Prognostic Significance of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

The prognostic significance of KIT mutations in core-binding factor acute myeloid leukemia (CBF-AML), including inv(16) and t(8;21) AML, is uncertain. We performed a systematic review and meta-analysis of the effect of KIT mutations on the complete remission (CR) and relapse rates and overall survival (OS) of CBF-AML. PubMed, Embase, Web of Science, and the Cochrane Library were searched and relevant studies were included. Negative effect was indicated on relapse risk of CBF-AML (RR [relative risk], 1.43; 95%CI [confidence interval], 1.20–1.70) and t(8;21) AML (RR, 1.70; 95% CI, 1.31–2.21), not on OS of CBF-AML (RR, 1.09; 95% CI, 0.97–1.23), CR (OR [odds ratio], 0.95; 95% CI, 0.52–1.74), relapse risk (RR, 1.12; 95% CI, 0.90–1.41) or OS (RR, 1.03; 95% CI, 0.90–1.18) of inv(16) AML. Subgroup analysis of t(8,21) AML showed negative effect of KIT mutations on CR (OR, 2.03; 95%CI: 1.02–4.05), relapse risk (RR, 1.89; 95%CI: 1.51–2.37) and OS (RR, 2.26; 95%CI: 1.35–3,78) of non-Caucasians, not on CR (OR, 0.61; 95%CI: 0.19–1.95) or OS (RR, 1.12; 95%CI: 0.90–1.40) of Caucasians. This study indicates KIT mutations in CBF-AML to be included in the initial routine diagnostic workup and stratification system of t(8,21) AML. Prospective large-scale clinical trials are warranted to evaluate these findings.     

Interleukin-6 Levels in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

Background

The change of serum interleukin-6(IL-6) levels in women with polycystic ovary syndrome (PCOS), as well as the relations between IL-6 levels and body mass index (BMI), insulin resistance(IR) and androgen status of PCOS patients, are not fully understood.

Methods

A literature search was performed in October 2015 using PubMed, Embase and the Cochrane Library databases to identify studies. Random-effects model was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs).

Results

Twenty articles with 25 case-control studies included 1618 women (922 PCOS patients and 696 controls) were included in this study. IL-6 levels in controls were significantly lower than that of PCOS patients (SMD = 0.78, 95%CI = 0.41–1.16, P<0.001), with significant heterogeneity across studies (I² = 91% and P<0.001). Meta-regression analysis model indicated IR status was the main source of heterogeneity (P = 0.005). Results from group analysis suggested that high IL-6 levels in PCOS were significantly associated with Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR) ratio and total testosterone ratio (T ratio), and was found in both lean and obese women with PCOS. Cumulative meta-analysis results indicated the total effect size (SMD) had tend to be stable since 2012(0.79 to 0.92).

Conclusions

A high IL-6 level is not an intrinsic characteristic of PCOS, but may be a useful monitoring biomarker for the treatment of PCOS.     

CX3CR1-Mediated Akt1 Activation Contributes to the Paclitaxel-Induced Painful Peripheral Neuropathy in Rats

Painful peripheral neuropathy is a serious dose-limiting side effect of paclitaxel therapy, which unfortunately often happens during the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms of the painful peripheral neuropathy remain largely unknown. Here, we found that paclitaxel treatment (3 × 8 mg/kg, cumulative dose 24 mg/kg) upregulated the expression of CX3CR1 and phosphorylated Akt1 in DRG and spinal dorsal horn. Blocking of Akt1 pathway activation with different inhibitor (MK-2206 or LY294002) significantly attenuated mechanical allodynia and thermal hyperalgesia induced by paclitaxel. Furthermore, inhibition of CX3CR1 by using neutralizing antibody not only prevented Akt1 activation in DRG and spinal dorsal horn but also alleviated pain-related behavior induced by paclitaxel treatment. This study suggested that CX3CR1/Akt1 signaling pathway may be a potential target for prevention and reversion of the painful peripheral neuropathy induced by paclitaxel.     

Human T-cell leukemia virus type 1 (HTLV-1) infection of mice: proliferation of cell clones with integrated HTLV-1 provirus in lymphoid organs

Human T-cell leukemia virus type 1 (HTLV-1) is suggested to cause adult T-cell leukemia after 40 to 50 years of latency in a small percentage of carriers. However, little is known about the pathophysiology of the latent period and the reservoir organs where polyclonal proliferation of cells harboring integrated provirus occurs. The availability of animal models would be useful to analyze the latent period of HTLV-1 infection. At 18 months after HTLV-1 infection of C3H/HeJ mice inoculated with the MT-2 cell line, which is an HTLV-1-producing human T-cell line, HTLV-1 provirus was detected in spleen DNA from eight of nine mice. No more than around 100 proviruses were found per 10(5) spleen cells. Cellular sequences flanking the 3' long terminal repeat (LTR) and the clonalities of the cells which harbor integrated HTLV-1 provirus were analyzed by linker-mediated PCR. The results showed that the flanking sequences are of mouse genome origin and that polyclonal proliferation of the spleen cells harboring integrated HTLV-1 provirus had occurred in three mice. A sequence flanking the 5' LTR was isolated from one of the mice and revealed the presence of a 6-nucleotide duplication of cellular sequences, consistent with typical retroviral integration. Moreover, PCR was performed on DNA from infected tissues, with LTR primers and primers derived from seven novel flanking sequences of the three mice. Data revealed that the expected PCR products were found from lymphatic tissues of the same mouse, suggesting that the lymphatic tissues were the reservoir organs for the infected and proliferating cell clones. The mouse model described here should be useful for analysis of the carrier state of HTLV-1 infection in humans.     

