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Previously, we showed that mice treated with cyclophosphamide (CTX) 4 days before intravenous injection of breast cancer cells had more cancer cells in the lung at 3 h after cancer injection than control counterparts without CTX. At 4 days after its injection, CTX is already excreted from the mice, allowing this pre-treatment design to reveal how CTX may modify the lung environment to indirectly affect cancer cells. In this study, we tested the hypothesis that the increase in cancer cell abundance at 3 h by CTX is due to an increase in the adhesiveness of vascular wall for cancer cells. Our data from protein array analysis and inhibition approach combined with in vitro and in vivo assays support the following two-prong mechanism. (1) CTX increases vascular permeability, resulting in the exposure of the basement membrane (BM). (2) CTX increases the level of matrix metalloproteinase-2 (MMP-2) in mouse serum, which remodels the BM and is functionally important for CTX to increase cancer abundance at this early stage. The combined effect of these two processes is the increased accessibility of critical protein domains in the BM, resulting in higher vascular adhesiveness for cancer cells to adhere. The critical protein domains in the vascular microenvironment are RGD and YISGR domains, whose known binding partners on cancer cells are integrin dimers and laminin receptor, respectively.

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization—despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.

Good software documentation encourages good software engineering, but the meaning of "good" documentation is vaguely defined in the software engineering literature. To clarify this ambiguity, we draw on work from the data and information quality community to propose a framework that decomposes documentation quality into ten dimensions of structure, content, and style. To demonstrate its application, we recruited technical editors to apply the framework when evaluating examples from several genres of software documentation. We summarise their assessments -- for example, reference documentation and README files excel in quality whereas blog articles have more problems -- and we describe our vision for reasoning about software documentation quality and for the expansion and potential of a unified quality framework., to appear in the Visions and Reflections Track of the ACM Joint European Software Engineering Conference and Symposium on the Foundations of Software Engineering 2020

For modern data analytics, practices from software development are increasingly necessary to manage data, but they must be incorporated alongside other statistical and scientific skills. Therefore, we ask: how does a community recontextualize software development through the unique pressures of their work? To answer this, we explore the analytic community around baseball, or sabermetrics. To discover software development's place in the search for robust statistical insight in sports, we interview 10 participants in the sabermetric community and survey over 120 more data analysts, both in baseball and not. We explore how their work lives at the intersection of science and entertainment, and as a consequence, baseball data serves as an accessible yet deep subject to practice analytic skills. Software development exists within an iterative research process that cycles between defining rigorous statistical methods and preserving the flexibility to chase interesting problems. In this question-driven process, members of the community inhabit several overlapping roles of intentional work, in which software development can become the priority to support research and statistical infrastructure, and we discuss the way that the community can foster the balance of these skills.

In NSCLC alterations in PDGF receptors are markers of worst prognosis and efficient targeting of these receptors is yet to be achieved. In this study, we explored PDGFR-regulated microRNAs demonstrating that miR-23b cluster and miR-125a-5p are downregulated by increased expression of PDGFR-α or PDGFR-β in NSCLC cells. Mechanistically, the expression of these microRNAs is positively regulated by p53 and negatively modulated by NF-kB p65. Forced expression of miR-23b cluster or miR-125a-5p enhanced drug sensitivity and suppressed invasiveness of NSCLC cells by silencing several genes involved in oncogenic KRAS and NF-kB pathways, including SOS1, GRB2, IQGAP1, RALA, RAF-1, IKKβ, AKT2, ERK2 and KRAS itself. Of note, an inverse correlation between miR-23b cluster, miR-125a-5p and respective target genes was also found in vivo in a large dataset of lung adenocarcinoma samples. Furthermore, in vivo delivery of miR-23b cluster or miR-125a-5p significantly repressed tumour growth in a highly aggressive NSCLC circulating tumour cell (CTC) patient derived explant (CDX) mouse model. In conclusion, our finding sheds light on the PDGFR signaling and endorses the possibility to employ miR-23b cluster and miR-125a-5p as therapeutic tools to silence simultaneously a range of redundant pathways and main effectors of tumorigenesis in NSCLC.

Diversity, including gender diversity, is valued by many software development organizations, yet the field remains dominated by men. One reason for this lack of diversity is gender bias. In this paper, we study the effects of that bias by using an existing framework derived from the gender studies literature. We adapt the four main effects proposed in the framework by posing hypotheses about how they might manifest on GitHub, then evaluate those hypotheses quantitatively. While our results show that effects of gender bias are largely invisible on the GitHub platform itself, there are still signals of women concentrating their work in fewer places and being more restrained in communication than men.

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of adaptive-response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

Many software engineering researchers use sentiment and politeness analysis tools to study the emotional environment within collaborative software development. However, papers that use these tools rarely establish their reliability. In this paper, we evaluate popular existing tools for sentiment and politeness detection over a dataset of 589 manually rated GitHub comments that represent developer discussions. We also develop a coding scheme on how to quantify politeness for conversational texts found on collaborative platforms. We find that not only do the tools have a low agreement with human ratings on sentiment and politeness, human raters also have a low agreement among themselves.

Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications.

Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of ∼ 24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC.

Spreadsheets are ubiquitous. Thus, it is important to understand the challenges faced by spreadsheet users in practice. To better understand these challenges, we surveyed ABB employees and then interviewed a cross-section of survey respondents. We used a two-phase coding process to classify the challenges they described. Our survey findings demonstrate that practices in our single-company setting are consistent with practices in broader settings. Our interviews revealed both individual and organizational challenges. For instance, individual participants described data pipeline challenges related to importing data from external sources or storing and archiving spreadsheet data. Further, participants' collective responses revealed challenges pertaining to knowledge distribution within the organization. We outline possible interventions to address these challenges. Our results will help guide researchers and tool designers in addressing the practical challenges facing spreadsheet users.

