the monoclinic space group C2/c and had a Zn–O–Zn–O four-membered ring. The structure determinations show that substituted group at the 4,4′-position of the this kind of Salen ligands are important factors influencing the crystalline array. The fluorescent properties of the two compounds at ambient temperature both in solid state and solution were also investigated. The results provided interesting insights into ligand effects on the structures and fluorescent properties of zinc(II) coordination complexes.

Background. Circulating Epstein-Barr virus (EBV) DNA concentrations were reported to have prognostic value for NK/T-cell lymphoma patients in limited small-scale studies. In this study, we aimed to evaluate the clinical utility of circulating EBV-DNA concentrations to a large sample of NK/T-cell lymphoma patients. Methods. We conducted this meta-analysis, which included a total of 15 prospective and retrospective comparable studies to assess the association between pretreatment EBV-DNA (pre-DNA), posttreatment EBV-DNA (post-DNA), and clinical outcomes of NK/T-cell lymphoma patients. We chose overall survival (OS) as the primary endpoint and progression-free survival (PFS), complete response (CR), and overall response rate (ORR) as secondary endpoints. Results. High pre-DNA and detectable post-DNA were both significantly correlated with poorer OS in NK/T-cell lymphoma patients (P<0.05), with hazard radios (HRs) equal to 3.45 and 2.30, respectively. High pre-DNA and detectable post-DNA also predicted poorer PFS. Additionally, high pre-DNA was found to be significantly correlated with both worse CR and ORR, which indicated worse treatment response. Conclusion. Circulating EBV-DNA concentrations provides prognostic values of survival and treatment response in NK/T-cell lymphoma patients.

Treatment modalities for primary gastric diffuse large B-cell lymphoma (PG-DLBCL) have changed significantly during the past decades. However, limited information on the trends of clinical outcome of PG-DLBCL patients has been reported. Here, we conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database to compare the survival trends of PG-DLBCL patients from 1973 to 2014. Patients were divided into 2 eras based on the year of diagnosis in relation to immunotherapy with the anti-CD20 antibody rituximab that was approved in 1997 and became a widely used drug in 2000. There was a significant improvement in survival among PG-DLBCL patients diagnosed in the 2001–2014 era (n=4186) compared to patients diagnosed in the 1973–2000 era (n=2865), with the 5-year overall survival rates of 53% and 47%, respectively (p=0.001). Multivariable analysis revealed that the 2001–2014 era (HR = 0.892, p=0.001) was associated with lower mortality and that patients of older age, Black race, advanced stage, and male gender were associated with poor prognosis. Although outcome of PG-DLBCL has significantly improved over time, more effective therapies are needed for older patients to further improve their survival.

Background Methotrexate is the first systemic therapeutics of psoriasis. It is reported that 40% of the patients achieved a PASI75 after 12 weeks with a small dose of methotrexate (15 mg / w) treatment. So far there is not any large-scale exome sequencing been used to predict the efficacy of methotrexate in the treatment of psoriasis vulgaris. Objective To analyze the genetic polymorphism to predict methotrexate efficacy in Chinese patients with psoriasis vulgaris. Methods In this study, we used the whole exon high-throughput sequencing technology to detect the DNA sequence of 22 psoriasis vulgaris patients (11 responders, 11 non-responders) treated with methotrexate and captured approximately 236 variants with statistically significant in the whole exon sequencing, then in accordance with statistical differences and clinical relevance, we further selected 36 SNPs and 14 SNPs that have been reported in articles associated with the response of methotrexate. We used MassARRAY method to verify the 50 SNPs in 100 psoriatic patients treated with methotrexate. Results We found 3 SNPs, rs216195T > C in SMG6, rs1050301G > A in IMMT, rs2285421T > C in UPK1A which might associate with the drug response of methotrexate. Conclusion We have searched 3 new SNPs that could predict the efficacy of methotrexate in psoriasis vulgaris to some extent, providing a theoretical basis for precision medicine of methotrexate in future.

