The recent emergence of human infection with influenza A(H10N8) virus is an urgent public health concern. Genomic analysis showed that the virus was conserved in chicken eggs but presented substantial adaptive mutations in MDCK cells. Our results provide additional evidence for the avian origin of this influenza virus.
influenza A virus; mutation; genome; avian-origin; antiviral drug resistance; viruses; A(H10N8)
Gastric mucosa tissue was collected from patients with gastroduodenal diseases in a region of norrteastern China showing a high risk of gastric cancer incidence. The presence of EBV and HPV were assayed to investigate the relationship between gastric carcinomas and virus infection. Neither EBV nor HPV DNA was detected in tissue from the patients. The role of EBV and HPV in gastric cancer is not well understood and still needs to be clarified.
Human papillomavirus; Epstein-Barr virus; polymerase chain reaction; gastric carcinoma
Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (IK1) is believed to be an important regulator of reentrant-spiral dynamics and a major component of AF-related electrical remodeling. MicroRNA-26 (miR-26) is predicted to target the gene encoding KIR2.1, KCNJ2. We found that miR-26 was downregulated in atrial samples from AF animals and patients and this downregulation was accompanied by upregulation of IK1/KIR2.1 protein. miR-26 overexpression suppressed expression of KCNJ2/KIR2.1. In contrast, miR-26 knockdown, inhibition, or binding-site mutation enhanced KCNJ2/KIR2.1 expression, establishing KCNJ2 as a miR-26 target. Knockdown of endogenous miR-26 promoted AF in mice, whereas adenovirus-mediated expression of miR-26 reduced AF vulnerability. Kcnj2-specific miR-masks eliminated miR-26–mediated reductions in Kcnj2, abolishing miR-26’s protective effects, while coinjection of a Kcnj2-specific miR-mimic prevented miR-26 knockdown-associated AF in mice. Nuclear factor of activated T cells (NFAT), a known actor in AF-associated remodeling, was found to negatively regulate miR-26 transcription. Our results demonstrate that miR-26 controls the expression of KCNJ2 and suggest that this downregulation may promote AF.
Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating
type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1
mimetics currently on the market or under development. This concern has led to a continued
interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we
briefly review the discovery, characterization and current status of a novel class of
cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its
newly discovered analogue WB4–24. Although the oral bioavailability of such
compounds still poses great challenges, the progress made so far encourages us to identify
a truly 'druggable' small molecule agonist for GLP-1R.
type 2 diabetes; glucagon-like peptide-1; non-peptidic agonist; Boc5; G-protein coupled receptor
MicroRNAs (miRNAs) are a class of endogenous, small, non-coding RNAs that regulate gene expression by targeting mRNAs and inhibiting expression via translation repression or RNA degradation. Emerging evidence indicates that miRNAs play a crucial role in the pathogenesis of human diseases, including tumor development. We profiled the miRNA expression between mature ovarian teratoma samples and matched normal tissues using miRNA microarrays, followed by validation with quantitative RT-PCR (qRT-PCR). The most highly expressed miRNAs in mature ovarian teratoma tissues were miRNA-520a-5p, miRNA-26b*, miRNA-421, miRNA-492 and miRNA-555, with a 1.3- to 2.6-fold change, whereas the least expressed miRNAs were miRNA-142-3p, let-7a, miRNA-19a, miRNA-34a, miRNA-620, miRNA-934, miRNA-657, miRNA-720, miRNA-22, miRNA-629 and miRNA-214, with a decreased level of 55–87% compared with normal tissues. The findings of the present study are the first to provide an altered miRNA profile for mature ovarian teratomas and differentially expressed miRNAs, which, if validated in future studies, may be essential in the pathogenesis of mature ovarian teratomas.
microRNAs; mature ovarian teratomas; microarrays
Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined as patients older than 50 years alone. However, recent studies showed young patients with sound immune status could also be affected. In this study, we investigated the clinical features and outcomes of patients with EBV positive DLBCL in the different age groups using different EBER cut-off values. The prevalence of EBV positive DLBCL was 14.0% (35/250) and 10.4% (26/250) for EBER cut-off of 20% and 50%, respectively. With both EBER cut-off values, patients with EBV DLBCL shared many unfavorable prognostic characteristics, regardless of age. EBV positive patients, both in the elderly and young groups, showed significantly worse overall survival and progression-free survival than negative cases. Moreover, no significant differences of outcomes were identified between different age groups with EBV positive DLBCL. In conclusion, EBV positive DLBCL patients, regardless of age, shared similar poor prognostic features and showed worse outcome than negative cases. We suggest that the age criterion of EBV positive DLBCL of the elderly, and possibly the name itself, be modified in future.
