T-cell therapies for T-cell lymphoma

T-cell lymphomas represent a subpopulation of non-Hodgkin lymphomas with poor outcomes when treated with conventional chemotherapy. A variety of novel agents have been introduced as new treatment strategies either as first-line treatment or in conjunction with chemotherapy. Immunotherapy has been demonstrated to be a promising area for new therapeutics, including monoclonal antibodies and adoptive cellular therapeutics. T-cell therapeutics have been shown to have significant success in the treatment of B-cell malignancies and are rapidly expanding as potential treatment options for other cancers including T-cell lymphomas. Although treating T-cell lymphomas with T-cell therapeutics has unique challenges, multiple targets are currently being studied both preclinically and in clinical trials.     

CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

Aberrant expression of CUL4B was identified in various types of solid cancers. Cumulative evidences support the oncogenic role of CUL4B in cancers, including regulation of cell proliferation and signal transduction. However, its clinical value and potential pathogenic mechanism in diffuse large B-cell lymphoma (DLBCL) have not been described previously. Therefore, we hypothesize that overexpressed CUL4B may contribute to the pathogenesis of DLBCL. The aim of this study is to assess the expression and the biological function of CUL4B in DLBCL progression. In our study, CUL4B overexpression was observed in DLBCL tissues, and its upregulation was closely associated with poor prognosis in patients. Furthermore, the functional roles of CUL4B was detected both in vitro and in vivo. We demonstrated that silencing CUL4B could not only induce cell proliferation inhibition, cell cycle arrest, and motility attenuation of DLBCL cells in vitro, but also decrease tumor growth in DLBCL xenografts mice. In addition, we identi?ed that CUL4B may act as a potent inductor of JNK phosphorylation in regulation of autophagy. Our findings demonstrated a significant role of CUL4B in the development and progression of DLBCL. CUL4B may act as a useful biomarker and a novel therapeutic target in DLBCL.     

Nurse sow strategies in the domestic pig: II. Consequences for piglet growth,suckling behaviour and sow nursing behaviour

Nurse sow strategies are used to manage large litters on commercial pig farms. However, new-born piglets transferred to nurse sows in late lactation might be compromised in terms of growth and survival. We investigated the effects of two nurse sow strategies on piglet growth, suckling behaviour and sow nursing behaviour. At 1-day post-farrowing, the four heaviest piglets from large litters were transferred to a nurse sow either 21 (1STEP21, n=9 litters) or 7 (2STEP7, n=10 litters) days into lactation. The remainder of the litter remained with their mother and was either kept intact (remain intact (RI), n=10 litters) or had some piglets cross-fostered to equalise birth weights (remain equalised (RE), n=9 litters). The 7-day-old piglets from 2STEP7 were transferred onto a sow 21 days into lactation (2STEP21, n=10 litters). The growth of new-born piglets on 1STEP21 and 2STEP7 nurse sows was initially lower than in RI litters (F_3,33.8=4.61; P<0.01), but weaning weights did not significantly differ (F_4,32.7=0.78; P>0.5). After the 1^st week of lactation, the weights and growth rates did not differ between treatments. Fighting behaviour during nursing bouts decreased over time. The frequency of fights was higher in 1STEP21 and 2STEP21 litters compared with RI litters (t₁₂₂=3.06 and t₁₂₃=3.00, respectively, P<0.05). The 2STEP21 litters had shorter nursing bouts than RI and 1STEP21 litters (t₁₀₇=−2.81 and t_81.7=2.8, respectively, P<0.05), which were more frequently terminated by 2STEP21 than RI sows (t₅₉₅=2.93; P<0.05). Transferring heaviest piglets from RI and RE litters to nurse sows reduced the percentage of teat changes during nursing bouts (RI: F_1,275=16.61; RE: F_1,308=43.59; P<0.001). In conclusion, nurse sow strategies do not appear to compromise piglet growth. However, new-born piglets transferred onto sows in late lactation experienced more competition at the udder, suggesting that the sows’ stage of lactation is of importance to how achievable nurse sow strategies are. Thus, the two-step nurse sow strategy is likely the best option (in relation to growth and suckling behaviour), as it minimises the difference between piglet age and sow stage of lactation.     