An improved level set evolution model is proposed to segment the ultrasound images accurately and efficiently in this paper. At first, the multi-scale gradient vector field is employed to reduce the image noise. We assign the standard deviation as a scale to set up several scales images, and use the gradient direction information between the adjacent scales to refine the multi-scale gradient vector field, which highlights the real boundaries and reduces the noise. Besides, the divergence operator of the multi-scale gradient vector field is used to overcome the sensitivity problem of initialization and avoid boundary leakage. The experiments results demonstrate that the performance of the proposed method is very close to the ground truths obtained from manual segmentation by specialists with higher area similarity measure (ASM) and lower mean contour distance (MCD), which demonstrated that the proposed method is reliable, accurate and robust for the tumor boundary segmentation in ultrasound images.

Aim Elevated neutrophil-to-lymphocyte ratio (NLR) has been demonstrated to be a poor prognostic factor in multiple types of malignancies, whereas the effect of NLR on the prognosis of epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) patients treated with first-line EGFR tyrosine kinase inhibitors (TKIs) is not fully addressed. Methods 81 metastatic NSCLC patients harboring EGFR mutation treated with first-line EGFR TKIs were retrospectively included. The associations between baseline clinical characteristics, including NLR, and tumor response, progression and survival were investigated. Results Elevated NLR (≥3.5) was observed in 33 of 81 patients. The progression-free and overall survival of the patients with increased NLR was significantly worse than that of the patients with decreased NLR (8.20 vs 10.60 months, P

Four gene variants related to lipid metabolism (including the rs562338 and rs503662 variants of the APOB gene, the rs7767084 variant of the LPA gene and the rs2246942 variant of the LIPA gene) have been shown to be associated with coronary heart disease (CHD). The aim of the present study was to assess their association with CHD in the Han Chinese population and to assess the contribution of these gene variants to CHD. Using the standardized coronary angiography method, we enrolled 290 CHD patients and 193 non-CHD patients as non-CHD controls from Lihuili Hospital (Ningbo, China). In addition, we recruited 330 unrelated healthy volunteers as healthy controls from the Xi Men Community (Ningbo, China). Our results demonstrated that the rs503662 and rs562338 variants of the APOB gene were extremely rare in the Han Chinese population (minor allele frequency

The optimal treatment strategy for relapsed natural killer/T-cell lymphoma (NKTCL) remains largely unknown. We retrospectively reviewed the treatment modalities and prognosis of 56 relapsed NKTCL patients. Chemotherapy was the initial salvage treatment, followed by radiotherapy (RT) or autologous hematopoietic stem cell transplantation (AHSCT) as consolidative therapy, depending on the status of remission and the pattern of relapse. For patients with locoregional relapse alone, consolidative RT after salvage chemotherapy significantly improved prognosis compared with follow-up (5-year OS: 83.3 vs. 41.7%, P = 0.047). For patients with distant relapse, consolidative AHSCT after salvage chemotherapy significantly prolonged survival compared with follow-up (2-year OS: 100.0 vs. 20.0%, P = 0.004). Patients without consolidative treatment after response to salvage chemotherapy exhibited a comparable survival to those who experienced stable or progressive disease after chemotherapy. Asparaginase (ASP)-containing salvage chemotherapy failed to confer a survival advantage over ASP-absent chemotherapy (5-year OS: 44.2 vs. 39.3%, P = 0.369). In conclusion, consolidative RT or AHSCT improved prognosis in patients with relapsed NKTCL who responded to initial salvage chemotherapy, and the role of ASP in salvage chemotherapy requires further exploration in prospective studies.

Patients with newly diagnosed acute lymphoblastic leukemia (ALL) at a single institution were analyzed retrospectively. From 2006 to 2010, 47 patients were treated using the MRC UKALLXII/ECOG E2993 protocol. Prior to July 2005, 40 patients had been treated with the JALSG ALL 87 protocol. A complete remission (CR) rate of 91.5% was achieved with the E2993 protocol, which was not significantly higher than the 80% achieved using JALSG (P > 0.05). The median duration of CR in months was 19 for all patients treated with the MRC UKALLXII/ECOG E2993 protocol. Ph+ patients showed a median CR duration of 11.5 months, while Ph− patients had a significantly longer CR duration of 19 months (P = 0.019). Further, Ph− patients at standard risk (stratified on the basis of age and white blood cell count at diagnosis) had a CR duration of 21 months, which was significantly longer than the 12-month CR duration for the ten Ph− patients at high risk (P = 0.001). Significant differences were found in the 2-year event-free survival and overall survival rates between the MRC UKALLXII/ECOG E2993 and JALSG ALL 87 groups in the following three cohorts: all patients (P = 0.009 and 0.022, respectively), Ph− patients (P = 0.009 and 0.018, respectively), and standard-risk patients (P = 0.014 and 0.007, respectively). The overall mortality rate for induction therapy in the MRC UKALLXII/ECOG E2993 group was 2.1% (1 of 47 patients). One or more instances of grade IV myelosuppression occurred during induction therapy. Among the non-hematological toxicities, alopecia and elevated ALT and AST levels were the most common. The levels of ALT and AST could be reduced to less than twofold the normal values within 1–2 weeks. The data indicate that the MRC UKALLXII/ECOG E2993 regimen is well tolerated in Chinese adults with ALL and can improve survival compared with the JALSG ALL 87 protocol. Risk stratification at diagnosis based on age and WBC count is suitable for adults with ALL, and it is necessary to adopt different strategies as determined by diagnostic results. Lastly, Ph+ patients have an extremely poor prognosis.

