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Supplementary Methods

Supplementary Figure S2. This supplementary figure depicts the non-correlation of average erlotinib peak intensities with survival or tumor grading or overall morphological feature

Supplementary Table S1, Gene sets that are enriched in Hmga2/GFP-positive and -negative PDAC cells; Supplementary Table S2, A stringent list of Blimp1-dependent genes that are either induced or repressed under hypoxia; Supplementary Table S3, GO terms enriched in hypoxia-induced, Blimp1-dependent genes by FuncAssociate 3.0.

Supplementary Figure S1. Isolation of the Hmga2-GFPpos PDAC sub-population from the KPCcolors mice and GFPpos PDAC cells are a highly metastatic state;Supplementary Figure S2. Highly metastatic PDAC cells have a gene signature that is not enriched for CSC markers and distal PDAC metastases reveal minor gene expression changes related to glucose metabolism;Supplementary Figure S3. Identification of top candidate pro-metastatic genes and interrogation of Blimp1 function in PDAC metastasis;Supplementary Figure S4. Hmga2positive PDAC areas overlap with hypoxic areas and Hmga2 protein is slightly induced by hypoxia but not critical to the expression of hypoxia-induced target genes;Supplementary Figure S5. Hypoxia-induced Blimp1 expression is linked to functional HRE motifs 240 kb upstream of its transcription start site;Supplementary Figure S6. Blimp1 may contribute to migratory and clonal growth ability and is critical for a subset of hypoxia-induced gene expression changes that are independent of changes in chromatin accessibility;Supplementary Figure S7. Blimp1 regulates a subset of hypoxia-induced genes; Supplementary Figure S8. Blimp1 is required for hypoxia-induced cell cycle arrest and the expression of metastasis modulators.

Supplemental material and methods file

Extended Data relating to Main Figure 3/AKT-driven progression of ALDH1A1+ cells in glioblastoma. A, Flow cytometry histograms showing ALDH1A1 expression in the paired treatment-naive vs. clinical relapse patient samples quantified in main Fig. 3A. Isotype controls in gray. B, Flow cytometry histograms of ALDH1A1 derived from treatment-naive and paired experimental relapse (TMZ→eR) BN46 cells. Data quantification in Supplementary Fig. S2B. C, Cartoon illustrating course of neurosphere experiments, quantified in main Fig. 3B and in Supplementary Fig. S3D, applying treatment-naive and paired experimental and clinical relapse patient cells. Right: Exemplary qRT-PCR data presenting knockdown efficacy of the siRNA approach in respective cells, normalized to siNT control. Mean of duplicates ± SD. D, Source data for Fig. 3B, and for Supplementary Fig. S3E. Dotplots show percent neurosphere-forming cells estimated from neurospheres at 12 days after seeding. Paired patient cell analysis, evaluating 1° and 2° neurospheres of indicated knockdown (siALDH1A1) and respective control (siNT) cell samples. Data shown as mean ± SD. E, Neurosphere assay, similar to main Fig. 3B on paired treatment-naive vs. experimental relapse (TMZ→eR) BN46 cells. Source data in Supplementary Fig. S3D. Data as mean ± SD. F, Protein patterns, similar to Fig. 3D. on paired cells from 2 additional discovery cohort samples. G, Flow cytometry histograms depicting pAKT(Ser473) expression in the paired treatment-naive vs. clinical relapse patient samples quantified in main Fig. 3E. Isotype controls in gray. H, Flow cytometry histograms of pAKT(Ser473) and, right, quantification of data derived from treatment-naive and paired experimental relapse (TMZ→eR) BN46 cells. Data represent mean fluorescence intensities (MFI), ± SD, normalized to isotype control (gray). I, Representative source data for Fig. 3F. Flow cytometry profiles of ALDH1A1/pAKT(Ser473)-labeled, paired treatment-naive vs. clinical relapse cell samples. J, Flow cytometry profiles of of ALDH1A1/pAKT(Ser473)-labeled, paired treatment-naive vs. experimental relapse conditions of BN46 cells (in vitro exposure to TMZ (TMZ→eR) or irradiation (RT→eR)).

Purpose:Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy.Experimental Design:To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts.Results:We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy.Conclusions:Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.