Due to its high prevalence and associated sight-threatening pathologies, myopia has emerged as a major health issue in East Asia. The purpose was to test the impact on myopia development of a school-based intervention program aimed at increasing the time student spent outdoors.
A total of 3051 students of two primary (grades 1-5, aged 6-11) and two junior high schools (grades 7-8, aged 12-14) in both urban and rural Northeast China were enrolled. The intervention group (n = 1735) unlike the control group (n = 1316) was allowed two additional 20-min recess programs outside the classroom. A detailed questionnaire was administered to parents and children. Uncorrected visual acuity (UCVA) was measured using an E Standard Logarithm Vision Acuity Chart (GB11533-2011) at baseline, 6-month and 1-year intervals. A random subsample (n = 391) participated in the clinic visits and underwent cycloplegia at the beginning and after 1 year.
The mean UCVA for the entire intervention group was significantly better than the entire control group after 1 year (P < 0.001). In the subgroup study, new onset of myopia and changes in refractive error towards myopia were direction during the study period was significantly lower in the intervention group than in the control group (3.70 % vs. 8.50 %, P = 0.048; -0.10 ± 0.65 D/year vs. -0.27 ± 0.52 D/year, P = 0.005). Changes in axial length and IOP were also significantly lower following the intervention group (0.16 ± 0.30 mm/year vs. 0.21 ± 0.21 mm/year, P = 0.034; -0.05 ± 2.78 mmHg/year vs. 0.67 ± 2.21 mmHg/year, P = 0.006).
Increasing outdoor activities prevented myopia onset and development, as well as axial growth and elevated IOP in children.
Current controlled trials NCT02271373.
Electronic supplementary material
The online version of this article (doi:10.1186/s12886-015-0052-9) contains supplementary material, which is available to authorized users.
Myopia; Refractive error; Outdoor activity; Schoolchildren; Intervention studies
EHBP1 rs721048(A) was first identified as a prostate cancer (PCa) risk in Caucasians by genome-wide association study, but subsequent replication studies involving Caucasian and other ethnicities did not produce consistent results. The aim of this study was to obtain a more definite association between rs721048(A) and PCa risk.
We comprehensively searched several databases updated to September 2014, including PubMed, Web of Science, EBSCO, and Google Scholar. Two authors independently screened and reviewed the eligibility of each study. The quality of the included studies was assessed by the Newcastle–Ottawa scale. The association of rs721048(A) and PCa risk was assessed by pooling odds ratios (ORs) with 95% confidence intervals (CIs).
A total of 17 studies, including 48,135 cases and 102,543 controls, published between 2008 and 2014 were included in the meta-analysis. Overall, the pooled analysis demonstrated that rs721048(A) was significantly associated with the risk of PCa under the allele model (OR=1.14, 95% CI=1.11–1.17, P=0.000). Subgroup analysis based on ethnicity revealed a significant association between rs721048(A) and PCa in Caucasian (OR=1.14, 95% CI=1.11–1.16, P=0.000), African descent (OR=1.11, 95% CI=1.01–1.23, P=0.025), and Asian (OR=1.35, 95% CI=1.12–1.64, P=0.002).
Our results provided strong evidence that rs721048(A) could be a risk factor for PCa.
EHBP1; rs721048; meta-analysis; prostate cancer
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against β3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIbα, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti–β3 integrin–mediated, but not anti-GPIbα–mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti–β3 integrin–mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signaling, and increased endothelial cell apoptosis, all of which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis were further reproduced in neonates by injection of anti–β3 integrin, but not anti-GPIbα antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and AKT phosphorylation were inhibited only by murine anti–β3 integrin antisera and human anti–HPA-1a IgG purified from mothers with FNAIT children. Our data suggest that fetal hemostasis is distinct and that impairment of angiogenesis rather than thrombocytopenia likely causes FNAIT-associated ICH. Additionally, our results indicate that maternal IVIG therapy can effectively prevent this devastating disorder.