Background As a surrogate marker of systemic inflammation, the lymphocyte-to-monocyte ratio (LMR) is an independent prognostic factor for various malignancies. This study investigated the prognostic significance of the pre-chemotherapy LMR in patients with previously untreated metastatic colorectal cancer (mCRC) receiving chemotherapy. Methods The present study included newly diagnosed mCRC patients treated between January 2005 and December 2013 with FOLFOX chemotherapy, specifically oxaliplatin 180 mg/m2 on day 1, with leucovorin 400 mg/m2 administered as a 2-hour infusion before the administration of 5-fluorouracil 400 mg/m2 as an intravenous bolus injection, and 5-fluorouracil 2400 mg/m2 as a 46-h infusion immediately after 5-fluorouracil bolus injection. The LMR was calculated as the absolute count of lymphocytes divided by the absolute count of monocytes. COX proportional hazards analysis was performed to evaluate the association of LMR with survival outcomes. Results A total of 488 patients were included. Patients with high pre-chemotherapy LMR experienced significant improvements in progression-free survival (PFS, 9.2 vs. 7.6 months, P

The treatment of Burkitt’s lymphoma with rituximab is controversial, and studies that compared the efficacy of chemotherapy alone with chemotherapy plus rituximab have not been powered to test differences in overall survival (OS). We conducted this systematic review and meta-analysis to identify the value of rituximab for the treatment of BL to guide treatment decisions. Based on the PubMed, Web of Science, and Cochrane library online electronic databases, all retrospective and randomized clinical trial studies that compared the aforementioned two regimens were included. The pooled hazard ratio and odds ratio were analyzed using Review Manager 5.3. The primary outcome was the 2-year OS. A total of 581 publications were identified using a predetermined search strategy. One randomized controlled trial (RCT) and five retrospective studies, which included 646 cases (351 cases for the chemotherapy with rituximab group and 295 cases for the chemotherapy alone group), fulfilled the selection criteria and were included in the meta-analysis. The chemotherapy with rituximab group was associated with a higher 2-year OS (hazard ratio 0.62, 95 % CI 0.45–0.85, P = 0.003), 2-year progression-free survival (hazard ratio 0.46, 95 % CI 0.43–0.50, P

Patients with stage IE/IIE natural killer T (NK/T) cell lymphomas have discrepant survival outcome. This study aims to establish a prognostic model based on the pretreatment platelet lymphocyte ratio (PLR) specifically for localized extranodal NK/T cell lymphoma to guide the therapy. We retrospectively analyzed the data of 252 patients with early-stage upper aerodigestive tract NK/T cell lymphoma. The 5-year overall survival rate in 252 patients was 67.1%. Prognostic factors for survival were female (P = 0.025; relative risk, 0.51; 95% CI 0.28-0.92), older age (P = 0.000; relative risk, 3.34; 95% CI 1.94-5.75), stage II(P = 0.020; relative risk, 1.79; 95% CI 1.10-2.91), lactate dehydrogenase (LDH) level (P = 0.009; relative risk, 2.00; 95% CI 1.19-3.35), and PLR (P = 0.020; relative risk, 1.77; 95% CI 1.10-2.87). Based on these five parameters, we identified three different risk groups: group 1(106 cases, 43.4%), no or one adverse factor; group 2(85 cases, 34.8%), two factors; group 3(53 cases, 21.7%), three to five factors. Five-year overall survival was 83.3% for group 1, 62.2% for group 2, and 43.1% for group 3 (P = 0.000). Compared with International Prognostic Index and Korean Prognostic Index, the new model has a better prognostic discrimination for the patients of stage IE/IIE upper aerodigestive tract NK/T cell lymphoma. The PLR-based prognosis model is useful to stratify patients with localized extranodal NK/T cell lymphoma into different risk groups and guide the treatment modalities selection.

