Increased T regulatory cells and decreased Th1 pro-inflammatory cytokines correlate with culture-positive infection in febrile neutropenia childhood oncology patients

BackgroundPaediatric oncology patients with febrile neutropenia are usually hospitalised and treated with empirical broad-spectrum antibiotic therapy to counter the risk of infection. However, there is currently no method available to rapidly identify bacteremia in these patients. T-helper-type-1 (Th1) cytokines are required for effective immune response to many pathogenic organisms and T regulatory cells are known suppressors of Th1 cells. We hypothesized that characterization of reduced intracellular Th1 cytokines and increased T regulatory cells (Tregs) may prove useful in identifying infection in childhood oncology patients with febrile neutropenia.MethodsIntracellular Th 1 cytokines and Tregs were enumerated in peripheral blood from a group of childhood oncology patients with febrile neutropenia using multiparameter flow cytometry.ResultsThere was a significant increase in the percentage of CD25⁺ CD127^? CD8^? CD3⁺ Tregs and a significant decrease in Th1 intracellular cytokines IFNγ, IL-2 and TNFα in the blood of culture positive patients compared with culture negative patients.ConclusionsEnumeration of Tregs and intracellular Th1 cytokines may provide a sensitive, specific test for determining infection in childhood oncology patients before blood culture results become available.     

The value of microparticles in detecting acute rejection episodes after liver transplantation

Context: Non-invasive markers for diagnosis of acute rejection (AR) following liver transplantation have not been developed, yet.

Objective: We analyzed the correlation of plasma microparticle levels (MP) with AR.

Materials and Methods: MP (CD4, CD8, CD25, CD31, MHC) of 11?AR patients and 11 controls were analyzed within the first week after transplantation.

Results: CD4, CD8 and CD31 positive MP were higher in the AR, whereas overall MP count, CD25 and MHCI positive MP proportions did not differ between both groups.

Discussion and Conclusion: MP dynamics within the first period of transplantation could help to clarify on-going mechanisms of immunomodulation.     

Clinical Studies with Liposomal Doxorubicin

Abstract

To present data on a continuing phase I study of liposomal doxorubicin at this time may seem like a giant leap backwards. Liposomally encapsulated doxorubicin has been available for clinical use for some years. Phase I studies have been completed, and phase II studies have been conducted in patients with breast cancer (1,2). Two major obstacles to the commercial exploitation of drugs encapsulated in liposomes were evident. the first was to find a preparation that could be given safely to humans. the second was to develop a pharmaceutical preparation that could be commercially exploited by fulfilling the requirements for manufacture and sale as a drug. the first of these problems was solved a number of years ago, but only recently have we had preparations that fulfilled the second requirement. Two of these have entered clinical trials at Roswell Park Memorial Institute (RPMI). One of these, the liposomally encapsulated muramyl tripeptide derivative (MTP-PE), has been presented previously (3,4). Accordingly, in this paper we will focus on our studies of liposomally encapsulated doxorubicin.     

非小细胞肺癌CD166+干细胞的分离和鉴定

目的:分选人非小细胞肺癌中的CD166+细胞,并验证其肿瘤干细胞的特性。方法:收集手术切除的15例非小细胞癌组织标本以及患者的临床资料,并通过流式细胞术对组织中CD166+的表达水平进行检测,对CD166+细胞进行原代培养,对比CD166+细胞和CD166-细胞的成球能力和集落形成能力;并将CD166+细胞和CD166-细胞注射到小鼠体内,比较其体内肿瘤形成能力。结果:在15例临床样本中均检测到CD166+细胞,CD166阳性表达率最高为12.1%,最低为0.3%。CD166的高表达与肿瘤TNM分期、肿瘤转移、以及肿瘤分型密切相关(P均0.05)。CD166+细胞的成球形成能力和集落形成能力显著的高于CD166-细胞,且CD166+细胞在裸鼠体内肿瘤形成能力显著高于CD166-细胞(P均0.05)。结论:非小细胞肺癌CD166+细胞具有肿瘤干细胞的特征,CD166在非小细胞肺癌的发生发展中可能具有重要的作用。     

Role of Type I Interferon Receptor Signaling on NK Cell Development and Functions

