Contradictory mRNA and protein misexpression of EEF1A1 in ductal breast carcinoma due to cell cycle regulation and cellular stress

Encoded by EEF1A1, the eukaryotic translation elongation factor eEF1α1 strongly promotes the heat shock response, which protects cancer cells from proteotoxic stress, following for instance oxidative stress, hypoxia or aneuploidy. Unexpectedly, therefore, we find that EEF1A1 mRNA levels are reduced in virtually all breast cancers, in particular in ductal carcinomas. Univariate and multivariate analyses indicate that EEF1A1 mRNA underexpression independently predicts poor patient prognosis for estrogen receptor-positive (ER+) cancers. EEF1A1 mRNA levels are lowest in the most invasive, lymph node-positive, advanced stage and postmenopausal tumors. In sharp contrast, immunohistochemistry on 100 ductal breast carcinomas revealed that at the protein level eEF1α1 is ubiquitously overexpressed, especially in ER+ , progesterone receptor-positive and lymph node-negative tumors. Explaining this paradox, we find that EEF1A1 mRNA levels in breast carcinomas are low due to EEF1A1 allelic copy number loss, found in 27% of tumors, and cell cycle-specific expression, because mRNA levels are high in G1 and low in proliferating cells. This also links estrogen-induced cell proliferation to clinical observations. In contrast, high eEF1α1 protein levels protect tumor cells from stress-induced cell death. These observations suggest that, by obviating EEF1A1 transcription, cancer cells can rapidly induce the heat shock response following proteotoxic stress, and survive

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

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

Low baseline pulmonary levels of cytotoxic lymphocytes as a predisposing risk factor for severe COVID-19

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and currently has detrimental human health, community, and economic impacts around the world. It is unclear why some SARS-CoV-2-positive individuals remain asymptomatic, while others develop severe symptoms. Baseline pulmonary levels of antiviral leukocytes, already residing in the lung prior to infection, may orchestrate an effective early immune response and prevent severe symptoms. Here, “in silico\ua0flow cytometry” was used to deconvolute the levels of all seven types of antiviral leukocytes in 1,927 human lung tissues. Baseline levels of CD8+\ua0T cells, resting NK cells, and activated NK cells, as well as cytokines that recruit these cells, are significantly lower in lung tissues with high expression of the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2). This is observed in univariate analyses, in multivariate analyses, and in two independent data sets. Importantly, ACE2 mRNA and protein levels very strongly correlate in human cells and tissues. The above findings also largely apply to the SARS-CoV-2 entry protease TMPRSS2. Both SARS-CoV-2-infected lung cells and COVID-19 lung tissues show upregulation of CD8+\ua0T cell- and NK cell-recruiting cytokines. Moreover, tissue-resident CD8+\ua0T cells and inflammatory NK cells are significantly more abundant in bronchoalveolar lavage fluids from mildly affected COVID-19 patients compared to severe cases. This suggests that these lymphocytes are important for preventing severe symptoms. Elevated ACE2 expression increases sensitivity to coronavirus infection. Thus, the results suggest that some individuals may be exceedingly susceptible to develop severe COVID-19 due to concomitant high preexisting ACE2 and TMPRSS expression and low baseline cytotoxic lymphocyte levels in the lung

Pathogenesis of split-hand/split-foot malformation

Split-hand/split-foot malformation (SHFM), also known as ectrodactyly, is a congenital limb malformation, characterized by a deep median cleft of the hand and/or foot due to the absence of the central rays. SHFM may occur as an isolated entity or as part of a syndrome. Both forms are frequently found in association with chromosomal rearrangements such as deletions or translocations. Detailed studies of a number of mouse models for ectrodactyly have revealed that a failure to maintain median apical ectodermal ridge (AER) signalling is the main pathogenic mechanism. A number of factors complicate the identification of the genetic defects underlying human ectrodactyly: the limited number of families linked to each SHFM locus, the large number of morphogens involved in limb development, the complex interactions between these morphogens, the involvement of modifier genes, and the presumed involvement of multiple genes or long-range regulatory elements in some cases of ectrodactyly. So far, the only mutations known to underlie SHFM in humans have been found in the TP63 gene. The identification of novel human and mouse mutations for ectrodactyly will enhance our understanding of AER functions and the pathogenesis of ectrodactyly

Overexpression of Ran GTPase components regulating nuclear export, but not mitotic spindle assembly, marks chromosome instability and poor prognosis in breast cancer

