Search

Most patients treated with US Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies. Editor's summary: The currently available chimeric antigen receptor (CAR) T cell therapies have had limited efficacy for a wide range of solid cancers and hematological malignancies, due in part to CAR T cell dysfunction. The scavenger receptor CD5 associates with the T cell receptor (TCR) and inhibits T cell function. Patel et al. show that genetic deletion of CD5 in CAR and TCR T cells enhances expansion, persistence, and cytotoxicity and is effective in preclinical solid tumor and hematological malignancy models. These results suggest that CD5 may be a critical negative regulator of CAR T cells that can be therapeutically targeted. —Christiana Fogg [ABSTRACT FROM AUTHOR]

Flammable litter such as Pinus koraiensis needle accumulation increases the risk of wildfire. In the event of a high-intensity fire, forest resources can be severely damaged. To reduce the occurrence of forest fires, it is important to reduce loads and modify structures. This study conducted 270 indoor degradation experiments to determine physicochemical properties of Pinus koraiensis during the combustion degradation process. Combustion degradation treatment variables were constructed with different durations, Trichoderma fungi, and doses. The results show that the physicochemical properties of flammable litter changed significantly after degradation, with a maximum degradation rate of 11. The degradation rate was affected by time and microbial agents, but there was no significant difference between different doses. Principal component analysis was used to determine overall combustibility, and it was found that a dose of 4 mL of Trichoderma harzianum had the best effect on degradation for 42 days, reducing combustibility by 203%. It was found that the 6ml composite mould had the best inhibitory effect on fire spread rate, reaching the lowest value. After 42 days, the flame intensity of 4 mL Trichoderma harzianum reached its lowest value of 57.17 kw/m, which represents a decrease of 54% compared to the initial value. Similarly, the flame's length reached its lowest value of 4.91 cm, which represents a decrease of 31% compared to the same period last year. The aim of this study is to establish the relationship between time, microbial agents, dosage, flammable physical and chemical properties, overall flammability, and potential fire behaviour. The values of the goodness-of-fit index and the comparative fit index are both >0.98, and the values of the standardised root mean square residual and the approximate root mean square error are both <0.05. This study has a positive effect on accelerating the decomposition of combustibles, reducing the content of flammable components, reducing flammability and potential fire behaviour, and reducing the risk of forest fires. It is of great significance for strengthening natural resource management and forest ecological conservation. [ABSTRACT FROM AUTHOR]

Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS (KRASMUT) colorectal cancers. Using pooled lentiviral single-guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human colorectal cancer cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRASMUT colorectal cancer, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase or ketohexokinase was growth inhibitory in vivo In addition, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRASMUT tumors. Cancer Res; 77(22); 6330-9. ©2017 AACR.

Although elevational gradients in microbial biodiversity have attracted increasing attention recently, the generality in the patterns and underlying mechanisms are still poorly resolved. Further, previous studies focused mostly on species richness, while left understudied evenness, another important aspect of biodiversity. Here, we studied the elevational patterns in species richness and evenness of stream biofilm bacteria and diatoms in six mountains in Asia and Europe. We also reviewed published results for elevational richness patterns for soil and stream microbes in a literature analysis. Our results revealed that even within the same ecosystem type (that is, stream) or geographical region, bacteria and diatoms showed contrasting patterns in diversity. Stream microbes, including present stream data, tend to show significantly increasing or decreasing elevational patterns in richness, contrasting the findings for soil microbes that typically showed nonsignificant or significantly decreasing patterns. In all six mountains for bacteria and in four mountains for diatoms, species richness and evenness were positively correlated. The variation in bacteria and diatom richness and evenness were substantially explained by anthropogenic driven factors, such as total phosphorus (TP). However, diatom richness and evenness were also related to different main drivers as richness was mostly related to pH, while evenness was most explained by TP. Our results highlight the lack of consistent elevational biodiversity patterns of microbes and further indicate that the two facets of biodiversity may respond differently to environmental gradients.