Type I interferons (IFN) are unique cytokines transcribed from intronless genes. They have been extensively studied because of their anti-viral functions. The anti-viral effects of type I IFN are mediated in part by natural killer (NK) cells. However, the exact contribution of type I IFN on NK cell development, maturation and activation has been somewhat difficult to assess. In this study, we used a variety of approaches to define the consequences of the lack of type I interferon receptor (IFNAR) signaling on NK cells. Using IFNAR deficient mice, we found that type I IFN affect NK cell development at the pre-pro NK stage. We also found that systemic absence of IFNAR signaling impacts NK cell maturation with a significant increase in the CD27⁺CD11b⁺ double positive (DP) compartment in all organs. However, there is tissue specificity, and only in liver and bone marrow is the maturation defect strictly dependent on cell intrinsic IFNAR signaling. Finally, using adoptive transfer and mixed bone marrow approaches, we also show that cell intrinsic IFNAR signaling is not required for NK cell IFN-γ production in the context of MCMV infection. Taken together, our studies provide novel insights on how type I IFN receptor signaling regulates NK cell development and functions.     

Mevinolin enhances osteogenic genes (ALP,type I collagen and osteocalcin), CD44, CD47 and CD51 expression during osteogenic differentiation

AimsIn this study, we evaluated the effect of mevinolin on the expressions of osteogenic genes and surface molecules expression during osteogenesis.Main methodsD1 cells were cultured in osteogenic differentiation medium (ODM) for 6 days, treated with mevinolin for 2 days, and then subjected to alizarin red S staining, MTT assays, alkaline phosphatase (ALP) activity determinations, energy dispersive X-ray spectrophotometry (EDX), real-time PCR, Western blot, fluorescence microscopy and FACS analysis.Key findingsMevinolin is commonly prescribed and widely used to lower cholesterol levels, and offers an important, effective approach to the treatment of hypercholesterolemia and arteriosclerosis. However, the direct effect of mevinolin on osteogenesis in vitro has not been clarified. ODM has been previously shown to increase the osteoblast differentiation of D1 cells. In the present study, we investigated the expressions of osteogenic genes and surface molecules during osteoblast differentiation induced by mevinolin. We found that the induction of ALP, type I collagen, osteocalcin, CD44, CD47 and CD51 by mevinolin is responsible for the osteoblastic differentiation of D1 cells.SignificanceOur data show that mevinolin enhances the expressions of proteins and surface molecules related to osteogenesis.     

Amniotic fluid-derived extracellular vesicles: characterization and therapeutic efficacy in an experimental model of bronchopulmonary dysplasia

Background aimsExtracellular vesicles (EVs) are being tested for their use as novel therapeutics. However, the optimal source of EVs is currently under investigation. Amniotic fluid (AF) is a natural source of EVs that can be easily obtained for use in regenerative medicine, yet AF-EV characterization has not been fully explored.MethodsHere the authors demonstrate AF as a rich source of EVs and identify the microRNA and proteomic cargo. Bioinformatics analysis of this cargo revealed multiple pathway targets, including immunomodulatory, anti-inflammatory and free radical scavenging networks. The authors further demonstrated the therapeutic potential of this EV product as a novel preventative agent for bronchopulmonary dysplasia (BPD).ResultsIntra-tracheal administration of AF-EVs preserved alveolar development, attenuated vascular remodeling and pulmonary hypertension, decreased lung pro-inflammatory cytokine expression and reduced macrophage infiltration in an experimental BPD model.ConclusionsThe authors’ results suggest that AF is a viable biological fluid for EV harvest and that AF-EVs have strong therapeutic potential for pulmonary diseases, such as BPD, warranting further development to transition this novel EV product into the clinic.     

一例少见青少年T幼淋巴细胞白血病的病例报道及文献回顾

目的:报道一例少见幼年幼淋巴细胞白血病(T-PLL)患者的病例资料及诊疗过程,并通过文献复习总结了T-PLL的临床特点和诊疗措施。方法:对病例资料进行对比分析,同时通过文献回顾研究T-PLL的特点及发生、发展及诊疗情况。结果:本病例为少见青少年型幼淋巴细胞白血病,细胞以成熟小淋巴细胞为主,特征免疫表型为CD7~+CD5~+CD4~+CD8~+CD3~+,无染色体异常,有TCR基因重排。结论:T-PLL病例具有多态性及复杂性,在临床诊断中需要密切联系临床特点及实验室诊断,综合判断疾病情况,做出最优治疗方案。     

Human bone marrow mesenchymal cells express NG2: possible increase in discriminative ability of flow cytometry during mesenchymal stromal cell identification