Angiogenesis; Hematology; Vascular Biology
Duodenal adenocarcinoma, especially duodenal bulb with neuroendocrine features (NEF), is extremely rare. Here, we report one such case of duodenal bulb adenocarcinoma with neuroendocrine features. A 63-year-old Han Chinese woman was admitted to our department with the diagnosis of a duodenal bulb polyp and underwent an endoscopic mucosal resection. The pathological findings confirmed it as duodenal bulb adenocarcinoma with NEF. The patient remains curative after one and half a years of follow-up. Duodenal adenocarcinoma with NEF might be a low malignant neuroendocrine tumor rather than a conventional adenocarcinoma. Endoscopic treatment, including endoscopic mucosal resection, might be an ideal option for the adenocarcinomas with NEF.
Duodenal adenocarcinoma; Neuroendocrine features; Endoscopic mucosal resection; Duodenal bulb; Rarity
Coronaviruses (CoVs) continuously threaten human health. However, to date, the evolutionary mechanisms that govern CoV strain persistence in human populations have not been fully understood. In this study, we characterized the evolution of the major antigen-spike (S) gene in the most prevalent human coronavirus (HCoV) OC43 using phylogenetic and phylodynamic analysis. Among the five known HCoV-OC43 genotypes (A to E), higher substitution rates and dN/dS values as well as more positive selection sites were detected in the S gene of genotype D, corresponding to the most dominant HCoV epidemic in recent years. Further analysis showed that the majority of substitutions were located in the S1 subunit. Among them, seven positive selection sites were chronologically traced in the temporal evolution routes of genotype D, and six were located around the critical sugar binding region in the N-terminal domain (NTD) of S protein, an important sugar binding domain of CoV. These findings suggest that the genetic drift of the S gene may play an important role in genotype persistence in human populations, providing insights into the mechanisms of HCoV-OC43 adaptive evolution.
The human FOXP3 molecule is an oligomeric transcriptional factor able to mediate activities that characterize T regulatory cells, a class of lymphocytes central to the regulation of immune responses. The activity of FOXP3 is regulated at the post-translational level, in part by two histone acetyltransferases (HAT), TIP60 and p300. TIP60 and p300 work cooperatively to regulate FOXP3 activity. Initially p300 and TIP60 interactions lead to the activation of TIP60 and facilitate acetylation of K327 of TIP60, which functions as a molecular switch to allow TIP60 to change binding partners. Subsequently, p300 is released from this complex and TIP60 interacts with and acetylates FOXP3. Maximal induction of FOXP3 activities is observed when both p300 and TIP60 are able to undergo cooperative interactions. Conditional knockout of TIP60 in Treg cells significantly decreases the Treg population in the peripheral immune organs, leading to a scurfy-like fatal autoimmune disease.
We elucidated a number of facets regarding glutathione (GSH)-bismuth ferrite (BiFeO3, BFO) interactions and reactivity that have previously remained unexplored on a molecular level. In this approach, the cation-modified reduced GSH (or oxidised glutathione (GS·)) formed on the (111)-oriented BiFeO3 membrane (namely BFO-(111)) can serve as an efficient quencher, and the luminescence mechanism is explained in aqueous conditions. Notably, we suggest the use of Fe2+↓ ion as an electron donor and K+ ion as an electron acceptor to exert a “gluing” effect on the glutamic acid (Glu) and glycine (Gly) side chains, producing an exposed sulfhydryl (−SH) configuration. This method may enable the rational design of a convenient platform for biosensors.
