Bacterial abundance and biomass were extensively measured in the euphotic zone at several oligotrophic and mesotrophlc sites of coastal and open Pacific ocean during different seasons. Cornpansons with phytoplankton biomass and l a t h particulate organic carbon (POC) were made in order to determine the quantitative significance of bacteria as a carbon and nitrogen pool in the euphotic zone. Analysis of our data and that from the literature showed that bacterial abundance in the euphotic zone has a lower threshold of ca 3 X 105 1111-' or 6 pg C 1-' Consequently, with increasingly oligotrophic condit~ons photoautotrophic bion~ass may decrease well below the bacterial b~omass. In oligotrophic waters bacterial biomass was comn~only 2 to 3 times greater than phytoplankton biomass. In contrast, In mesotrophic to eutrophic waters bactenal biomass was generally much less than phytoplankton biomass. Cornpanson w~t h total POC (which included bacterial carbon) showed that in o l~g o t r o p h~c waters bacterial b~o m a s s averaged 40 % (range 26 to 62 '6) of POC inexplicably, the sum of bacterial carbon and phytoplankton carbon was always about one-half of POC The dominance of bacterial biomass over phytoplankton biomass in oligotrophlc oceans has sign~ficant impl~cations for the food-web structure, nutr~ent cycling pathways, and for s i n l n g flux of organic matter Future studies should examine the physiological and trophic mechan~sms which lead to the dominance of bacterial biomass in oligotrophlc systems but of photoautotrophic biomass In the e u t r o p h~c systems

We have synthesized the information on marine and lirnnetic bacterial biomass carbon (BOC) and phytoplankton biomass carbon (PhytoC) to examine the relationships between these major biotic carbon pools. On the basis of 6 limnetic and 6 marine studies we found a good similarity for the correlations of BOC vs PhytoC in both systems although the slope was substantially lower than for sim~lar correlations on the basis of bacterial abundance and chlorophyll a. Limnetic systems, however, differed from marine systems In that they supported more BOC relative to PhytoC, as indicated by signlficantly higher y-intercepts of the correlation (p < 0.001). Our dnalysis also generalizes findings from manne to limnetic environments that the food-web structure in oligotrophic systems is fundamentally different from eutrophic systems, e.g that BOC/PhytoC dramatically increases with decreasing PhytoC concentrations. This has impl~cat~ons for the significance of planktonic bacteria in particle abundance and size-dependent properties of lakes and oceans such as trace metal and radionuclide adsorption, biogeochernical dynamics and in light scattering and remote sensing.

Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine–cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent inhibition of the Met and FGFR pathways may have synergistic clinical benefits when targeting FGFR-dependent LC.

Background: PD-1 blockade is now standard treatment for advanced non-small cell lung cancer (NSCLC) and has recently shown impressive efficacy in promoting major pathologic response (MPR) and delaying relapse in the neoadjuvant setting. The role of tumor mutational burden, and specifically T cells targeting neoantigens derived from these mutations, in facilitating tumor clearance has been demonstrated in advanced NSCLC. However, it is unknown how neoadjuvant PD-1 blockade impacts the frequency and function of tumor specific T cells and their ability to promote major pathologic response, or how these factors may synergize to prevent or delay relapse after surgical resection. Method: Whole exome sequencing and neoantigen prediction was performed on pre-treatment tumor biopsies and matched normal tissue from 11 patients with resectable NSCLC treated with neoadjuvant nivolumab as part of a clinical trial (NCT02259621). T cell recognition of peptides representing candidate neoantigens was evaluated using the MANAFEST assay, which identifies T cell receptor clonotypes corresponding to antigen specificities. T cell receptor sequencing was additionally performed on serial peripheral blood T cells, pre-treatment tumor biopsies, and resected post-treatment tissues. A bioinformatic platform was developed to evaluate the dynamics of intratumoral T cell clonotypes, and more specifically neoantigen-specific clonotypes detected before, during, and after treatment and during long-term follow-up. Result: High-magnitude, polyclonal neoantigen-specific T cell responses were detected in the peripheral blood and persisted for many months after surgical resection and cessation of treatment. Binding to and stability with cognate HLA I molecules was validated for reactive neoantigens. Significant treatment-induced systemic perturbations in the tumor-specific T cell repertoire and an influx of peripheral T cell clonotypes into tumor tissue and lymph nodes was observed in patients regardless of pathologic response, whereas peripheral clonotypic reshaping of the anti-tumor repertoire and intratumoral T cell clonality were associated with MPR status. Conclusion: We show significant and systemic alterations in the peripheral anti-tumor T cell repertoire in NSCLC patients treated with neoadjuvant anti-PD-1 regardless of MPR status. Notwithstanding, the impaired restructuring of the anti-tumor T cell repertoire in patients without MPR highlights a potential immunological deficiency to overcome in future therapeutic approaches aiming to increase the MPR rate in NSCLC patients treated with neoadjuvant PD-1 blockade.Background: Chemoradiation (CRT) is standard of care for unresectable stage III NSCLC. Tecemotide is a MUC1 antigen-specific cancer immunotherapy. Bevacizumab is considered to have a significant role in immune modulation. Immunotherapy in combination with VEGF blockade was tested in this phase II trial combining tecemotide and bevacizumab in patients with stage III NS-NSCLC. Method: Subjects with stage III NS-NSCLC suitable for defini...

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