Supplementary Table S1. Discovery cohort of vital cells; Supplementary Table S2. Validation cohort/FFPE tissue samples; Supplementary Table S3. Differentially regulated genes; Supplementary Table S4. Selected gene variants compared between the paired treatment-naive vs. relapse cell samples.

Supplementary Data Table S9

Extended online methods

Supplementary Data Table S7 and S8

Supplementary Figures S1-S5

Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer-related deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent nonmetastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines in vitro and metastases analyzed ex vivo from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than nonmetastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin in vivo. These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited.Significance:This study characterizes altered mitochondria functionality of the metastatic cell state in lung cancer and opens new avenues for metastasis-specific therapeutic targeting.

Purpose: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. Experimental Design: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. Results: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. Conclusions: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.

Although most cancer drugs modulate the activities of cellular pathways by changing posttranslational modifications (PTMs), little is known regarding the extent and the time- and dose-response characteristics of drug-regulated PTMs. In this work, we introduce a proteomic assay called decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action. Examples range from detecting DNA damage by chemotherapeutics, to identifying drug-specific PTM signatures of kinase inhibitors, to demonstrating that rituximab kills CD20-positive B cells by overactivating B cell receptor signaling. DecryptM profiling of 31 cancer drugs in 13 cell lines demonstrates the broad applicability of the approach. The resulting 1.8 million dose-response curves are provided as an interactive molecular resource in ProteomicsDB.

Introduction Mutant RAS guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRASG12C variant has recently become targetable by a new drug class specifically locking KRASG12C in its inactive guanosine diphosphate (GDP)-bound state. Clinical activity was demonstrated in patients with advanced lung cancers harbouring KRASG12C mutations but was limited by the development of resistance. Methods A biopsy from progressing lung cancer of a patient treated with the KRASG12C inhibitor sotorasib was obtained, and the underlying resistance factors were analysed. Mechanistic studies were performed in vitro and in vivo to uncover strategies to overcome resistance to KRASG12C inhibition. Results We demonstrated acquisition of HER2 copy number gain and KRASG12C mutation retention in the post-progression biopsy. To explore HER2 gain as the relevant resistance mechanism, we generated KRASG12C lung cancer models overexpressing HER2. MAPK pathway signalling remained active despite KRASG12C inhibitor treatment. Combined pharmacological inhibition of KRASG12C and SHP2 synergistically overcame HER2-mediated resistance in vitro and in vivo. Conclusions These findings establish HER2 copy number gain as a clinically relevant mechanism of resistance to pharmacological KRASG12C inhibition that can be overcome by co-targeting SHP2.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial–mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.

Simple Summary Pancreatic cancer is one of the hardest-to-treat cancers. This is mainly due to its heterogeneity, where subsets of cancer cells possess distinct properties and abilities that determine if and how they metastasize or respond to therapy. DNA barcoding technologies have emerged as a powerful tool to study this heterogeneity, as they allow labeling of individual tumor cells within a cancer cell pool and follow their cellular states and fates during metastasis or upon therapy. The aim of this review was to provide an overview of the various levels of tumor heterogeneity in pancreatic cancer, the obstacles these levels of heterogeneity can cause for effective personalized treatment strategies, and how different barcoding approaches can be applied to study these important questions. Abstract Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.

DNA barcoding allows the quantitative, biomarker-free tracking of individual cell populations in mixed/heterogeneous cell pools. Here, we describe a multiplexed in vivo screening platform based on DNA barcoding technology to interrogate compound libraries for their effect on metastatic seeding in vivo. We apply next-generation sequencing (NGS) technology to quantitatively analyze high-throughput compound screening in mice. Up to 96 compounds and controls can be screened for their effect on metastatic ability in a single mouse.

A measurement of the double-polarization observable E for the reaction $$\gamma p\rightarrow \pi ^0 p$$ γ p → π 0 p is reported. The data were taken with the CBELSA/TAPS experiment at the ELSA facility in Bonn using the Bonn frozen-spin butanol (C$$_4$$ 4 H$$_9$$ 9 OH) target, which provided longitudinally-polarized protons. Circularly-polarized photons were produced via bremsstrahlung of longitudinally-polarized electrons. The data cover the photon energy range from $$E_\gamma =600$$ E γ = 600 to 2310 MeV and nearly the complete angular range. The results are compared to and have been included in recent partial wave analyses.