Density functional theory; Bismuth ferrite; Glutathione; Quantum dot
Objectives: The aim of this study was to develop a small interfering RNA (siRNA) against the expression of KIR3DL1 receptor on natural killer (NK) cells, in order to promote the ability of NK cells to destroy human immunodeficiency virus (HIV)-infected cells and thus prevent failure of siRNA therapy targeting human immunodeficiency virus type 1 (HIV-1) virus among HIV-1 infected patients in vitro. Methods: A siRNA targeting KIR3DL1 was synthesized and then modified with cholesterol, methylene, and sulfate. The inhibitory action of the siRNAs on primary cultured NK cells was detected. The amount of IFN-γ and TNF-α secretions in NK cells was measured. The intended functions of NK cells in vitro were analyzed by CFSE and PI methods. Results: There were no significant differences in inhibiting the expression of KIR3DL1 on NK cells between the modified and unmodified siRNAs, while inhibition by each of them differed significantly from controls. The amount of IFN-γ and TNF-α secretions in the NK cells was abundant due to unsuccessful expression of KIR3DL1 on NK cells, which further promoted function of the NK cells. Conclusion: The siRNA against KIR3DL1 could enhance the ability of the NK cells to kill the HIV-1 infected cells in vitro and successfully prevented the failure of siRNA therapy targeting the HIV-1 virus. Therefore, it can act as a potential gene therapeutic agent among HIV-1 infected people.
Fibroblasts, which play an important role in cardiac function/dysfunction, including arrhythmogenesis, have voltage-dependent (Kv) currents of unknown importance. Here, we assessed the differential expression of Kv currents between atrial and ventricular fibroblasts from control dogs and dogs with an atrial arrhythmogenic substrate caused by congestive heart failure (CHF).
Methods and results
Left atrial (LA) and ventricular (LV) fibroblasts were freshly isolated from control and CHF dogs (2-week ventricular tachypacing, 240 bpm). Kv currents were measured with whole-cell voltage-clamp, mRNA by quantitative polymerase chain reaction (qPCR) and fibroblast proliferation by 3H-thymidine incorporation. Robust voltage-dependent tetraethylammonium (TEA)-sensitive K+ currents (IC50 ∼1 mM) were recorded. The morphologies and TEA responses of LA and LV fibroblast Kv currents were similar. LV fibroblast Kv-current densities were significantly greater than LA, and Kv-current densities were significantly less in CHF than control. The mRNA expression of Kv-channel subunits Kv1.5 and Kv4.3 was less in LA vs. LV fibroblasts and was down-regulated in CHF, consistent with K+-current recordings. Ca2+-dependent K+-channel subunit (KCa1.1) mRNA and currents were less expressed in LV vs. LA fibroblasts. Inhibiting LA fibroblast K+ current with 1 mmol/L of TEA or KCa1.1 current with paxilline increased proliferation.
Fibroblast Kv-current expression is smaller in CHF vs. control, as well as LA vs. LV. KCa1.1 current is greater in LA vs. LV. Suppressing Kv current with TEA enhances fibroblast proliferation, suggesting that Kv current might act to check fibroblast proliferation and that reduced Kv current in CHF may contribute to fibrosis. Fibroblast Kv-current remodelling may play a role in the atrial fibrillation (AF) substrate; modulating fibroblast K+ channels may present a novel strategy to prevent fibrosis and AF.
Fibroblast; Ionic channel; Congestive heart failure; Remodelling; Proliferation
Social norms around condom use and safe sex as well as HIV/AIDS stigma are used to identify persons at higher risk for HIV. These measures have been developed and tested in a variety of settings and populations. While efforts have been undertaken to develop context specific measures of these domains among Chinese MSM, the feasibility of using existing measures is unknown. A survey of MSM, based on respondent-driven sampling (RDS), was conducted in Beijing. Existing measures of condom social norms, attitudes towards safer sex and HIV/AIDS stigma were piloted. Internal consistency of all measures was high. As expected higher levels of condom social norms and positive attitudes towards safer sex were associated with condom use. HIV / AIDS stigma and discrimination had a significant relationship with never having an HIV test and lack of discussion of HIV/AIDS with male partners. Correlates of low condom social norms were age, education, employment and resident status. Existing measures of condom social norms, attitudes towards safer sex and HIV/AIDS stigma appear to be appropriate for use among Chinese MSM. Using existing measures as opposed to developing new measures has the potential to expedite investigations into psychosocial correlates of HIV risk behavior.