Big‐sized trees overrule remaining trees' attributes and species richness as determinants of aboveground biomass in tropical forests

Large‐diameter, tall‐stature, and big‐crown trees are the main stand structures of forests, generally contributing a large fraction of aboveground biomass, and hence play an important role in climate change mitigation strategies. Here, we hypothesized that the effects of large‐diameter, tall‐stature, and big‐crown trees overrule the effects of species richness and remaining trees attributes on aboveground biomass in tropical forests (i.e., we term the “big‐sized trees hypothesis”). Specifically, we assessed the importance of: (a) the “top 1% big‐sized trees effect” relative to species richness; (b) the “99% remaining trees effect” relative to species richness; and (c) the “top 1% big‐sized trees effect” relative to the “99% remaining trees effect” and species richness on aboveground biomass. Using environmental factor and forest inventory datasets from 712 tropical forest plots in Hainan Island of southern China, we tested several structural equation models for disentangling the relative effects of big‐sized trees, remaining trees attributes, and species richness on aboveground biomass, while considering for the full (indirect effects only) and partial (direct and indirect effects) mediation effects of climatic and soil conditions, as well as interactions between species richness and trees attributes. We found that top 1% big‐sized trees attributes strongly increased aboveground biomass (i.e., explained 55%–70% of the accounted variation) compared to species richness (2%–18%) and 99% remaining trees attributes (6%–10%). In addition, species richness increased aboveground biomass indirectly via increasing big‐sized trees but via decreasing remaining trees. Hence, we show that the “big‐sized trees effect” overrides the effects of remaining trees attributes and species richness on aboveground biomass in tropical forests. This study also indicates that big‐sized trees may be more susceptible to atmospheric drought. We argue that the effects of big‐sized trees on species richness and aboveground biomass should be tested for better understanding of the ecological mechanisms underlying forest functioning.     

Integrating anthropogenic factors into regional‐scale species distribution models—A novel application in the imperiled sagebrush biome

Species distribution models (SDMs) that rely on regional‐scale environmental variables will play a key role in forecasting species occurrence in the face of climate change. However, in the Anthropocene, a number of local‐scale anthropogenic variables, including wildfire history, land‐use change, invasive species, and ecological restoration practices can override regional‐scale variables to drive patterns of species distribution. Incorporating these human‐induced factors into SDMs remains a major research challenge, in part because spatial variability in these factors occurs at fine scales, rendering prediction over regional extents problematic. Here, we used big sagebrush (Artemisia tridentata Nutt.) as a model species to explore whether including human‐induced factors improves the fit of the SDM. We applied a Bayesian hurdle spatial approach using 21,753 data points of field‐sampled vegetation obtained from the LANDFIRE program to model sagebrush occurrence and cover by incorporating fire history metrics and restoration treatments from 1980 to 2015 throughout the Great Basin of North America. Models including fire attributes and restoration treatments performed better than those including only climate and topographic variables. Number of fires and fire occurrence had the strongest relative effects on big sagebrush occurrence and cover, respectively. The models predicted that the probability of big sagebrush occurrence decreases by 1.2% (95% CI: ?6.9%, 0.6%) when one fire occurs and cover decreases by 44.7% (95% CI: ?47.9%, ?41.3%) if at least one fire occurred over the 36 year period of record. Restoration practices increased the probability of big sagebrush occurrence but had minimal effect on cover. Our results demonstrate the potential value of including disturbance and land management along with climate in models to predict species distributions. As an increasing number of datasets representing land‐use history become available, we anticipate that our modeling framework will have broad relevance across a range of biomes and species.     

Inhibition of diverse opportunistic viruses by structurally optimized retrograde trafficking inhibitors

Opportunistic viruses are a major problem for immunosuppressed individuals, particularly following organ or stem cell transplantation. Current treatments are non-existent or suffer from problems such as high toxicity or development of resistant strains. We previously published that a trafficking inhibitor that targets a host protein greatly reduces the replication of human cytomegalovirus. This inhibitor was also shown to be moderately effective against polyomaviruses, another family of opportunistic viruses. We have developed a panel of analogues for this inhibitor and have shown that these analogues maintain their high efficacy against HCMV, while substantially lowering the concentration required to inhibit polyomavirus replication. By targeting a host protein these compounds are able to inhibit the replication of two very different viruses. These observations open up the possibility of pan-viral inhibitors for immunosuppressed individuals that are effective against multiple, diverse opportunistic viruses.     

