Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy

Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment refractory B cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF, and TNFα from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemoimmunotherapeutic regimen represents a potent strategy for using conventional anticancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.Massachusetts Institute of Technology. Ludwig Center for Molecular OncologyKathy and Curt Marble Cancer Research FundSingapore-MIT Alliance for Research and TechnologyGerman Research Foundation (KFO286)German Research Foundation (Fellowship)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Sicher sind wir wichtig - irgendwie.? Der Einfluss von Eltern auf das Berufswahlverhalten von Maedchen; eine Untersuchung

Ein zentrales Anliegen dieser Untersuchung war es, Erkenntnisse ueber den Stellenwert von Eltern im Berufswahlprozess von Maedchen und ueber ihren Einfluss auf die Berufs- und Lebensplanung ihrer Toechter zu gewinnen. Das Interesse richtete sich nicht nur auf die bewussten Einflussnahmen der Eltern sondern auch auf die Frage, ob und in welcher Weise Vaeter und Muetter durch 'unbewusste Botschaften' auf die Planung und Entscheidung ihrer Toechter einwirken. U.a. wurde untersucht: wie Eltern ihre Bedeutung in bezug auf den Berufswahlprozess der Tochter bewerten; inwieweit Eltern sich der Problematik der Berufswahl von Maedchen bewusst sind; welche Vorstellungen und Wuensche Vaeter und Muetter im Hinblick auf die Lebensplanung ihrer Tochter haben; welche Faehigkeiten und Staerken die Tochter in den Augen ihrer Eltern besitzt und welche beruflichen Vorstellungen damit verknuepft werden; welche Berufsvorstellungen Eltern fuer ihre Toechter entwickeln und welche Kriterien sie zugrunde legen; welche Einstellungen Muetter und Vaeter zu frauenuntypischen Berufswahlen haben, insbesondere zu einer freuenuntypischen Berufswahl der eigenen Tochter; wie der Kontakt zwischen Eltern und den anderen am Berufswahlprozess beteiligten Institutionen zum gegenwaertigen Zeitpunkt ist und wie Eltern ihn bewerten; wie zufrieden Eltern mit den Leistungen der Institutionen sind; ob Eltern Interesse an einer staerkeren Einbeziehung haben und zu welchem Zeitpunkt, mit welchen Themen, auf welchem Wege und mit welchen Angeboten sie angesprochen werden wollen. Befragt wurden 165 Muetter und Vaeter von Schuelerinnen der Klassen 8 bis 10 an Haupt-, Real- und Gesamtschulen. Ergaenzend wurden Maedchen (439) dieser Klassen befragt, um zu pruefen, inwieweit Maedchen und Eltern in ihrer Einschaetzung des elterlichen Einflusses uebereinstimmen. (IAB2)Available from IAB-96-230-52 BE 989 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

High-resolution transcriptome of human macrophages.

Macrophages are dynamic cells integrating signals from their microenvironment to develop specific functional responses. Although, microarray-based transcriptional profiling has established transcriptional reprogramming as an important mechanism for signal integration and cell function of macrophages, current knowledge on transcriptional regulation of human macrophages is far from complete. To discover novel marker genes, an area of great need particularly in human macrophage biology but also to generate a much more thorough transcriptome of human M1- and M1-like macrophages, we performed RNA sequencing (RNA-seq) of human macrophages. Using this approach we can now provide a high-resolution transcriptome profile of human macrophages under classical (M1-like) and alternative (M2-like) polarization conditions and demonstrate a dynamic range exceeding observations obtained by previous technologies, resulting in a more comprehensive understanding of the transcriptome of human macrophages. Using this approach, we identify important gene clusters so far not appreciated by standard microarray techniques. In addition, we were able to detect differential promoter usage, alternative transcription start sites, and different coding sequences for 57 gene loci in human macrophages. Moreover, this approach led to the identification of novel M1-associated (CD120b, TLR2, SLAMF7) as well as M2-associated (CD1a, CD1b, CD93, CD226) cell surface markers. Taken together, these data support that high-resolution transcriptome profiling of human macrophages by RNA-seq leads to a better understanding of macrophage function and will form the basis for a better characterization of macrophages in human health and disease

Inflammatory Pre-Conditioning of Adipose-Derived Stem Cells with Cerebrospinal Fluid from Traumatic Brain Injury Patients Alters the Immunomodulatory Potential of ADSC Secretomes

Immunomodulation by adipose-tissue-derived stem cells (ADSCs) is of special interest for the alleviation of damaging inflammatory responses in central nervous system injuries. The present study explored the effects of cerebrospinal fluid (CSF) from traumatic brain injury (TBI) patients on this immunomodulatory potential of ADSCs. CSF conditioning of ADSCs increased messenger RNA levels of both pro- and anti-inflammatory genes compared to controls. Exposure of phorbol-12-myristate-13-acetate-differentiated THP1 macrophages to the secretome of CSF-conditioned ADSCs downregulated both proinflammatory (cyclooxygenase-2, tumor necrosis factor alpha) and anti-inflammatory (suppressor of cytokine signaling 3, interleukin-1 receptor antagonist, and transforming growth factor beta) genes in these cells. Interleukin-10 expression was elevated in both naive and conditioned secretomes. ADSC secretome treatment, further, induced macrophage maturation of THP1 cells and increased the percentage of CD11b(+), CD14(+), CD86(+), and, to a lesser extent, CD206(+) cells. This, moreover, enhanced the phagocytic activity of CD14(+) and CD86(+) cells, though independently of pre-conditioning. Secretome exposure, finally, also induced a reduction in the percentage of CD192(+) adherent cells in cultures of peripheral blood mononuclear cells (PBMCs) from both healthy subjects and TBI patients. This limited efficacy (of both naive and pre-conditioned secretomes) suggests that the effects of lymphocyte-monocyte paracrine signaling on the fate of cultured PBMCs are strongest upon adherent cell populations