DNA barcoding allows the quantitative, biomarker-free tracking of individual cell populations in mixed/heterogeneous cell pools. Here, we describe a multiplexed in vivo screening platform based on DNA barcoding technology to interrogate compound libraries for their effect on metastatic seeding in vivo. We apply next-generation sequencing (NGS) technology to quantitatively analyze high-throughput compound screening in mice. Up to 96 compounds and controls can be screened for their effect on metastatic ability in a single mouse.

Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter-and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question. OA Förderung 2021

Data on the beam asymmetry Σ in the photoproduction of η mesons off protons are reported for tagged photon energies from 1130 to 1790 MeV (mass range from W=1748 MeV to W=2045 MeV). The data cover the full solid angle that allows for a precise moment analysis. For the first time, a strong cusp effect in a polarization observable has been observed that is an effect of a branch-point singularity at the pη^{'} threshold [E_{γ}=1447 MeV (W=1896 MeV)]. The latest BnGa partial wave analysis includes the new beam asymmetry data and yields a strong indication for the N(1895)1/2^{-} nucleon resonance, demonstrating the importance of including all singularities for a correct determination of partial waves and resonance parameters.

Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer-related deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent nonmetastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines in vitro and metastases analyzed ex vivo from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than nonmetastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin in vivo. These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited. Significance: This study characterizes altered mitochondria functionality of the metastatic cell state in lung cancer and opens new avenues for metastasis-specific therapeutic targeting.

Data on the beam asymmetry Σ in the photoproduction of η mesons off protons are reported for tagged photon energies from 1130 to 1790 MeV (mass range from W=1748 MeV to W=2045 MeV). The data cover the full solid angle that allows for a precise moment analysis. For the first time, a strong cusp effect in a polarization observable has been observed that is an effect of a branch-point singularity at the pη^{'} threshold [E_{γ}=1447 MeV (W=1896 MeV)]. The latest BnGa partial wave analysis includes the new beam asymmetry data and yields a strong indication for the N(1895)1/2^{-} nucleon resonance, demonstrating the importance of including all singularities for a correct determination of partial waves and resonance parameters.

A cellular condition called oxidative stress can kill cancer cells. The finding that skin cancer cells evade such destruction using lipids acquired while passing through lymphatic vessels reveals a mechanism that boosts cancer spread. Tumour cells acquire lipid that helps them to avoid death by ferroptosis.

A measurement of the double-polarization observable E for the reaction \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\gamma p\rightarrow \pi ^0 p$$\end{document}γp→π0p is reported. The data were taken with the CBELSA/TAPS experiment at the ELSA facility in Bonn using the Bonn frozen-spin butanol (C\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$_4$$\end{document}4H\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$_9$$\end{document}9OH) target, which provided longitudinally-polarized protons. Circularly-polarized photons were produced via bremsstrahlung of longitudinally-polarized electrons. The data cover the photon energy range from \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$E_\gamma =600$$\end{document}Eγ=600 to 2310 MeV and nearly the complete angular range. The results are compared to and have been included in recent partial wave analyses.

The polarization observables T , E , P , H , and G in photoproduction of η mesons off protons are measured for photon energies from threshold to W = 2400 MeV (T), 2280 MeV (E), 1620 MeV ( P , H ), or 1820 MeV (G), covering nearly the full solid angle. The data are compared to predictions from the SAID, MAID, JuBo, and BnGa partial-wave analyses. A refit within the BnGa approach including further data yields precise branching ratios for the Nη decay of nucleon resonances. A Nη-branching ratio of 0.33 ± 0.04 for N ( 1650 ) 1 / 2 − is found, which reduces the large and controversially discussed Nη-branching ratio difference of the two lowest mass J P = 1 / 2 − -resonances significantly.