To help users gain awareness of tools and features available in applications, recommender systems can automatically suggest useful tools. Such systems aim to present recommendations just like users would recommend tools to one another, but little is known about the nature of these user-to-user recommendations. This paper explores user-to-user recommendations through a study of 13 pairs of software users performing data analysis tasks. We found that users were more likely to adopt tools when they were receptive to the recommendation, but did not find the recommendations were any more likely to be effective when they contained other characteristics such as politeness, persuasiveness, or referred to observable tools. These findings suggest that, for example, automated systems should avoid recommending obscure and unfamiliar tools, but making recommendations politely is not a critical design goal.

Chemotherapy is a double-edged sword. It is anticancer because of its cytotoxicity. Paradoxically, by increasing chemoresistance and cancer metastasis, it is also procancer. However, the underlying mechanisms for chemotherapy-induced procancer activities are not well understood. Here we describe the ability of paclitaxel (PTX), a frontline chemotherapeutic agent, to exacerbate metastasis in mouse models of breast cancer. We demonstrate that, despite the apparent benefit of reducing tumor size, PTX increased the circulating tumor cells in the blood and enhanced the metastatic burden at the lung. At the primary tumor, PTX increased the abundance of the tumor microenvironment of metastasis, a landmark microanatomical structure at the microvasculature where cancer cells enter the blood stream. At the metastatic lung, PTX improved the tissue microenvironment (the "soil") for cancer cells (the "seeds") to thrive; these changes include increased inflammatory monocytes and reduced cytotoxicity. Importantly, these changes in the primary tumor and the metastatic lung were all dependent on Atf3, a stress-inducible gene, in the noncancer host cells. Together, our data provide mechanistic insights into the procancer effect of chemotherapy, explaining its paradox in the context of the seed-and-soil theory. Analyses of public datasets suggest that our data may have relevance to human cancers. Thus, ATF3 in the host cells links a chemotherapeutic agent-a stressor-to immune modulation and cancer metastasis. Dampening the effect of ATF3 may improve the efficacy of chemotherapy.

Biases against women in the workplace have been documented in a variety of studies. This paper presents a large scale study on gender bias, where we compare acceptance rates of contributions from men versus women in an open source software community. Surprisingly, our results show that women’s contributions tend to be accepted more often than men’s. However, for contributors who are outsiders to a project and their gender is identifiable, men’s acceptance rates are higher. Our results suggest that although women on GitHub may be more competent overall, bias against them exists nonetheless.

Software engineering researchers have a tendency to be optimistic about the future. Though useful, optimism bias bolsters unrealistic expectations towards desirable outcomes. We argue that explicitly framing software engineering research through pessimistic futures, or dystopias, will mitigate optimism bias and engender more diverse and thought-provoking research directions. We demonstrate through three pop culture dystopias, Battlestar Galactica, Fallout 3, and Children of Men, how reflecting on dystopian scenarios provides research opportunities as well as implications, such as making research accessible to non-experts, that are relevant to our present.

Spreadsheet environments offer many functions to manipulate data, which users can combine into complex formulae. However, for both researchers and practitioners who want to study formulae to improve spreadsheet practices, anticipating these combinations is difficult. Therefore, we developed Perquimans, a tool that analyzes spreadsheet collections to visualize patterns of function combination as an interactive tree, representing both the most common and most anomalous patterns of formula construction and their contexts. Using spreadsheets from the Enron corpus, we conduct a case study and a user study to explore Perquimans' various applications, such as those in flexible smell detection and spreadsheet education.

We performed an empirical study to understand interoperability issues in C and Fortran programs. C/Fortran interoperability is very common and is representative of general language interoperability issues, such as how interfaces between languages are defined and how data types are shared. Fortran presents an additional challenge, since several ad hoc approaches to C/Fortran interoperability were in use long before a standard mechanism was defined. We explored 20 applications, automatically analyzing over 12 million lines of code. We found that only 3% of interoperability instances follow the ISO standard to describe interfaces; the rest follow a combination of compiler-dependent ad hoc approaches. Several parameters in cross-language functions did not have standards-compliant interoperable types, and about one-fourth of the parameters that were passed by reference could be passed by value. We propose that automated refactoring tools may provide a viable way to migrate programs to use the new interoperability features. We present two refactorings to transform code for this purpose and one refactoring to evolve code thereafter; all of these are instances of multiple language refactorings.

Biases against women in the workplace have been documented in a variety of studies. This paper presents the largest study to date on gender bias, where we compare acceptance rates of contributions from men versus women in an open source software community. Surprisingly, our results show that women's contributions tend to be accepted more often than men's. However, when a woman's gender is identifiable, they are rejected more often. Our results suggest that although women on GitHub may be more competent overall, bias against them exists nonetheless.

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.

TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.

Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-α/β and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-α/β by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells.

Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined.To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided.In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype.The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC.

MicroRNAs have become recognized as key players in the development of cancer. They are a family of small non-coding RNAs that can negatively regulate the expression of cancer-related genes by sequence-selective targeting of mRNAs, leading to either mRNA degradation or translational repression. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. MicroRNAs have been confirmed to play roles in lung cancer development, epithelial-mesenchymal transition and response to therapy. They are also being studied for their future use as diagnostic and prognostic biomarkers and as potential therapeutic targets. In this review we focus on the role of dysregulated microRNA expression in lung tumorigenesis. We also discuss the role of microRNAs in therapeutic resistance and as biomarkers. We further look into the progress made and challenges remaining in using microRNAs for therapy in lung cancer.