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Background Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK + non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK + NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. Methods/design In this exploratory prospective phase II clinical trial, newly diagnosed ALK + NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. Discussion Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK + NSCLC according to molecular features. Patients with low molecular risk and the perspective of a “chronic disease” will be distinguished from “high-risk” cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. Trial registration Clinicaltrials.gov , NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019–001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36

Although deregulated expression of microRNAs (miRNAs) demonstrably contributes to the development and progression of all types of human cancers, little data are available about the changes in miRNA expression levels in malignant melanoma. In our study, we performed microarray-based miRNA profiling of melanocytes and melanoma cell lines derived from either primary tumors or metastatic melanomas. In addition, we analyzed miRNA expression patterns of melanoma cell clones in which the expression of melanoma specific genes was stably knocked down by antisense techniques. We also generated miRNA expression profiles for two derivatives of a melanoma cell line that differ in their invasive potential. Comparing miRNA expression patterns of melanocytes and subsets of melanoma cell lines, we identified large cohorts of miRNAs associated with malignant transformation as well as with the progression of the disease and with metastatic colonization. Surprisingly, the bulk of miRNAs that deregulated most strongly was not described to be of importance in tumor development before. The results of our study, therefore, not only provide insights into alterations in the miRnomes of melanocytes and melanoma cell lines during melanoma progression but also present a large assortment of miRNAs to be analyzed for their potential as diagnostic markers or targets for therapies in the future.

Since bone morphogenetic proteins (BMPs) play an important role in melanoma progression, we aimed to determine the molecular mechanisms leading to overexpression of BMP4 in melanoma cells compared to normal melanocytes. With our experimental approach we revealed that loss of expression of a microRNA represents the starting point for a signaling cascade finally resulting in overexpression of BMP4 in melanoma cells. In detail, strongly reduced expression of the microRNA miR-196a in melanoma cells compared to healthy melanocytes leads to enhanced HOX-B7 mRNA and protein levels, which subsequently raise Ets-1 activity by inducing basic fibroblast growth factor (bFGF). Ets-1 finally accounts for induction of BMP4 expression. We were furthermore able to demonstrate that bFGF-mediated induction of migration is achieved via activation of BMP4, thus determining BMP4 as major modulator of migration in melanoma. In summary, our study provides insights into the early steps of melanoma progression and might thereby harbor therapeutic relevance.

Background Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases. Methods This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled. Discussion If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention. Trial registration The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014–002665-30.

Background Recently, the combination of the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab with first-line chemotherapy has demonstrated to improve outcome for patients with advanced small cell lung cancer (SCLC), leading to approval of this regimen. At the same time, accumulating (pre-)clinical data suggest synergisms of radiotherapy and immunotherapy via the radiation-mediated induction of anti-tumor immunogenicity. Combining the recent findings, the TREASURE trial aims at further enhancing response to upfront chemo-immunotherapy by the addition of thoracic radiotherapy (TRT). Methods/design The TREASURE trial is a randomized, multicenter, phase II clinical trial ( ClinicalTrials.gov identifier, NCT04462276). One hundred four patients suffering from extensive disease (ED) SCLC, with any response to the standard of care induction chemo-immunotherapy will be randomized to receive atezolizumab maintenance therapy with or without TRT. The primary endpoint of this study is overall survival (OS). Secondary endpoints include further measures of efficacy, safety, and the collection of biomarker samples. A safety interim analysis will take place after n  = 23 patients receiving TRT have been observed for three months after the end of TRT. Discussion This trial will investigate whether treatment efficacy can be improved by adding TRT to atezolizumab maintenance therapy in ED SCLC patients with any response after chemo-immunotherapy. Safety and feasibility of such a regimen will be evaluated, and biomaterials for a translational research project will be collected. Together, the results of this trial will deepen our comprehension of how checkpoint inhibition and radiotherapy interact and contribute to the evolving landscape of SCLC therapy. Trial registration Clinicaltrials.gov identifier: NCT04462276 (Date of initial registration: 8th July 2020), https://clinicaltrials.gov/ct2/show/NCT04462276 Eudra-CT Number: 2019-003916-29 (Date of initial registration: 30th March 2020), https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003916-29/DE

Microorganisms are an integral component of human health on Earth as well as for life on the International Space Station. However, inescapably, fomites in human habitats can serve as crucial niches for opportunistic pathogens. To explore potential countermeasures for the associated infection risk, the Touching Surfaces experiment evaluated antibacterial surfaces as high-touch surfaces on the International Space Station and on Earth. We used copper-based surfaces that integrate chemical antimicrobial properties with topography, thereby creating a metasurface. 16 S rRNA sequencing revealed that most bacteria found were human associated. While no significant distinction was observed between the microbial communities on the reference and antibacterial surfaces, isolation of microorganisms from the surfaces suggests that copper-based nanometer-structured surfaces exhibit enhanced antibacterial efficacy. The antibacterial efficacy of touched surfaces was reduced, as assessed by wet contact killing assays carried out using a methicillin-resistant Staphylococcus aureus (MRSA) isolate. The simplicity of implementing the surfaces allowed for straightforward testing of surfaces in both space and on Earth.