The Thioredoxin GbNRX1 Plays a Crucial Role in Homeostasis of Apoplastic Reactive Oxygen Species in Response to Verticillium dahliae Infection in Cotton

Examining the proteins that plants secrete into the apoplast in response to pathogen attack provides crucial information for understanding the molecular mechanisms underlying plant innate immunity. In this study, we analyzed the changes in the root apoplast secretome of the Verticillium wilt-resistant island cotton cv Hai 7124 (Gossypium barbadense) upon infection with Verticillium dahliae. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry analysis identified 68 significantly altered spots, corresponding to 49 different proteins. Gene ontology annotation indicated that most of these proteins function in reactive oxygen species (ROS) metabolism and defense response. Of the ROS-related proteins identified, we further characterized a thioredoxin, GbNRX1, which increased in abundance in response to V. dahliae challenge, finding that GbNRX1 functions in apoplastic ROS scavenging after the ROS burst that occurs upon recognition of V. dahliae. Silencing of GbNRX1 resulted in defective dissipation of apoplastic ROS, which led to higher ROS accumulation in protoplasts. As a result, the GbNRX1-silenced plants showed reduced wilt resistance, indicating that the initial defense response in the root apoplast requires the antioxidant activity of GbNRX1. Together, our results demonstrate that apoplastic ROS generation and scavenging occur in tandem in response to pathogen attack; also, the rapid balancing of redox to maintain homeostasis after the ROS burst, which involves GbNRX1, is critical for the apoplastic immune response.Cotton (Gossypium spp.) is one of the most economically important crops worldwide and a number of pathogens affect the growth and development of cotton plants. The soil-borne pathogen Verticillium dahliae (V. dahliae) causes the destructive vascular disease Verticillium wilt, which results in devastating reductions in plant mass, lint yield, and fiber quality (Bolek et al., 2005; Cai et al., 2009). To date, Verticillium wilt has not been effectively controlled in the most common cultivated cotton species, upland cotton (Gossypium hirsutum), and cultivars with stably inherited resistance to this disease are currently unavailable (Aguado et al., 2008; Jiang et al., 2009; Zhang et al., 2012a). Unlike upland cotton, sea-island cotton (Gossypium barbadense), which is only cultivated on a small scale, possesses Verticillium wilt resistance. Exploring the molecular mechanisms involved in the defense responses against V. dahliae invasion in G. barbadense can provide useful information for generating wilt-resistant G. hirsutum species through molecular breeding.During the past decades, progress has been made in studying the defense responses against V. dahliae infection in cotton. Global analyses have demonstrated that several signaling pathways, including those mediated by salicylic acid, ethylene, jasmonic acid, and brassinosteroids, activate distinct processes involved in V. dahliae defense (Bari and Jones, 2009; Grant and Jones, 2009; Gao et al., 2013a). Accumulating evidence indicates that many V. dahliae-responsive genes, such as GbWARKY1, GhSSN, GbERF, GhMLP28, GhNDR1, GhMKK2, and GhBAK1 (Qin et al., 2004; Gao et al., 2011, 2013b; Li et al., 2014a; Sun et al., 2014; Yang et al., 2015), play crucial roles in defense against Verticillium wilt. In addition, the biosynthesis of terpenoids, lignin, and gossypol also makes important contributions to V. dahliae resistance in cotton (Tan et al., 2000; Luo et al., 2001; Xu et al., 2011; Gao et al., 2013a). Together, these studies have greatly improved our understanding of the complex innate defense systems against V. dahliae infection in cotton.The initial interaction between plants and pathogens takes place in the apoplast, the compartment of the plant cell outside the cell membrane, including the cell wall and intercellular space (Dietz, 1997). In response to pathogen colonization, the attacked plant cells undergo significant cellular and molecular changes, such as reinforcement of the cell wall and secretion of antimicrobial molecules into the apoplastic space (Bednarek et al., 2010). Thus, the apoplast serves as the first line of defense against microbe invasion, and apoplast immunity can be considered an important component of the plant immune response to pathogens.Upon recognition of pathogen infection, rapid production of reactive oxygen species [the reactive oxygen species (ROS) burst] occurs in the apoplast (Lamb and Dixon, 1997; Torres et al., 2006; Torres, 2010). This ROS burst is regarded as a core component of the early plant immune response (Daudi et al., 2012; Doehlemann and Hemetsberger, 2013). During defense responses, apoplastic ROS can diffuse into the cytoplasm and serve as signals, interacting with other signaling processes such as phosphorylation cascades, calcium signaling, and hormone-mediated pathways (Kovtun et al., 2000; Mou et al., 2003). Apoplastic ROS can also directly strengthen the host cell walls by oxidative cross linking of glycoproteins (Bradley et al., 1992; Lamb and Dixon, 1997) or the precursors of lignin and suberin polymers (Hückelhoven, 2007). Moreover, apoplastic ROS can directly affect pathogens by degrading nucleic acids and peptides from microbes or causing lipid peroxidation and membrane damage in the microbe (Mehdy, 1994; Lamb and Dixon, 1997; Apel and Hirt, 2004; Montillet et al., 2005).ROS levels in the apoplast increase rapidly in response to a variety of pathogens, but subsequently return to basal levels. The rapid production and dissipation of apoplastic ROS indicate that this process is finely regulated. Two classes of enzymes, NADPH oxidases and class III peroxidases, account for the rapid ROS burst in the apoplast (Bolwell et al., 1995; O’Brien et al., 2012). NADPH oxidases are directly phosphorylated by the receptor-like kinase BIK1 to enhance ROS generation (Li et al., 2014b). Also, due to the toxicity of high levels of ROS, plants have evolved enzymatic and nonenzymatic mechanisms to eliminate ROS, thereby preventing or reducing oxidative damage (Rahal et al., 2014; Torres et al., 2006). However, the molecular system responsible for the regulation of apoplastic ROS homeostasis during the immune response is not well understood.In this study, we performed a comparative analysis of the apoplastic proteomes in control roots compared with V. dahliae-inoculated roots of Gossypium barbadense (wilt-resistant sea-island cotton) using the two-dimensional differential gel electrophoresis (2D-DIGE) technique. Among the differentially expressed apoplastic proteins, ROS-related proteins were found to be major components, including a thioredoxin, GbNRX1, which functions as an ROS scavenger in response to V. dahliae infection. Knock-down of GbNRX1 expression in cotton by virus-induced gene silencing (VIGS) resulted in reduced resistance to V. dahliae. Our results demonstrate that maintaining apoplastic ROS homeostasis is a crucial component of the apoplastic immune response and that GbNRX1 is an important regulator of this process.     