Background: Ran GTPase regulates nuclear import, nuclear export, and mitotic spindle assembly. The multifunctional involvement of seventeen Ran GTPase components in these processes has complicated research into how each contributes to cancer development. Objective: To assess whether individual and process-specific misexpression of Ran GTPase components contribute to chromosome instability (CIN) and worsen breast cancer patient prognosis. Methods: Using publicly available datasets, we studied the degree of misexpression of all Ran GTPase signaling components in breast cancer, assessed their involvement in CIN and used four clinical tests to evaluate whether their misregulation may constitute independent prognostic predictors. Results: A significant majority of Ran GTPase signaling components is overexpressed in breast cancer. Strikingly, spindle assembly components are overexpressed and associated with CIN with only marginal significance and four independent tests indicate that this does not worsen patient outcome. Overexpression of nuclear import components is neither CIN-associated nor clinically significant. In sharp contrast, overexpression of nuclear export components constitutes a strong independent marker for both CIN and poor patient prognosis. We identify Exportin 2/CSE1L, Exportin 3/XPOT, Exportin 5/XPO5, and RANBP1 as novel potential targets. Conclusions: We find that overexpression of Ran GTPase components involved in nuclear export, but not nuclear import or mitotic spindle assembly, is a strong CIN-associated marker for poor breast cancer prognosis. This could mean that increased nuclear export (of, for instance, pRb, p53, p73, BRCA1, p21, p27, E2F4, IκB, survivin), rather than spindle defects, mainly drives CIN and tumorigenesis. Hence, selective inhibitors of nuclear export may be effective for treating the most aggressive and chromosomally unstable breast cancers. [Figure not available: see fulltext.

Treating cancer with microRNA replacement therapy: A literature review

microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally by interfering with the translation of one or more target mRNAs. The unique miRNA sequences are involved in many physiological and pathological processes. Dysregulation of miRNAs contributes to the pathogenesis of all types of cancer. Notably, the diminished expression of tumor suppressor miRNAs, such as members of the Let-7 and miR-34 family, promotes tumor progression, invasion and metastasis. The past lustrum in particular, has witnessed substantial improvement of miRNA replacement therapy. This approach aims to restore tumor suppressor miRNA function in tumor cells using synthetic miRNA mimics or miRNA expression plasmids. Here, we provide a comprehensive review of recent advances in miRNA replacement therapy for treatment of cancer and its advantages over conventional gene therapy. We discuss a wide variety of delivery methods and vectors, as well as obstacles that remain to be overcome. Lastly, we review efforts to reverse epigenetic alterations, which affect miRNA expression in cancer cells, and the promising observation that restoring miRNA function re-sensitizes resistant tumor cells to chemotherapeutic drugs. The fact that various miRNA replacement therapies are currently in clinical trial demonstrates the great potential of this approach to treat cancer

EYA4 promotes breast cancer progression and metastasis through its role in replication stress avoidance

Abstract The Eyes Absent (EYA) family of proteins is an atypical group of four dual-functioning protein phosphatases (PP), which have been linked to many vital cellular processes and organogenesis pathways. The four family members of this PP family possess transcriptional activation and phosphatase functions, with serine/threonine and tyrosine phosphatase domains. EYA4 has been associated with several human cancers, with tumor-suppressing and tumor-promoting roles. However, EYA4 is the least well-characterized member of this unique family of PP, with its biological functions and molecular mechanisms in cancer progression, particularly in breast cancer, still largely unknown. In the present study, we found that the over-expression of EYA4 in breast tissue leads to an aggressive and invasive breast cancer phenotype, while the inhibition of EYA4 reduced tumorigenic properties of breast cancer cells in vitro and in vivo. Cellular changes downstream of EYA4, including cell proliferation and migration, may explain the increased metastatic power of breast cancer cells over-expressing EYA4. Mechanistically, EYA4 prevents genome instability by inhibiting the accumulation of replication-associated DNA damage. Its depletion results in polyploidy as a consequence of endoreplication, a phenomenon that can occur in response to stress. The absence of EYA4 leads to spontaneous replication stress characterized by the activation of the ATR pathway, sensitivity to hydroxyurea, and accumulation of endogenous DNA damage as indicated by increased γH2AX levels. In addition, we show that EYA4, specifically its serine/threonine phosphatase domain, plays an important and so far, unexpected role in replication fork progression. This phosphatase activity is essential for breast cancer progression and metastasis. Taken together, our data indicate that EYA4 is a novel potential breast cancer oncogene that supports primary tumor growth and metastasis. Developing therapeutics aimed at the serine/threonine phosphatase activity of EYA4 represents a robust strategy for killing breast cancer cells, to limit metastasis and overcome chemotherapy resistance caused by endoreplication and genomic rearrangements