Evaluation of transcriptionally regulated genes identifies NCOR1 in hormone receptor negative breast tumors and lung adenocarcinomas as a potential tumor suppressor gene

Regulation of transcription is a key process in cellular homeostasis. It depends on regulators that either repress or stimulate the transcription of genes, therefore controlling different biological functions. The Nuclear Receptor Corepressor 1 (NCOR1) is one of those co-repressors that regulate the transcription by facilitating the recruitment of HDAC1, 2, 3, 4, 5 and 7. In our article, by using an in silico approach, we evaluate the mutational status of NCOR1 in breast and lung tumors. We identified that NORC1 is mutated in more than 3% of breast tumors and lung adenocarcinomas and linked this fact with detrimental outcome in some subtypes, particularly in those that are hormone receptor negative. In addition to these findings, as mutations in this gene are deleterious, we confirmed that high levels of this gene were linked with good prognosis in the same tumor subtypes. Findings in the same direction were identified in lung adenocarcinomas, with mutations associated with detrimental prognosis and high expression with better outcome. In conclusion, hereby we describe the presence and prognostic role of mutations in the NCOR1 gene in hormone receptor negative breast and lung adenocarcinomas, and we also confirm that NCOR1 is a tumor suppressor gene. Further studies should be performed to explore therapeutic mechanisms to restore its function

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

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

Momentum scale calibration of the LHCb spectrometer

For accurate determination of particle masses accurate knowledge of the momentum scale of the detectors is crucial. The procedure used to calibrate the momentum scale of the LHCb spectrometer is described and illustrated using the performance obtained with an integrated luminosity of 1.6 fb-1 collected during 2016 in pp running. The procedure uses large samples of J/ψ → μ + μ - and B+ → J/ψ K + decays and leads to a relative accuracy of 3 × 10-4 on the momentum scale

Genetic mutational status of genes regulating epigenetics: Role of the histone methyltransferase KMT2D in triple negative breast tumors.

PurposeEpigenetic regulating proteins like histone methyltransferases produce variations in several functions, some of them associated with the generation of oncogenic processes. Mutations of genes involved in these functions have been recently associated with cancer, and strategies to modulate their activity are currently in clinical development.MethodsBy using data extracted from the METABRIC study, we searched for mutated genes linked with detrimental outcome in invasive breast carcinoma (n = 772). Then, we used downstream signatures for each mutated gene to associate that signature with clinical prognosis using the online tool "Genotype-2-Outcome" (http://www.g-2-o.com). Next, we performed functional annotation analyses to classify genes by functions, and focused on those associated with the epigenetic machinery.ResultsWe identified KMT2D, SETD1A and SETD2, included in the lysine methyltransferase activity function, as linked with poor prognosis in invasive breast cancer. KMT2D which codes for a histone methyltransferase that acts as a transcriptional regulator was mutated in 6% of triple negative breast tumors and found to be linked to poor survival. Genes regulated by KMT2D included RAC3, KRT23, or KRT14, among others, which are involved in cell communication and signal transduction. Finally, low expression of KMT2D at the transcriptomic level, which mirror what happens when KMT2D is mutated and functionally inactive, confirmed its prognostic value.ConclusionIn the present work, we describe epigenetic modulating genes which are found to be mutated in breast cancer. We identify the histone methyltransferase KMT2D, which is mutated in 6% of triple negative tumors and linked with poor survival

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

10.1038/nn.2794Nature Neuroscience145562-570NANE

Observation of Ξb0→Ξc+Ds−\Xi_b^0 \rightarrow \Xi_c^+ D_s^- and Ξb−→Ξc0Ds−\Xi_b^- \rightarrow \Xi_c^0 D_s^- decays

