A high interferon gamma signature of CD8+ T cells predicts response to neoadjuvant immunotherapy plus chemotherapy in gastric cancer

BackgroundWhile the tumor microenvironment (TME) affects immune checkpoint blockade (ICB) efficacy, ICB also reshapes the characteristics of TME. Thus far, studies have focused on the TME evolution during neoadjuvant or adjuvant ICB therapy in gastric cancer (GC). However, the interaction between TME characteristics and neoadjuvant immunotherapy plus chemotherapy remains to be elucidated.MethodsWe performed single-cell RNA sequencing on ten GC specimens pre- and post-neoadjuvant camrelizumab plus mFOLFOX6 to determine the impact of the TME on the efficacy of the combination therapy and the remodeling of TME by the therapy.ResultsA high baseline interferon gamma (IFN-γ) signature in CD8+ T cells predicts better responses to the combination therapy. We also observed that the IFN-γ signature significantly decreased in multiple cell types, and the exhausted signature of CD8+ T cells was significantly suppressed during the neoadjuvant therapy.ConclusionsOur data reveal interactions between the TME and neoadjuvant immunotherapy plus chemotherapy in GC. Importantly, it also highlights the signature of CD8+ T cells in predicting response to the combination therapy in GC

Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain

Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1’s role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical “developmental tumor”, NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation. DOI: http://dx.doi.org/10.7554/eLife.14713.00

Comprehensive Investigation and Remediation of Concealed Karst Collapse Columns in Renlou Coal Mine, China

Coal mining in China has exposed numerous karst collapse columns of tens of meters in diameter and hundreds of meters in height. Hydraulically conductive collapses have functioned as groundwater pathways between the underground workings and the aquifers, resulting in water inrushes during coal mining. Over the last 40 years, water inrushes through these collapses have caused fatalities, economic losses, and degradation in the environment. Two such collapse features were unexpectedly encountered during operations in Renlou Coal Mine of China. The first encounter caused flooding of the entire mine. Although no serious damages occurred at the second encounter, because of timely and effective grouting measures, the production rate was reduced. Proactive detection of any concealed karst collapses and determination of their hydrogeological characteristics were essential components of a comprehensive investigation program in preventing water inrush incidents and ensuring normal coal production in the mine. The investigation program included surface and underground geophysical surveys with five geophysical techniques and directional drilling of three exploratory boreholes at completion depths ranging from 902 to 986 m. A new collapse feature was identified through systematic analysis of the data collected in the investigation program. Although the bottom of the collapse feature has not been determined, its total height is more than 135 m. The roof was at approximately 785 m depth, and there was an open void 1.5 - 2 m high at the top. Geotechnical properties, results from packer testing and tracer testing, monitoring of potentiometric pressures, and geochemical fingerprinting suggested that this collapse column was hydraulically conductive and still actively developing. Water in the confined thin-bedded limestone and Ordovician limestone aquifer that either overlies or underlie coal seams could flow into the mining areas if this feature were not identified in advance but encountered during mining. A grouting program was designed and implemented to construct a water plug in the collapse that effectively cut off the hydraulic connections from the aquifers to underground workings. Successful construction of the water plug in the collapse was confirmed by water intake tests in the grouting holes, water flow measurements in the mining area, and groundwater level monitoring in the aquifer

Comprehensive Investigation and Remediation of Concealed Karst Collapse Columns in Renlou Coal Mine, China

Coal mining in China has exposed numerous karst collapse columns of tens of meters in diameter and hundreds of meters in height. Hydraulically conductive collapses have functioned as groundwater pathways between the underground workings and the aquifers, resulting in water inrushes during coal mining. Over the last 40 years, water inrushes through these collapses have caused fatalities, economic losses, and degradation in the environment. Two such collapse features were unexpectedly encountered during operations in Renlou Coal Mine of China. The first encounter caused flooding of the entire mine. Although no serious damages occurred at the second encounter, because of timely and effective grouting measures, the production rate was reduced. Proactive detection of any concealed karst collapses and determination of their hydrogeological characteristics were essential components of a comprehensive investigation program in preventing water inrush incidents and ensuring normal coal production in the mine. The investigation program included surface and underground geophysical surveys with five geophysical techniques and directional drilling of three exploratory boreholes at completion depths ranging from 902 to 986 m. A new collapse feature was identified through systematic analysis of the data collected in the investigation program. Although the bottom of the collapse feature has not been determined, its total height is more than 135 m. The roof was at approximately 785 m depth, and there was an open void 1.5 - 2 m high at the top. Geotechnical properties, results from packer testing and tracer testing, monitoring of potentiometric pressures, and geochemical fingerprinting suggested that this collapse column was hydraulically conductive and still actively developing. Water in the confined thin-bedded limestone and Ordovician limestone aquifer that either overlies or underlie coal seams could flow into the mining areas if this feature were not identified in advance but encountered during mining. A grouting program was designed and implemented to construct a water plug in the collapse that effectively cut off the hydraulic connections from the aquifers to underground workings. Successful construction of the water plug in the collapse was confirmed by water intake tests in the grouting holes, water flow measurements in the mining area, and groundwater level monitoring in the aquifer

A new model for simulating spring discharge recession and estimating effective porosity of karst aquifers

Quantitative analysis of recession curves of karst spring hydrographs is a vital tool for understanding karst hydrology and inferring hydraulic properties of karst aquifers. This paper presents a new model for simulating karst spring recession curves. The new model has the following characteristics: (1) the model considers two separate but hydraulically connected reservoirs: matrix reservoir and conduit reservoir; (2) the model separates karst spring hydrograph recession into three stages: conduit-drainage stage, mixed-drainage stage (with both conduit drainage and matrix drainage), and matrix-drainage stage; and (3) in the mixed-drainage stage, the model uses multiple conduit layers to present different levels of conduit development. The new model outperforms the classical Mangin model and the recently developed Fiorillo model for simulating observed discharge at the Madison Blue Spring located in northern Florida. This is attributed to the latter two characteristics of the new model. Based on the new model, a method is developed for estimating effective porosity of the matrix and conduit reservoirs for the three drainage stages. The estimated porosity values are consistent with measured matrix porosity at the study site and with estimated conduit porosity reported in literature. The new model for simulating karst spring hydrograph recession is mathematically general, and can be applied to a wide range of karst spring hydrographs to understand groundwater flow in karst aquifers. The limitations of the model are discussed at the end of this paper