men who have sex with men; condom social norms; safer sex; HIV/AIDS stigma; China
Neural damage is a devastating outcome of physical trauma. The glia are one of the main effectors of neuronal repair in the nervous system, but the dynamic interactions between peripheral neurons and Schwann cells during injury and regeneration remain incompletely characterized. Here, we combine laser microsurgery, genetic analysis, high-resolution intravital imaging and lattice light-sheet microscopy to study the interaction between Schwann cells and sensory neurons in a zebrafish model of neurotrauma. We found that chronic denervation by neuronal ablation leads to Schwann-cell death, whereas acute denervation by axonal severing does not affect the overall complexity and architecture of the glia. Neuronal-circuit regeneration begins when Schwann cells extend bridging processes to close the injury gap. Regenerating axons grow faster and directionally after the physiological clearing of distal debris by the Schwann cells. This might facilitate circuit repair by ensuring that axons are guided through unoccupied spaces within bands of Büngner towards their original peripheral target. Accordingly, in the absence of Schwann cells, regenerating axons are misrouted, impairing the re-innervation of sensory organs. Our results indicate that regenerating axons use haptotaxis as a directional cue during the reconstitution of a neural circuit. These findings have implications for therapies aimed at neurorepair, which will benefit from preserving the architecture of the peripheral glia during periods of denervation.
Summary: Schwann cells are important components of the peripheral glia. We use microsurgery and high-resolution live imaging to show how Schwann cells control the regeneration of a sensorineural circuit.
High-resolution imaging; Neurotrauma; Regeneration; Schwann cells; Haptotaxis
Neonatal pneumoperitoneum is a surgical emergency indicative of gastrointestinal perforation that requires immediate treatment to prevent death. There have been non-surgical conditions secondary to neonatal pneumoperitoneum (e.g., mechanical ventilation, pulmonary diseases and pneumatosis cystoides intestinalis) that neonates were able to overcome without the need for abdominal exploration. Idiopathic pneumoperitoneum, although similar to perforation of the alimentary tract and the previously mentioned non-surgical conditions, is a more rare and benign condition that does not yet have a definite cause. Hence, inexperienced surgeons may have a difficult time providing the right treatment for idiopathic pneumoperitoneum. We report a case of a neonate with a massive pneumoperitoneum who obtained a favorable outcome without surgical intervention. Nonetheless, the cause of pneumoperitoneum remains unclear. We hypothesize that the right sized perforation (range: 2 mm to 4 mm in diameter) at the anterior wall of the stomach is needed for pneumoperitoneum to occur. As the baby cries (aerophagia), the air in the stomach accumulates until it can enter the intraperitoneal cavity through the leak compressed by gastric peristalsis, hence forming a large pneumoperitoneum. Small amounts of gastric juice are able to penetrate the gastric wall; therefore, no signs or symptoms of peritonitis occur. The gastric leak self-seals, preventing further passage of the air, allowing the intraperitoneal free gas to dissipate gradually. This case demonstrated that laparotomy can be avoided in neonates with idiopathic pneumoperitoneum if a timely diagnosis is established.
Intestinal perforation; Pneumoperitoneum; Newborn; Therapeutics
Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody-producing plasma B-cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously-derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B-cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and suggest that MM may an inherently non-cell autonomous malignancy.
HIV is spreading among Chinese MSM and may possibly lead to infection of female partner. Pressure to marry may drive a greater proportion of Chinese MSM to have female partners than MSM elsewhere in the world. Measurement of the size of the potential risk to female partners of Chinese MSM is inconsistent in literature. From samples of MSM in two Chinese cities, we documented numbers of sexual partners and sexual activity with those partners. About 500 MSM were sampled in each city. 11.0% and 12.6% of men reported having any female partners in the past six months in Chongqing and Beijing, respectively. Men also reported that only 7.3% and 6.7% of their entire partnerships were with women in Chongqing and Beijing, respectively. Defining transmission risk accounting for receptive anal sex among men and condom non-use with both male and female partners 3.4% of MSM in both Chongqing and Beijing would have the potential to transmit HIV to female partners. Only 9 (1.8%) men in Chongqing and 2 (0.4%) in Beijing were HIV-positive and also had unprotected intercourse with females. The majority of HIV transmission risk among MSM in China is not from MSM to females.