Background: The ADD1 Gly460Trp polymorphism has been linked to essential hypertension (EH) in multiple populations, but the results were inconsistent. The goal of our study is to investigate the contribution of ADD1 Gly460Trp polymorphism and environmental factors to the risk of EH. Methods: We conducted a case-control study including 1020 hypertensive cases and 1020 controls, and the gender and age were well matched between hypertensive and control groups. Blood samples and participants information were also collected. Using the melting temperature shift technology, the ADD1 Gly460Trp polymorphism was genotyped among all subjects. Multifactor dimensionality reduction (MDR) was used to identify the interactions among the ADD1 Gly460Trp polymorphism and the nongenetic factors. Results: Our results showed that body mass index (BMI), total cholesterol, triglycerides, and drinking were significantly associated with EH (P

The aim of this study is to investigate the incidence and clinical outcomes of primary mediastinal large B-cell lymphoma (PMBL).Here we did a retrospective analysis using the surveillance, epidemiology, and end results (SEER) database to analyze the incidences and survival of patients with PMBL diagnosed during 2001-2012 among major ethnic groups.During 2001-2012, a total of 426 PMBL patients were identified, including 336 whites, 46 blacks, and 44 others. The incidence rates of female to male ratios in white, black, and other were 1.4938, 1.1202, and 1.7303 respectively, suggesting that the female-prominent disease occurrence was seen only in whites and others, but not in black population. Compared to white, the other had a worse 5-year overall survival (OS); however, factors including age, race, socioeconomic status, and stage associated with OS showed no significant difference among ethnic groups; thus, biology factors should be explored to explain the racial difference in OS.In conclusion, our findings revealed diversities in demographic features and prognosis among different racial groups.

Background The accumulation of iron in the brain is a hallmark of hemorrhagic stroke and several neurodegenerative diseases. Iron overload has been reported to induce brain injury through necrotic and apoptotic mechanisms. This study was taken to examine whether iron in the brain contributes to autophagic cell death. Methods Sprague-Dawley rats received an intracerebral ventricular injection of either ferrous chloride or saline. The expression levels of autophagic markers were measured by Western blot analysis. Immunofluorescent double labeling was used to identify the cell types expressing Beclin 1. Transmission electron microscopy was performed to examine the ultrastructural changes in neural cells 1 day after ferrous iron injection. Results Western blot analysis showed that the ratios of LC3-II to LC3-I and ATG5 levels were significantly upregulated at 6 hours and 1 day after ferrous iron injection. Beclin 1 expression was markedly elevated as early as 6 hours, reaching a peak at 24 hours and remaining elevated at 3 days after the injection. Beclin 1 immunoreactivity was located in both neurons and astrocytes under confocal microscopy. Induction of autophagic cell death was manifested by accumulation of autophagic vacuoles in the contralateral parietal cortex under transmission electron microscopy. Conclusions Our data showed that increased ferrous iron levels in the brain induced autophagic cell death. These results also suggest that autophagy form of programmed cell death may be a mechanism of brain injury in iron overload disorders.

Puerarin, a traditional Chinese medicine, exerts a powerful neuroprotective effect in cerebral ischemia/reperfusion injury, but its mechanism is unknown. Here, we established rat models of middle cerebral artery ischemia/reperfusion injury using the suture method. Puerarin (100 mg/kg) was administered intraperitoneally 30 minutes before middle cerebral artery occlusion and 8 hours after reperfusion. Twenty-four hours after reperfusion, we found that puerarin significantly improved neurological deficit, reduced infarct size and brain water content, and notably diminished the expression of Toll-like receptor-4, myeloid differentiation factor 88, nuclear factor kappa B and tumor necrosis factor-α in the ischemic region. These data indicate that puerarin exerts an anti-inflammatory protective effect on brain tissue with ischemia/reperfusion damage by downregulating the expression of multiple inflammatory factors.