The fine dead fuel load on forest floors is the most critical classification feature in fuel description systems, affecting several parameters in the manifestation of wildland fires. An accurate determination of this fine dead fuel load contributes substantially to effective wildland fire prevention, monitoring, and suppression. This study investigated the viability of incorporating image Euler numbers into predictive models of fine dead fuel load via the taking photos method. Pinus massoniana needles and Quercus fabri broad leaves—typical fuel types in karst areas—served as the research subjects. Accurate field data were collected in the Tianhe Mountain forests, China, while artificial fine dead fuelbeds of differing loads were constructed in the laboratory. Images of the artificial fuelbeds were captured and uniformly digitized according to various conversion thresholds. Thereafter, the Euler numbers were extracted, their relationship with fuel load was analyzed, and this relationship was applied to generate three load-prediction models based on stepwise regression, nonlinear fitting, and random forest algorithms. The Euler number had a significant relationship with both P. massoniana and Q. fabri fuel loads. At low conversion thresholds, the Euler number was negatively correlated with fuel load, whereas a positive correlation was recorded when this threshold exceeded a certain value. The random forest model showed the best prediction performance, with mean relative errors of 9.35% and 14.54% for P. massoniana and Q. fabri, respectively. The nonlinear fitting model displayed the next best performance, while the stepwise regression model exhibited the largest error, which was significantly different from that of the random forest model. This study is the first to propose the use of image features to predict the fine fuel load on a surface. The results are more objective, accurate, and time-saving than current fuel load estimates, benefiting fuel load research and the scientific management of wildland fires. [ABSTRACT FROM AUTHOR]

As a cigarette butt falls onto the forest surface fuel, it first smolders the fuel, then ignites into flames, and spreads as forest fire under certain conditions. In this study, the needles under a typical stand of P. massoniana were used as the research object. Needle beds with different moisture content and packing ratios were constructed indoors. Cigarette butt-ignition experiments were conducted under different wind velocities, and 30 experiment cycles were conducted under different conditions. There was a total of 5 (packing ratio) × 4 (moisture content) × 6 (wind velocity) = 120 sets of conditions, and a total of 3600 ignition experiments were conducted. The results showed that (1) the total ignition probability of the cigarette butts was 2.36%, which only occurred when the fuelbed moisture content was <10% and the wind velocity was >1 m/s. The ignition time of cigarette butts ranged from 2.73 to 7.25 min. (2) The fuelbed moisture content and wind velocity significantly influenced the ignition probability and time. With an increase in moisture content, the ignition probability of cigarette butts decreased, while the time required for ignition showed an increasing trend. Wind velocity had a dual effect on ignition. The ignition effect was optimal at a wind velocity of 4 m/s. With an increase in wind velocity, the ignition probability first increased and then decreased, and the ignition time first decreased and then increased. (3) The packing ratio had no significant effect on the ignition probability; however, the ignition time significantly decreased as the packing ratio increased. (4) The logistic regression method (LRM), general linear method (GLM), and nonlinear regression method (NLM) were used to establish a prediction model of ignition probability. The prediction effect of GLM was the worst, followed by LRM, and the NLM had the best prediction effect. The GLM was selected to establish the ignition time model, and the error was also within the allowance range. This study elucidated the underlying mechanism of factors affecting cigarette butt-based fuel ignition. In addition, the established prediction model provides a reference for human-caused forest fires and is highly significant for forest fire prevention. [ABSTRACT FROM AUTHOR]

As the main global terrestrial ecosystem component, grasslands are extremely sensitive to global climate change. With increasing human activities over the last century, grassland ecosystems have been degraded to different degrees. However, the evolution of lake-grassland ecosystems in recent centuries remains unclear due to the dearth of high-resolution records. Here, we present high-resolution lacustrine sediment grain size, pollen (Artemisia , Myriophyllum), Pediastrum , and n-alkane records from Ganggeng Nur Lake to investigate vegetation, lake evolution, and human effects in semiarid northern China. Four stages were identified from the last ca. 150 years: (1) the natural evolution stage (AD 1870–1945), in which there was a wet climate around Ganggeng Nur and the lake level rose from increased runoff; (2) the human disturbance stage (AD 1945–1967), in which the regional climate got drier and human activities began having a detectable effect on the grassland ecosystem; (3) the human transformation stage (AD 1967–2005), in which a completely arid climate coupled with the implementation of a series of land reclamation policies resulted in a large reduction in grassland areas, extensive soil erosion, exacerbated climate change, and shrinking lake areas; and (4) the posttreatment stage (AD 2005–2018), in which soil erosion was alleviated by policy implementation and a favorable humid climate. [ABSTRACT FROM AUTHOR]