MSM, sexual partnerships; China; HIV; risk taking; bridging; female partners
Tapping panel dryness (TPD) involves in the partial or complete cessation of latex flow thus seriously affect latex production in rubber tree (Hevea brasiliensis). Numerous studies have been conducted to define its origin and nature, but the molecular nature and mechanism of TPD occurrence remains unknown. This study is committed to de novo sequencing and comparative analysis of the transcriptomes of healthy (H) and TPD-affected (T) rubber trees to identify the genes and pathways related to the TPD.
Total raw reads of 34,632,012 and 35,913,020 bp were obtained from H and T library, respectively using Illumina Hiseq 2000 sequencing technology. De novo assemblies yielded 141,456 and 169,285 contigs, and 96,070 and 112,243 unigenes from H and T library, respectively.
Among 73597 genes, 22577 genes were identified as differential expressed genes between H and T library via comparative transcript profiling. A majority of genes involved in natural rubber biosynthesis and jasmonate synthesis with most potential relevance in TPD occurrence were found to be differentially expressed.
In TPD-affected trees, the expression of most genes related to the latex biosynthesis and jasmonate synthesis was severely inhibited and is probably the direct cause of the TPD. These new de novo transcriptome data sets provide a significant resource for the discovery of genes related to TPD and improve our understanding of the occurrence and maintainace of TPD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1562-9) contains supplementary material, which is available to authorized users.
Rubber tree; TPD; Transcriptome; Latex biosynthesis; Jasmonate synthesis
The incidence of primary central nervous system lymphoma (PCNSL) has increased in the last two decades and the clinical research regarding the treatment for PCNSL patients has also increased. However, the optimal induction chemotherapy has not been fully established. In the present retrospective study, the aim was to analyze the outcome in PCNSL patients treated with the combination of rituximab, methotrexate (MTX), cytarabine (Ara-C) and dexamethasone (R-MAD). Eighteen patients from Beijing Tiantan Hospital (Beijing, China) between January 2010 and March 2014 were newly diagnosed with PCNSL [diffuse large B-cell lymphoma (DLBCL) type] and received R-MAD as first-line treatment. The dosage was as follows: 375 mg/m2 rituximab was administered on day 0, 3.5 g/m2 MTX was administered on day 1, 1 g/m2 Ara-C was administered on day 2 and 10 mg dexamethasone was administered on days 1–3, every 3 weeks. After 6 cycles, the overall response rate was 94.5%. Ten (55.6%) patients achieved complete response (CR), 7 (38.9%) achieved partial response (PR) and 1 (5.6%) had progressive disease (PD). Patients were followed up from the start of the treatment, median 24.2 months (range 6–48). The overall survival (OS) rate was 94.5% and progression-free survival rate was 94.5%. The median OS was 22 months (95% confidence interval, 19.4–24.6). The high level of serum lactate dehydrogenase (LDH) concentration was associated with a poor outcome. Among 5 patients with an abnormally high LDH concentration, 1 achieved CR, 3 had PR and 1 had PD. None of the patients experienced any grade 4 toxicity. These results indicated that the R-MAD immunochemotherapy regimen is effective in PCNSL patients without serious toxicity. A prospective investigation with more patients should be administered in order to understand the more accurate effect of the regimen.