Background aimsMesenchymal stromal cells (MSC) exhibit non-specific hematopoietic cell and/or stromal cell markers (e.g. CD73, CD105 and CD166) that have been used to identify MSC by flow cytometry. Because a neural glial antigen, NG2 (a progenitor cell marker in the central nervous system), is expressed by several tissue cells originating in the mesenchyme but not hematopoietic cells, it might be useful for isolating and identifying MSC. We investigated NG2 expression on culture-expanded MSC by flow cytometry.MethodsHuman bone marrow (BM) samples taken from 12 donors were cultured for MSC to be used in up to nine serial passages. Using flow cytometry, the neural glial antigen NG2 and commonly used MSC markers CD73, CD105 and CD166, were analyzed on the surface of culture-expanded MSC. The multipotential differentiation of the MSC was examined by adipogenic and osteogenic induction.ResultsThe percentage of cells positive for NG2 was similar to the percentages of cells positive for CD73, CD105 and CD166 in all passages of BM samples. The mean fluorescent intensities of NG2 did not change with culture passage. The MSC was successfully differentiated into adipogenic and osteogenic lines. The cells showed no karyotypic abnormalities.ConclusionsNG2 seems to be a promising marker for investigating the biology of MSC.     

CD44及CD24在乳腺癌组织中的表达及与临床病理特征的关系研究

目的:探讨肿瘤标志因子CD44及CD24在乳腺癌组织中的表达及与临床病理特征的关系。方法:选择从2015年1月到2017年1月在我院接受手术治疗的乳腺癌患者80例纳入本次研究,另选同期在我院治疗的导管原位癌患者30例,小叶增生患者20例及导管单纯增生患者20例的组织提取标本进行对照,分析CD44及CD24在乳腺癌组织和不同病变类型中的表达,并分析CD44~+/CD24~-细胞在癌症免疫分型中的表达以及CD44~+/CD24~-细胞与乳腺浸润导管癌相关病理特征的关系。结果:乳腺癌组织内的CD44阳性率为52.50%,CD24的阳性率为57.50%,均显著高于癌旁组织的11.25%和15.00%,差异均有统计学意义(均P0.05)。CD44及CD24在导管原位癌及乳腺浸润导管癌中的阳性率高于小叶增生和导管单纯增生,导管原位癌的阳性率高于乳腺浸润导管癌,差异均有统计学意义(均P0.05),且CD44在乳腺浸润导管癌不同分化类型中的阳性率差异有统计学意义(P0.05)。CD24在乳腺浸润导管癌不同分化类型中的阳性率差异不显著(P0.05)。CD44~+/CD24~-细胞在不同癌症免疫分型以及不同分化中的阳性率比较差异均有统计学意义(P0.05)。CD44~+/CD24~-细胞与乳腺浸润导管癌患者的年龄、月经状态、肿瘤直径、淋巴结转移以及远处转移之间均无明显关系(均P0.05)。结论:CD44及CD24在乳腺癌组织内存在较高的阳性率,且CD44~+/CD24~-在乳腺原位癌及低分化的乳腺癌组织内具有更高的阳性率,临床上可尝试通过监测CD44~+/CD24~-的阳性表达情况评价患者的病情及预后。     

Dance and early childhood cognition: The Isadora Effect

ABSTRACT

This article proposes the existence of an Isadora Effect: the propositions that motor development plays a primal role in brain development, and the first understanding of symbolic meaning among young children occurs from an understanding of movement and gesture. Anecdotal evidence for the past few decades has demonstrated that dance education and the early use of symbolic movement greatly enhance cognitive development in young children. The author presents (a) background and historical information about dance in early childhood in the United States; (b) research in which physical, emotional, and social development has served the backbone for rationalizing inclusion of dance in early education; (c) The Isadora Effect in early childhood dance education and its relationship to cognitive development, brain development, and intelligence; (d) the 21st Century Skills in relation to early childhood development and dance education; and (e) early childhood dance education and the National Core Arts Standards. The author makes three recommendations for improving the development of American youth relative to early childhood dance education: increased inclusion of creative movement and dance in early childhood curricula, scientific study by the pediatric and neurological communities to investigate effects of motor development and early symbolic movement on brain development and cognitive growth, and ways dance educators can communicate with policy makers about the kinds of support needed to make the first two recommendations a reality.     

Serve and return: Communication foundations for early childhood music policy stakeholders

ABSTRACT

Serve-and-return interactions between a young child and caregiver are cited as integral to healthy child development and language development. In this article, the authors assert that serve-and-return interactions offer a relevant model for policy development in early childhood music education. They share contemporary evidence that music learning and development begins in the womb, continues during infancy, and needs to be prioritized in preschool and early elementary years. Next, they trace the policy landscape for early childhood education and music education in the United States since 2008. Although the landscape has remained stark, the authors offer recent glimmers of possibilities and conclude with actionable steps for improving early childhood music education policies.     

