How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 squamous cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of which (Inflamed, Redox) comprise 87% of tumors. The Inflamed subtype is enriched with neutrophils, B-cells, and monocytes and expresses more PD-1 . Redox tumours are enriched for oxidation-reduction and glutathione pathways and harbor more NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus. Proteomic subtypes are not associated with patient survival. However, B-cell-rich tertiary lymph node structures, more common in Inflamed, are associated with better survival. We identify metabolic vulnerabilities ( TP63 , PSAT1 , and TFRC ) in Redox. Our work provides a powerful resource for lung SCC biology and suggests therapeutic opportunities based on redox metabolism and immune cell infiltrates.

Seasonally fluctuating water levels, known as ‘flood pulses’, control the productivity of large river fisheries, but the extent and mechanisms through which flood pulses affect fishery yields are poorly understood. To quantify and better understand flood pulse effects on fishery yields, this study applied regression techniques to a hydrological and fishery record (years 1993–2004) for 42 species of the Amazon River floodplains. Models based on indices of fishing effort, high waters and low waters explained most of the interannual variability in yields (R2=0.8). The results indicated that high and low waters in any given year affected fishery yields two and three years later through changes in fish biomass available for harvesting, contributing 18% of the explained variability in yields. Fishing effort appeared to amplify high and low water effects by changing in direct proportion to changes in fish biomass available for harvesting, contributing 62% of the explained variability in yields. Although high waters are generally expected to have greater relative influence on fishery yields than low waters, high and low waters exerted equal forcing on these Amazonian river-floodplain fishery yields. These findings highlight the complex dynamics of river-floodplain fisheries in relation to interannual variability in flood pulses.

Purpose: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase 1/1b trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non-small cell lung cancer (NSCLC).Experimental Design: Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens.

Increased HDAC8 activity deacetylates c-JUN, leading to increased EGFR signaling and BRAF inhibitor resistance Low HDAC8 activity RTK c-Jun High HDAC8 activity BRAFi c-Jun Ras RAF ERK Cell death Survival and invasion BRAFi Ras RAF ERK RTK (EGFR) ac ac ac TRE ac ac TRE p TR HDAC8 Melanoma cells have the ability to switch to a dedifferentiated, invasive phenotype in response to multiple stimuli. Here, we show that exposure of melanomas to multiple stresses including BRAF-MEK inhibitor therapy, hypoxia, and UV irradiation leads to an increase in histone deacetylase 8 (HDAC8) activity and the adoption of a drugresistant phenotype. Mass spectrometry-based phosphoproteomics implicated HDAC8 in the regulation of MAPK and AP-1 signaling. Introduction of HDAC8 into drug-na€ ve melanoma cells conveyed resistance both in vitro and in vivo. HDAC8mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase activation, leading to MAPK signaling. Although HDACs function at the histone level, they also regulate nonhistone substrates, and introduction of HDAC8 decreased the acetylation of c-Jun, increasing its transcriptional activity and enriching for an AP-1 gene signature. Mutation of the putative c-Jun acetylation site at lysine 273 increased transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition. In vivo xenograft studies confirmed the key role of HDAC8 in therapeutic adaptation, with both nonselective and HDAC8-specific inhibitors enhancing the durability of BRAF inhibitor therapy. Our studies demonstrate that HDAC8-specific inhibitors limit the adaptation of melanoma cells to multiple stresses including BRAF-MEK inhibition. Significance: This study provides evidence that HDAC8 drives transcriptional plasticity in melanoma cells in response to a range of stresses through direct deacetylation of c-Jun.

Inland fisheries underpin food security in many tropical countries. The most productive inland fisheries in tropical and subtropical developing countries occur in large river–floodplain systems that are often impacted by land cover changes. However, few studies to date have assessed the effects of changes in floodplain land cover on fishery yields. Here, we integrated fisheries and satellite‐mapped habitat data to evaluate the effects of floodplain deforestation on fishery yields in 68 floodplain lake systems of the lower Amazon River, representing a wide range in relative amounts of woody, herbaceous and non‐vegetated land cover. We modelled relative fish yields (fish capture per unit effort [CPUE]) in the floodplain lakes as a function of the relative amounts of forest, shrub, aquatic macrophyte and bare/herbaceous habitats surrounding them. We found that forest amount was positively related (p = .0003) to multispecies CPUE. The validity of these findings was supported by rejection of plausible alternative causative mechanisms involving habitat‐related differences in amount of piscivores, fishing effort, lake area, and habitat effects on CPUE of the nine taxa dominating multispecies yields. Our results provide support to the idea that removal of floodplain forests reduces fishery yields per unit effort. Increased protection of floodplain forests is necessary to maintain the food, income and livelihood security services provided by large river–floodplain fisheries.