Soluble CXCL16 promotes TNF‐α‐induced apoptosis in DLBCL via the AMAD10‐NF‐κB regulatory feedback loop

We had previously identified that the co‐expression of transmembrane CXCL16 (TM‐CXCL16) and its receptor CXCR6 is an independent risk factor for poor survival in patients with diffuse large B‐cell lymphoma (DLBCL). However, the impact of the soluble form of CXCL16 (sCXCL16) on the pathogenesis of DLBCL remains unknown. In the present study, the synergistic effect of sCXCL16 and tumor necrosis factor α (TNF‐α) on apoptosis in DLBCL cell lines (OCI‐LY8 and OCI‐LY10) was investigated in vitro. sCXCL16 reinforced TNF‐α‐mediated inhibition of DLBCL cell proliferation, as determined by the cell counting kit‐8 assay. The results of annexin V staining showed that sCXCL16 enhanced TNF‐α‐induced apoptosis in OCI‐LY8 and OCI‐LY10 cells through a death receptor‐caspase signaling pathway. The results of gene microarray suggested a significant upregulation of differentially expressed genes in the TNF signaling pathway. sCXCL16 increased the concentration of extracellular TNF‐α by binding to CXCR6 to activate the nuclear factor‐κB (NF‐κB) signaling pathway. TNF‐α also induced the secretion of sCXCL16 by increasing the expression of ADAM10, which is known to cleave TM‐CXCL16 to yield sCXCL16. Moreover, bioinformatics analysis revealed that elevated TNF‐α and ADAM10 expression levels in tumor tissues predicted better survival in patients with DLBCL. Thus, our study suggests that sCXCL16 enhances TNF‐α‐induced apoptosis of DLBCL cells, which may involve a positive feedback loop consisting of TNF‐α, ADAM10, sCXCL16, and members of the NF‐κB pathway. sCXCL16 and TNF‐α may be used as prognostic markers in the clinic, and their combinational use is a promising approach in the context of DLBCL therapy.     

Microplastic ingestion ubiquitous in marine turtles

Despite concerns regarding the environmental impacts of microplastics, knowledge of the incidence and levels of synthetic particles in large marine vertebrates is lacking. Here, we utilize an optimized enzymatic digestion methodology, previously developed for zooplankton, to explore whether synthetic particles could be isolated from marine turtle ingesta. We report the presence of synthetic particles in every turtle subjected to investigation (n = 102) which included individuals from all seven species of marine turtle, sampled from three ocean basins (Atlantic [ATL]: n = 30, four species; Mediterranean (MED): n = 56, two species; Pacific (PAC): n = 16, five species). Most particles (n = 811) were fibres (ATL: 77.1% MED: 85.3% PAC: 64.8%) with blue and black being the dominant colours. In lesser quantities were fragments (ATL: 22.9%: MED: 14.7% PAC: 20.2%) and microbeads (4.8%; PAC only; to our knowledge the first isolation of microbeads from marine megavertebrates). Fourier transform infrared spectroscopy (FT‐IR) of a subsample of particles (n = 169) showed a range of synthetic materials such as elastomers (MED: 61.2%; PAC: 3.4%), thermoplastics (ATL: 36.8%: MED: 20.7% PAC: 27.7%) and synthetic regenerated cellulosic fibres (SRCF; ATL: 63.2%: MED: 5.8% PAC: 68.9%). Synthetic particles being isolated from species occupying different trophic levels suggest the possibility of multiple ingestion pathways. These include exposure from polluted seawater and sediments and/or additional trophic transfer from contaminated prey/forage items. We assess the likelihood that microplastic ingestion presents a significant conservation problem at current levels compared to other anthropogenic threats.     

Exotic vine invasions following cyclone disturbance in Australian Wet Tropics rainforests: A review

The Australian Wet Tropics region extends for almost 900 000 ha along the coastline of north‐east Queensland. The rainforests in this region have a rich and unique biodiversity and are World Heritage listed by UNESCO. Disturbance from tropical cyclones is a significant driver of the rainforest dynamics in this area, and when frequent or intense can facilitate the recruitment and expansion of exotic invasive species. Exotic vines are of particular concern for forest conservation as they can be highly competitive with native vegetation and may prevent forest regeneration. This literature review found evidence that fragmented forests, which are very common in the Australian Wet Tropics, are vulnerable to post‐cyclone vine invasion. In particular, although the diversity and abundance of herbaceous vines tend to decline as the canopy closes 2 years post‐cyclone disturbance, woody exotic vines and scramblers may persist for much longer or even increase in numbers. Since forest recovery in these systems is influenced by the severity and recurrence of disturbance, an increase in cyclone intensity under climate change may cause rapid changes in rainforest structure, composition and diversity, and increase exotic vine invasion. Post‐cyclone management of vines appears to require direct intervention, with manual cutting being currently the most effective method. However, there are a number of difficulties to its wide implementation in Australia, and further study on options for control is needed. Abstract in Spanish is available with online material.