Comparative analysis of phylogenetic relationships of grain amaranths and their wild relatives (Amaranthus; Amaranthaceae) using internal transcribed spacer, amplified fragment length polymorphism, and double-primer fluorescent intersimple sequence repeat markers.

The most economically important group of species in the genus Amaranthus is the A. hybridus species complex, including three cultivated grain amaranths, A. cruentus, A. caudatus, and A. hypochondriacus, and their putative wild progenitors, A. hybridus, A. quitensis, and A. powellii. Taxonomic confusion exists among these closely related taxa. Internal transcribed spacer (ITS) of nuclear ribosomal DNA, amplified fragment length polymorphism (AFLP), and double-primer fluorescent intersimple sequence repeat (ISSR) were employed to reexamine the taxonomic status and phylogenetic relationships of grain amaranths and their wild relatives. Low ITS divergence in these taxa resulted in poorly resolved phylogeny. However, extensive polymorphisms exist at AFLP and ISSR loci both within and among species. In phylogenetic trees based on either AFLP or ISSR or the combined data sets, nearly all intraspecific accessions can be placed in their corresponding species clades, indicating that these taxa are well-separated species. The AFLP trees share many features in common with the ISSR trees, both showing a close relationship between A. caudatus and A. quitensis, placing A. hybridus in the same clade as all grain amaranths, and indicating that A. powellii is the most divergent taxon in the A. hybridus species complex. This study has demonstrated that both AFLP and double-primer fluorescent ISSR have a great potential for generating a large number of informative characters for phylogenetic analysis of closely related species, especially when ITS diversity is insufficient.     

Variations in sexual and asexual reproduction of Scirpus mariqueter along an elevational gradient

In order to assess the importance of sexual and asexual reproduction during the life history of Scirpus mariqueter, its reproductive and growth characters were concurrently examined along an elevational gradient (from low elevation to high elevation). The proportions of flowering shoot and inflorescence mass, seed : flower ratio and seed weight were used to quantify the investment in sexual reproduction. The proportions of current-year shoot and rhizome mass were used to quantify the investment in asexual reproduction, and the proportion of corm mass was used for growth, respectively. It was found that vegetative propagation predominated at low elevation, whereas sexual reproduction predominated at high elevation; and that sexual reproduction increased with declining asexual reproduction along the gradient. The results suggest that asexual reproduction is relatively favored in the early life stage, whereas sexual reproduction is favored when the population becomes mature and aged, probably because of the functional differentiation between the two reproductive types. Sexual productive characters (i.e. the proportions of flowering shoot and inflorescence mass) were negatively correlated to both growth and asexual reproductive characters along the gradient, indicating there might exist some trade-offs among growth, sexual and asexual reproduction during the life history. However, no obvious pattern was found between asexual reproductive characters and growth characters along the elevational gradient, possibly because of the varied relationships between them at different life stages. The variations in sexual and asexual reproduction in the species and the relationship between them are thought to be of great significance for local population growth, species persistence and evolution.