Tomato ( Solanum lycopersicum ) is an established model for studying fruit biology; however, most studies of tomato fruit growth and ripening are based on homogenized pericarp, and do not consider the internal tissues, or the expression signatures of individual cell and tissue types. We present a spatiotemporally resolved transcriptome analysis of tomato fruit ontogeny, using laser microdissection (LM) or hand dissection coupled with RNA-Seq analysis. Regulatory and structural gene networks, including families of transcription factors and hormone synthesis and signaling pathways, are defined across tissue and developmental spectra. The ripening program is revealed as comprising gradients of gene expression, initiating in internal tissues then radiating outward, and basipetally along a latitudinal axis. We also identify spatial variations in the patterns of epigenetic control superimposed on ripening gradients. Functional studies elucidate previously masked regulatory phenomena and relationships, including those associated with fruit quality traits, such as texture, color, aroma, and metabolite profiles. Cell-type transcriptome profiling greatly elucidate organismal development. Here, the authors report a spatiotemporally resolved comprehensive transcriptome analysis of tomato fruit ontogeny and suggest a new model of fruit maturation which initiates in internal tissues then radiates outwards.

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical data sets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 data set consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1.5 to 4T scanners. The FBIRN Phase 2 and Phase 3 data sets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN's multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data. •This manuscript presents Function Biomedical Informatics Research Network data.•FBIRN data are shared via the BIRN Data Repository and SchizConnect.•FBIRN shares data from individuals with schizophrenia and healthy controls.•FBIRN shares structural and functional brain imaging, clinical, and cognitive data.

Objective. There is inadequate evidence of long-term benefit and growing evidence of the risks of chronic opioid therapy (COT). Opioid dose reduction, or opioid tapering, may reduce these risks but may also worsen pain and quality of life. Our objective was to explore patients’ perspectives on opioid tapering. Design. Qualitative study using in-person, semistructured interviews. Setting and Patients. English-speaking, adult primary care patients (N = 24) in three Colorado health care systems. Methods. Interviews were audio recorded, transcribed, and analyzed in ATLAS.ti. We used a team-based, mixed inductive and deductive approach guided by the Health Belief Model. We iteratively refined emergent themes with input from a multidisciplinary team. Results. Participants had a mean age of 52 years old, were 46% male and 79% white. Six participants (25%) were on COT and not tapering, 12 (50%) were currently tapering COT, and 6 (25%) had discontinued COT. Emergent themes were organized in four domains: risks, barriers, facilitators, and benefits. Patients perceived a low risk of overdose and prioritized the more immediate risk of increased pain with opioid tapering. Barriers included a perceived lack of effectiveness of nonopioid options and fear of opioid withdrawal. Among patients with opioid tapering experience, social support and a trusted health care provider facilitated opioid tapering. These patients endorsed improved quality of life following tapering. Conclusions. Efforts to support opioid tapering should elicit patients’ perceived barriers and seek to build on relationships with family, peers, and providers to facilitate tapering. Future work should identify patient-centered, feasible strategies to support tapering of COT.

Febrile neutropenia (FN) is the most common oncologic emergency and is among the most deadly. Guidelines recommend risk stratification and outpatient management of both pediatric and adult FN patients deemed to be at low risk of complications or mortality, but our prior single-center research demonstrated that the vast majority (95%) are hospitalized. From a nationwide perspective, to determine the proportion of cancer patients of all ages hospitalized after an emergency department (ED) visit for FN, and to analyze variability in hospitalization rates. Our a priori hypothesis was that >90% of US cancer-associated ED FN visits would end in hospitalization. Analysis of data from the Nationwide Emergency Department Sample, 2006-2014. Stratified probability sample of all US ED visits. Inclusion criteria were: (1) Clinical Classification Software code indicating cancer, (2) diagnostic code indicating fever, and (3) diagnostic code indicating neutropenia. We excluded visits ending in transfer. The hospital at which the visit took place. Our main outcome is the proportion of ED FN visits ending in hospitalization, with an a priori hypothesis of >90%. Our secondary outcomes are: (a) hospitalization rates among subsets, and (b) proportion of variability in the hospitalization rate attributable to which hospital the patient visited, as measured by the intra-class correlation coefficient (ICC). Of 348,868 visits selected to be representative of all US ED visits, 94% ended in hospitalization (95% Confidence Interval [CI] 93-94%). Each additional decade of age conferred 1.23x increased odds of hospitalization. Those with private (92%), self-pay (92%), and other (93%) insurance were less likely to be hospitalized than those with public insurance (95%, odds ratios [OR] 0.74-0.76). Hospitalization was least likely at non-metropolitan hospitals (84%, OR 0.15 relative to metropolitan teaching hospitals), and was also less likely at metropolitan non-teaching hospitals (94%, OR 0.64 relative to metropolitan teaching hospitals). The ICC adjusted for hospital random effects and patient and hospital characteristics was 26% (95%CI 23-29%), indicating that 26% of the variability in hospitalization rate was attributable to which hospital the patient visited. Nearly all cancer-associated ED FN visits in the US end in hospitalization. Inter-hospital variation in hospitalization practices explains 26% of the limited variability in hospitalization decisions. Simple, objective tools are needed to improve risk stratification for ED FN patients.