International audienceThe $\Xi_b^0 \rightarrow \Xi_c^+ D_s^-$ and $\Xi_b^- \rightarrow \Xi_c^0 D_s^-$ decays are observed for the first time using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}=13\mathrm{TeV}$, corresponding to an integrated luminosity of $5.1\mathrm{fb}^{-1}$. The relative branching fractions times the beauty-baryon production cross-sections are measured to be \begin{align*} \mathcal{R}\left(\frac{\Xi_b^0}{\Lambda_b^0}\right) \equiv \frac{\sigma\left(\Xi_b^0\right)}{\sigma\left(\Lambda_b^0\right)} \times \frac{\mathcal{B}\left(\Xi_b^0 \rightarrow \Xi_c^+ D_s^-\right)}{\mathcal{B}\left(\Lambda_b^0 \rightarrow \Lambda_c^0 D_s^-\right)} =(15.8\pm1.1\pm0.6\pm7.7)\%, \mathcal{R}\left(\frac{\Xi_b^-}{\Lambda_b^0}\right) \equiv \frac{\sigma\left(\Xi_b^-\right)}{\sigma\left(\Lambda_b^0\right)} \times \frac{\mathcal{B}\left(\Xi_b^- \rightarrow \Xi_c^0 D_s^-\right)}{\mathcal{B}\left(\Lambda_b^0 \rightarrow \Lambda_c^0 D_s^-\right)} =(16.9\pm1.3\pm0.9\pm4.3)\%, \end{align*} where the first uncertainties are statistical, the second systematic, and the third due to the uncertainties on the branching fractions of relevant charm-baryon decays. The masses of $\Xi_b^0$ and $\Xi_b^-$ baryons are measured to be $m_{\Xi_b^0}=5791.12\pm0.60\pm0.45\pm0.24\mathrm{MeV}/c^2$ and $m_{\Xi_b^-}=5797.02\pm0.63\pm0.49\pm0.29\mathrm{MeV}/c^2$, where the uncertainties are statistical, systematic, and those due to charm-hadron masses, respectively

Observation of strangeness enhancement with charmed mesons in high-multiplicity pPbp\mathrm{Pb} collisions at sNN=8.16 \sqrt {s_{\mathrm{NN}}}=8.16\,TeV

The production of prompt $D^+_{s}$ and $D^+$ mesons is measured by the LHCb experiment in proton-lead ($p\mathrm{Pb}$) collisions in both the forward ($1.5 < y^*<4.0$) and backward ($-5.0 < y ^*<-2.5$) rapidity regions at a nucleon-nucleon center-of-mass energy of $\sqrt {s_{\mathrm{NN}}}=8.16\,$TeV. The nuclear modification factors of both $D^+_{s}$ and $D^+$ mesons are determined as a function of transverse momentum, $p_{\mathrm{T}}$, and rapidity. In addition, the $D^+_{s}$ to $D^+$ cross-section ratio is measured as a function of the charged particle multiplicity in the event. An enhanced $D^+_{s}$ to $D^+$ production in high-multiplicity events is observed for the whole measured $p_{\mathrm{T}}$ range, in particular at low $p_{\mathrm{T}}$ and backward rapidity, where the significance exceeds six standard deviations. This constitutes the first observation of strangeness enhancement in charm quark hadronization in high-multiplicity $p\mathrm{Pb}$ collisions. The results are also qualitatively consistent with the presence of quark coalescence as an additional charm quark hadronization mechanism in high-multiplicity proton-lead collisionsThe production of prompt $D^+_{s}$ and $D^+$ mesons is measured by the LHCb experiment in proton-lead ($p\mathrm{Pb}$) collisions in both the forward ($1.5<y^*<4.0$) and backward ($-5.0<y^*<-2.5$) rapidity regions at a nucleon-nucleon center-of-mass energy of $\sqrt {s_{\mathrm{NN}}}=8.16\,$TeV. The nuclear modification factors of both $D^+_{s}$ and $D^+$ mesons are determined as a function of transverse momentum, $p_{\mathrm{T}}$, and rapidity. In addition, the $D^+_{s}$ to $D^+$ cross-section ratio is measured as a function of the charged particle multiplicity in the event. An enhanced $D^+_{s}$ to $D^+$ production in high-multiplicity events is observed for the whole measured $p_{\mathrm{T}}$ range, in particular at low $p_{\mathrm{T}}$ and backward rapidity, where the significance exceeds six standard deviations. This constitutes the first observation of strangeness enhancement in charm quark hadronization in high-multiplicity $p\mathrm{Pb}$ collisions. The results are also qualitatively consistent with the presence of quark coalescence as an additional charm quark hadronization mechanism in high-multiplicity proton-lead collisions

Search for prompt production of pentaquarks in charm hadron final states

International audienceA search for hidden-charm pentaquark states decaying to a range of $\Sigma_{c}\bar{D}$ and $\Lambda_{c}\bar{D}$ final states, as well as doubly-charmed pentaquark states to $\Sigma_{c}D$ and $\Lambda_{c}^{+}D$, is made using samples of proton-proton collision data corresponding to an integrated luminosity of $5.7fb^{-1}$ recorded by the LHCb detector at $\sqrt{s} = 13Te\kern -0.1em V$. Since no significant signals are found, upper limits are set on the pentaquark yields relative to that of the $\Lambda_{c}^{+}$ baryon in the $\Lambda_{c}^{+}\to pK^{-}\pi^{+}$ decay mode. The known pentaquark states are also investigated, and their signal yields are found to be consistent with zero in all cases