The production of $\eta^{\prime}$ mesons in coincidence with forward-going protons has been studied in photon-induced reactions on 12C and on a liquid hydrogen (LH2) target for incoming photon energies of 1.3-2.6 GeV at the electron accelerator ELSA. The $\eta^{\prime}$ mesons have been identified via the $\eta^{\prime} \rightarrow \pi^{0} \pi^{0}\eta \rightarrow 6 \gamma$ decay registered with the CBELSA/TAPS detector system. Coincident protons have been identified in the MiniTAPS BaF2 array at polar angles of $2^{\circ} \le \theta_{p} \le 11^{\circ}$ . Under these kinematic constraints the $\eta^{\prime}$ mesons are produced with relatively low kinetic energy ( $\approx 150$ MeV) since the coincident protons take over most of the momentum of the incident-photon beam. For the C-target this allows the determination of the real part of the $\eta^{\prime}$ -carbon potential at low meson momenta by comparing with collision model calculations of the $\eta^{\prime}$ kinetic energy distribution and excitation function. Fitting the latter data for $\eta^{\prime}$ mesons going backwards in the center-of-mass system yields a potential depth of $V = -(44 \pm 16(stat) \pm 15(syst))$ MeV, consistent with earlier determinations of the potential depth in inclusive measurements for average $\eta^{\prime}$ momenta of $\approx 1.1$ GeV/c. Within the experimental uncertainties, there is no indication of a momentum dependence of the $\eta^{\prime}$ -carbon potential. The LH2 data, taken as a reference to check the data analysis and the model calculations, provide differential and integral cross sections in good agreement with previous results for $\eta^{\prime}$ photoproduction off the free proton.

Expression of the chromatin-associated protein HMGA2 correlates with progression, metastasis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Hmga2 has also been identified as a marker of a transient subpopulation of PDAC cells that has increased metastatic ability. Here, we characterize the requirement for Hmga2 during growth, dissemination, and metastasis of PDAC in vivo using conditional inactivation of Hmga2 in well-established autochthonous mouse models of PDAC. Overall survival, primary tumour burden, presence of disseminated tumour cells in the peritoneal cavity or circulating tumour cells in the blood, and presence and number of metastases were not significantly different between mice with Hmga2-wildtype or Hmga2-deficient tumours. Treatment of mice with Hmga2-wildtype and Hmga2-deficient tumours with gemcitabine did not uncover a significant impact of Hmga2-deficiency on gemcitabine sensitivity. Hmga1 and Hmga2 overlap in their expression in both human and murine PDAC, however knockdown of Hmga1 in Hmga2-deficient cancer cells also did not decrease metastatic ability. Thus, Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC, however Hmga2 has limited if any direct functional impact on PDAC progression and therapy resistance.

Multiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits. © 2018 The Authors

The first measurements of the beam-target-helicity-asymmetries $E$ and $G$ in the photoproduction of $\omega$-mesons off protons at the CBELSA/TAPS experiment are reported. $E$ ($G$) was measured using circularly (linearly) polarised photons and a longitudinally polarised target. $E$ was measured over the photon energy range from close to threshold ($E_\gamma = 1108$~MeV) to $E_\gamma = 2300$~MeV and $G$ at a single energy interval of $1108 < E_\gamma, Comment: 6 pages, 6 figures

Data on the polarization observables T, P, and H for the reaction gamma p -> p pi(0) are reported. Compared to earlier data from other experiments, our data are more precise and extend the covered range in energy and angle substantially. The results were extracted from azimuthal asymmetries measured using a transversely polarized target and linearly polarized photons. The data were taken at the Bonn electron stretcher accelerator ELSA with the CBELSA/TAPS detector. Within the Bonn-Gatchina partial wave analysis, the new polarization data lead to a significant narrowing of the error band for the multipoles for neutral-pion photoproduction. (C) 2015 The Authors. Published by Elsevier B.V.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor BLIMP1 as a driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes, and hypoxia-mediated induction of BLIMP1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which upregulation of BLIMP1 links microenvironmental cues to a metastatic stem cell character. Significance: PDAC is an almost uniformly lethal cancer, largely due to its tendency for metastasis. We define a highly metastatic subpopulation of cancer cells, uncover a key transcriptional regulator of metastatic ability, and define hypoxia as an important factor within the tumor microenvironment that increases metastatic proclivity. Cancer Discov; 7(10); 1184–99. ©2017 AACR. See related commentary by Vakoc and Tuveson, p. 1067. This article is highlighted in the In This Issue feature, p. 1047