Abacavir-Reactive Memory T Cells Are Present in Drug Na?ve Individuals

BackgroundFifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.MethodsTo determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.ResultsAbacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.ConclusionsWe propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.     

Changing Epidemiological Characteristics of Hepatitis A in Zhejiang Province,China: Increased Susceptibility in Adults

BackgroundHepatitis A is a common acute hepatitis caused by hepatitis A virus (HAV). Annually, it affects 1.4 million people worldwide. Between 1991 and 1994, HAV infections were highly endemic in Zhejiang Province (China), with 78,720 reported HAV infections per year. Hepatitis A vaccine came on the market in 1995 and was implemented for voluntary immunization. Since 2008, hepatitis A vaccine has been integrated into the national childhood routine immunization program.ObjectiveTo understand the current epidemiological profile of hepatitis A in Zhejiang Province since hepatitis A vaccine has been available for nearly two decades.MethodsThis study used the 2005–2014 National Notifiable Diseases Reporting System data to evaluate the incidence rate of notified hepatitis A cases in Zhejiang Province.ResultsThe overall trend of incidence rate of notified hepatitis A cases significantly decreased from 2005 to 2014 (P< 0.001). During the study period, the reported incidence rate in individuals aged ≤19 years declined to the historically lowest record in 2014. Compared with individuals aged ≤19 years, those aged ≥20 years showed the highest incidence rate (P< 0.001). Majority of HAV infected cases were Laborers, accounting for approximately 70% of reported cases.ConclusionsChildhood immunization strategy with hepatitis A vaccine seemed to be effective in decreasing notified hepatitis A incidence rate in individuals aged ≤19 years. Those aged ≥20 years were observed to be the most susceptible population. The vast majority of hepatitis A cases were notified among Laborers. Therefore, we strongly suggest that future preventive and control measures should focus more on adults, particularly Laborers, in addition to the current childhood hepatitis A vaccination programme.     

Visualizing phosphatidylcholine via mass spectrometry imaging: relevance to human health

ABSTRACT

Introduction: Mass spectrometry imaging (MSI) techniques are nowadays widely used to obtain spatially resolved metabolite information from biological tissues. Since (phospho)lipids occur in all animal tissues and are very sensitively detectable, they are often in the focus of such studies. This particularly applies for phosphatidylcholines (PC) which are very sensitively detectable as positive ions due to the permanent positive charge of their choline headgroup.

Areas covered: After a short introduction of lipid species occurring in biological systems and approaches normally used to obtain spatially resolved mass spectra (with the focus on matrix-assisted laser desorption/ionization coupled to time-of-flight (MALDI-TOF) MSI) a survey will be given which diseases have so far been characterized by changes of the PC composition.

Expert commentary: Since PC species are very sensitively detectable by MS, sensitivity is not a major issue. However, spatial resolution is still limited and cellular dimensions can be hardly resolved by MALDI-TOF MSI, which is a critical point of the available approaches. Due to lacks of reproducibility and standardization further development is required.     

Type II arabinogalactan from Anoectochilus formosanus induced dendritic cell maturation through TLR2 and TLR4

BackgroundPolysaccharides, considered as immunomodulators with the capacity to activate immunity against microbial pathogens and tumors, have been employed for their dietary and medical benefits.PurposeThis study investigated the immunomodulatory effect of polysaccharide such as type II arabinogalactan from Anoectochilus formosanus (AGAF) on dendritic cell (DC) maturation and the underlying molecular mechanisms.Methods and resultsExposing DCs to AGAF induces cell maturation, which is characterized by the upregulation of CD86, CD83, CD80, CD40, and MHC class I and class II expression through flow cytometry analysis and morphological change without cytotoxicity. In addition, AGAF-triggered DC2.4 cells were involved in priming T-cell activation in vitro and in vivo. Transfection of toll-like receptor (TLR) 2 proteins and TLR4 siRNA suppressed DC maturation, suggesting that AGAF induced DC maturation through TLR2 and TLR4.ConclusionThese findings indicate that AGAF may be a potentially effective immunomodulator in stimulating DC maturation.     