primary central nervous system lymphoma; immunochemotherapy; rituximab; retrospective analysis; serum lactate dehydrogenase
The present study aimed to compare the antitumor effects of cascade primed immune (CAPRI) cells and cytokine-induced killer (CIK) cells in vitro, through investigating cell morphology, proliferation, cytotoxic activity to tumor cells and the ability of these cells to secrete cytokines. Peripheral blood samples (50 ml) were obtained from three healthy volunteers and peripheral blood mononuclear cells (PBMCs) were obtained from each via Ficoll-Conray density gradient centrifugation. Each suspension of PBMCs (1×106/ml) was divided into two parts; CAPRI cells were obtained from one part through a series of induction, amplification and cytokine cultures, while CIK cells were obtained from the other part through induction with different cytokines. During the culture process, the proliferation and morphological changes were observed for the two cell types using Trypan blue staining. At day 14, the cytotoxic activity of the two cell types was examined through determining lactate dehydrogenase release in the presence of K562 leukemia cells and MCF-7 breast cancer cells. In addition, secretory levels of interferon (IFN)-γ and interleukin (IL)-2 were detected using enzyme-linked immunospot (ELISPOT) technology. The results revealed that at day 5 and 14 of culture, there were significantly fewer CAPRI cells compared with CIK cells (P<0.001), although the survival rate of each cell type was >95%. The cytotoxic activity of CAPRI cells towards the K562 cell line was effector-target ratio-dependent (40:1 and 20:1) with values of 55.1±3.25 and 35.0±2.65%, respectively, which were significantly reduced compared with the corresponding data in CIK cells, 60.0±3.03 and 39.7±3.42% (P=0.004 and 0.005, respectively). Furthermore, the cytotoxic activity of CAPRI cells towards MCF-7 cells were 71.5±3.06, 56.0±3.76 and 40.2±2.90% at effector-target ratios 40:1, 20:1 and 10:1, respectively. These data were significantly higher than the corresponding values in CIK cells, 65.4±3.86, 49.5±3.91 and 36.1±3.73% (P=0.002, 0.003 and 0.02, respectively). As determined using ELISPOT technology at different cell concentrations (1×106/ml and 5×105/ml), IFN-γ secretion levels, determined by the number of spot-forming cells, of CAPRI cells were 126.2±10.31 and 48.8±10.99, respectively, which were significantly reduced compared with those of CIK cells, 409.3±7.76 and 159.3±15.45, respectively (P<0.001). IL-2 secretion levels in CAPRI cells were 325.1±16.24 and 113.8±11.29 at 1×106/ml and 5×105/ml, respectively, which were significantly increased compared with CIK cells, 212.0±16.58 and 70.7±10.57, respectively (P<0.001). In conclusion, the present study demonstrated that CAPRI cells had a reduced proliferation rate compared with CIK cells as well as a less potent cytotoxic effect on K562 cells; however, the two cell types had potent cytotoxic activity towards solid tumor MCF-7 cells. In addition, CAPRI cells secreted lower levels of IFN-γ and increased levels of IL-2 compared with CIK cells. These results indicated that antitumor activities of CAPRI and CIK cells proceeded via different mechanisms.
cascade primed immune cells; cytokine-induced killer cells; proliferation; cytotoxic activity; cytokine
Humoral and cellular immune responses play protective roles against Mycobacterium tuberculosis (MTB) infection. However, hookworm infection decreases the immune response to hookworm and bystander antigens. Currently, immune responses to co-infection of MTB and hookworm are still unknown, although co-infection has been one of the public health problems in co-endemic areas of pulmonary tuberculosis (PTB) and hookworm disease. Therefore, it is essential to evaluate B and T cell immune responses to the co-infection.
Seventeen PTB cases co-infected with hookworm, 26 PTB cases, 15 patients with hookworm infection, and 24 healthy controls without PTB or hookworm infection were enrolled in the study. Expressions of CD3, CD4, CD8, CD10, CD19, CD20, CD21, CD25, CD27, CD38, FoxP3, and PD-1 were assessed on B and T cell subsets using multicolor flow cytometry.
For the B cell (CD19+) subsets, naïve B cells (CD10−CD27−CD21+CD20+), plasma cells (CD10−CD27+CD21−CD20−), and tissue-like memory B cells (CD10−CD27−CD21−CD20+) had higher proportions, whilst resting memory B cells (CD10−CD27+CD21+CD20+) had lower proportions in the group co-infected with MTB and hookworm as compared to other groups. Frequencies of activated memory B cells (CD10−CD27+CD21−CD20+) did not differ among the four groups. For the T cell (CD3+) subsets, frequencies of regulatory T cells (CD4+CD25+Foxp3+) and exhausted CD4+ and CD8+ T cells (CD4+PD-1+ and CD8+PD-1+) were higher, and frequencies of activated CD4+ and CD8+ T cells (CD4+CD38+ and CD8+CD38+) were lower in the co-infected group as compared to the other groups.
The change patterns of the cell profile of circulating lymphocytes were indentified in human co-infection of MTB and hookworm, which might indicate that the humoral and cellular immune responses are more suppressed.
Electronic supplementary material
The online version of this article (doi:10.1186/s40249-015-0046-0) contains supplementary material, which is available to authorized users.
Co-infection; Mycobacterium tuberculosis; Hookworm; Immune response