Human umbilical cord blood-derived stromal cells prevent graft-versus-host disease in mice following haplo-identical stem cell transplantation

Background aimsHuman umbilical cord blood-derived stromal cells (hUCBDSC) comprise a novel population of CD34⁺ cells that has been isolated in our laboratory. They have been shown previously not only to be non-immunogenic but also to exert immunosuppressive effects on xenogenic T cells in vitro. This study investigated the role of hUCBDSC in immunomodulation in an acute graft-versus-host disease (GvHD) mouse model after haplo-identical stem cell transplantationMethodsAcute GvHD was induced in recipient (B6 × BALB/c)F₁ mice by irradiation (750 cGy) followed by infusion of bone marrow cells and splenocytes from donor C57BL/6 mice. hUCBDSC were co-transplanted in the experimental group. The survival time, body weight and clinical and histopathologic scores were recorded after transplantation. The expression of surface markers [major histocompatibility complex (MHC) I, MHC II, CD80 and CD86] on CD11c⁺ dendritic cells (DC), and the percentage of CD4⁺ regulatory T cells (Treg), in the spleens of recipient mice were examined by flow cytometryResultsThe survival time was significantly prolonged, and the clinical and histopathologic scores were reduced in mice co-transplanted with hUCBDSC. The expression levels of the surface markers on DC were significantly lower in mice transplanted with hUCBDSC compared with those without. The proportion of CD4⁺ Treg in the spleen was also increased in mice transplanted with hUCBDSCConclusionsThese results from a GvHD mouse model are in agreement with previous in vitro findings, suggesting that hUCBDSC possess immunosuppressive properties and may act via influencing DC and CD4⁺ Treg.     

MicroRNAs that affect prostate cancer: emphasis on prostate cancer in African Americans

Abstract

Although concerted efforts have been directed toward eradicating health disparities in the United States, the disease and mortality rates for African American men still are among the highest in the world. We focus here on the role of microRNAs (miRNAs) in the signaling pathways of androgen receptors and growth factors that promote the progression of prostate cancer to more aggressive disease. We explore also how differential expression of miRNAs contributes to aggressive prostate cancer including that of African Americans.     

Spatiotemporal Transmission Dynamics of Hemorrhagic Fever with Renal Syndrome in China, 2005–2012

BackgroundHemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem with 90% of the total reported cases in the world. This study describes the spatiotemporal dynamics of HFRS cases in China and identifies the regions, time, and populations at highest risk, which could help the planning and implementation of key preventative measures.MethodsData on all reported HFRS cases at the county level from January 2005 to December 2012 were collected from Chinese Center for Disease Control and Prevention. Geographic Information System-based spatiotemporal analyses including Local Indicators of Spatial Association and Kulldorff''s space-time scan statistic were performed to detect local high-risk space-time clusters of HFRS in China. In addition, cases from high-risk and low-risk counties were compared to identify significant demographic differences.ResultsA total of 100,868 cases were reported during 2005–2012 in mainland China. There were significant variations in the spatiotemporal dynamics of HFRS. HFRS cases occurred most frequently in June, November, and December. There was a significant positive spatial autocorrelation of HFRS incidence during the study periods, with Moran''s I values ranging from 0.46 to 0.56 (P<0.05). Several distinct HFRS cluster areas were identified, mainly concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties.ConclusionsThis study identified significant space-time clusters of HFRS in China during 2005–2012 indicating that preventative strategies for HFRS should be particularly focused on the northeastern, central, and eastern of China to achieve the most cost-effective outcomes.     

Drivers of human development: How relationships and context shape learning and development1

ABSTRACT

This article synthesizes knowledge on the role of relationships and key macroand micro-contexts - poverty, racism, families, communities, schools, and peers - in supporting and/or undermining the healthy development of children and youth, using a relational developmental systems framework. Relationships with parents, siblings, peers, caregivers, and teachers are explored in the context of early care and childhood settings, schools, classrooms, and school-based interventions. Additional contextual factors include; chronic stress, institutionalized racism, stereotype threat, and racial identity. A companion article focuses on how the human brain develops, and the major constructs that define human development, the constructive nature of development, and the opportunities for resilience. Human development occurs through reciprocal coactions between the individual and their contexts and culture, with relationships as the key drivers. Relationships and contexts, along with how children appraise and interpret them, can be risks and assets for healthy learning and development, and their influence can be seen across generations and can produce intra- as well as intergenerational assets and risks. This knowledge about the individual’s responsiveness to context and experience has both positive and negative implications across early childhood, adolescence and into adulthood. Sensitive periods for brain growth and development are considered within the contextual factors that influence development including; parental responsiveness and attunement, intentional skill development, mindfulness, reciprocal interactions, adversity, trauma, and enriching opportunities. The accumulated knowledge on human development and the power of context and culture can inform child-serving systems that support positive adaptations, resilience, learning, health, and well-being.