pinecone/core-2020-05-10-deduplication huggingface dataset:
Rho signaling research: history, current status and future directions

One of the main research areas in biology from the mid‐1980s through the 1990s was the elucidation of signaling pathways governing cell responses. These studies brought, among other molecules, the small GTPase Rho to the epicenter. Rho signaling research has since expanded to all areas of biology and medicine. Here, we describe how Rho emerged as a key molecule governing cell morphogenesis and movement, how it was linked to actin reorganization, and how the study of Rho signaling has expanded from cultured cells to whole biological systems. We then give an overview of the current research status of Rho signaling in development, brain, cardiovascular system, immunity and cancer, and discuss the future directions of Rho signaling research, with emphasis on one Rho effector, ROCK*. *The Rho GTPase family. Rho family GTPases have now expanded to contain 20 members. Amino acid sequences of 20 Rho GTPases found in human were aligned and the phylogenetic tree was generated by ClustalW2 software (EMBL‐EBI) based on NJ algorithm. The subfamilies of the Rho GTPases are highlighted by the circle and labeled on the right side. Rho cited in this review refers to the original members of Rho subfamily, RhoA, RhoB and RhoC, that are C3 substrates, and, unless specified, not to other members of the Rho subfamily such as Rac, Cdc42, and Rnd
Dependency Relationships within the Fission Yeast Polarity Network

The ability to regulate polarised cell growth is crucial to maintain the viability\ud
of cells. Growth is modulated to facilitate essential cell functions and respond\ud
to the external environment. Failure to do so can lead to numerous\ud
developmental and disease states including cancer. We have undertaken a\ud
detailed analysis of the regulatory interplay between molecules involved in the\ud
regulation and maintenance of polarised cell growth within fission yeast.\ud
Internally controlled live cell imaging was used to examine interactions\ud
between 10 key polarity proteins. Analysis reveals: interplay between the\ud
microtubule and actin cytoskeletons; multiple novel dependency pathways\ud
and feedback networks between groups of proteins. This study provides\ud
important insights into the conserved regulation of polarised cell growth within\ud
eukaryotes
Mirroring the multifaceted role of RNA and its partners in gene expression

In the early years of Molecular Biology, the role of RNA was largely considered to be the transmission of the genetic information stored in the DNA into polypeptides. Three major types of RNA engaged in these processes were known: messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA). However, within the last half century our knowledge about RNA classes, abundance and diversity of functions has increased dramatically. The discovery that the ribosome is essentially a ribozyme 1, 2 especially brought the central role of RNA for cellular life into the spotlight. The turn of the millennium was also the time of another far‐reaching realization, that of the pervasiveness of small RNA‐dependent regulation of gene expression 3. Within the decade that followed, RNAs were found in essentially all regulatory layers of gene expression, from the epigenetic layer at the top of the gene expression cascade 4, 5 to the most distal translation layer 6. Much of this rapid transition was enabled by sequencing technologies that were developed in the wake of the human genome project. Coupled with ingenious protocols for isolating RNAs of various sizes and molecular properties (e.g. 7) and computational methods to annotate various classes of small RNAs 8, the set of regulatory RNAs has expanded and diversified rapidly. We now know that < 2% of the human genome contains protein‐coding genes, whereas 80% is transcribed into noncoding RNAs (ncRNAs), classified based on their size into small and long noncoding RNAs (lncRNAs). Small ncRNAs include the highly investigated microRNAs (miRNAs) that were found to be increased in various cancer types where they exhibit pro‐oncogenic activity 9. LncRNAs are long (> 200 nucleotides) transcripts that functionally contribute to the control of cell differentiation and maintenance of cell identity. Notably, as most (~ 90%) of disease‐associated single nucleotide polymorphisms are located in gene regulatory or intergenic regions, long‐intergenic ncRNAs (lincRNAs) in particular may have pivotal impact for the development of personalized medicine therapies in the future10. Whether small or long, ncRNAs often bear domains enabling direct and specific interactions with other RNAs, forming RNA‐RNA hybrids that participate in the control of gene expression and biogenesis of RNAs 11
Synergistic activity of everolimus and 5-aza-2'-deoxycytidine in medullary thyroid carcinoma cell lines

Medullary thyroid cancer (MTC) is a tumor highly resistant to chemo- and radiotherapy. Drug resistance can be induced by epigenetic changes such as aberrant DNA methylation. To overcome drug resistance, we explored a promising approach based on the use of 5-aza-2'-deoxycytidine (AZA), a demethylating agent, in combination with the mTOR inhibitor everolimus in MTC cells (MZ-CRC-1 and TT). This combined treatment showed a strong synergistic antiproliferative activity through the induction of apoptosis. The effect of everolimus and/or AZA on genome-wide expression profiling was evaluated by Illumina BeadChip in MZ-CRC-1 cells. An innovative bioinformatic pipeline identified four potential molecular pathways implicated in the synergy between AZA and everolimus: PI3K-Akt signaling, the neurotrophin pathway, ECM/receptor interaction, and focal adhesion. Among these, the neurotrophin signaling pathway was most directly involved in apoptosis, through the overexpression of NGFR and Bax genes. The increased expression of genes involved in the NGFR-MAPK10-TP53-Bax/Bcl2 pathway during incubation with AZA plus everolimus was validated by western blotting in MZ-CRC-1 cells. Interestingly, addition of a neutralizing anti-NGFR antibody inhibited the synergistic cytotoxic activity between AZA and everolimus. These results open a new therapeutic scenario for MTC and potentially other neuroendocrine tumors, where therapy with mTOR inhibitors is currently approved
Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells

The reciprocal communication between cancer cells and their microenvironment is critical in cancer progression. Although involvement of cancer-associated fibroblasts (CAF) in cancer progression is long established, the molecular mechanisms leading to differentiation of CAFs from normal fibroblasts are poorly understood. Here, we report that kallikrein-related peptidase-4 (KLK4) promotes CAF differentiation. KLK4 is highly expressed in prostate epithelial cells of premalignant (prostatic intraepithelial neoplasia) and malignant lesions compared to normal prostate epithelia, especially at the peristromal interface. KLK4 induced CAF-like features in the prostate-derived WPMY1 normal stromal cell line, including increased expression of alpha-smooth muscle actin, ESR1 and SFRP1. KLK4 activated protease-activated receptor-1 in WPMY1 cells increasing expression of several factors (FGF1, TAGLN, LOX, IL8, VEGFA) involved in prostate cancer progression. In addition, KLK4 induced WPMY1 cell proliferation and secretome changes, which in turn stimulated HUVEC cell proliferation that could be blocked by a VEGFA antibody. Importantly, the genes dysregulated by KLK4 treatment of WPMY1 cells were also differentially expressed between patient-derived CAFs compared to matched nonmalignant fibroblasts and were further increased by KLK4 treatment. Taken together, we propose that epithelial-derived KLK4 promotes tumour progression by actively promoting CAF differentiation in the prostate stromal microenvironment
EMT and MET: necessary or permissive for metastasis?

Epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. These phenotypic transitions between states are not binary. Instead, carcinoma cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). While epithelial/mesenchymal plasticity has been observed preclinically and clinically, whether any of these phenotypic transitions are indispensable for metastatic outgrowth remains an unanswered question. Here, we focus on epithelial/mesenchymal plasticity in metastatic dissemination and propose alternative mechanisms for successful dissemination and metastases beyond the traditional EMT/MET view. We highlight multiple hypotheses that can help reconcile conflicting observations, and outline the next set of key questions that can offer valuable insights into mechanisms of metastasis in multiple tumor models
Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

Phenotypic plasticity, the ability of cells to reversibly alter their phenotypes in response to signals, presents a significant clinical challenge to treating solid tumors. Tumor cells utilize phenotypic plasticity to evade therapies, metastasize, and colonize distant organs. As a result, phenotypic plasticity can accelerate tumor progression. A well-studied example of phenotypic plasticity is the bidirectional conversions among epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) phenotype(s). These conversions can alter a repertoire of cellular traits associated with multiple hallmarks of cancer, such as metabolism, immune evasion, invasion, and metastasis. To tackle the complexity and heterogeneity of these transitions, mathematical models have been developed that seek to capture the experimentally verified molecular mechanisms and act as ‘hypothesis-generating machines’. Here, we discuss how these quantitative mathematical models have helped us explain existing experimental data, guided further experiments, and provided an improved conceptual framework for understanding how multiple intracellular and extracellular signals can drive E/M plasticity at both the single-cell and population levels. We also discuss the implications of this plasticity in driving multiple aggressive facets of tumor progression
Analysis of mutant allele fractions in driver genes in colorectal cancer – biological and clinical insights

Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (s, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of s of driver alterations in unpaired primary and metastatic colorectal cancer () at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 samples, 622 had detailed annotation on overall survival in the metastatic setting (met) and 89 received targeted agents matched to ( inhibitors), ( inhibitors), or 3 mutations (3K pathway inhibitors). s of each variant were normalized for tumor purity in the sample (adjs). We found lower adjs for 600E and 3 than for , , and non‐V600 variants. 53 and 600E adjs were higher in metastases as compared to primary tumors, and high adjs were found in metastases of patients with wild‐type primary tumors previously exposed to antibodies. Patients with ‐ or 600E ‐mutated tumors, irrespective of adjs, had worse met. There was no significant association between adjs and time to progression on targeted therapies matched to , , or 3 mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower 600E and 3 adjs in subsets of primary tumors indicate subclonality of these driver genes. Differences in adjs between metastases and primary tumors suggest that approved therapies may result in selection of 600E ‐ and ‐resistant clones and an increase in genomic heterogeneity with acquired 53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting
TRPM4 regulates Akt/GSK3-β activity and enhances β-catenin signaling and cell proliferation in prostate cancer cells

Indexación: Scopus.Increased expression of the TRPM4 channel has been reported to be associated with the progression of prostate cancer. However, the molecular mechanism underlying its effect remains unknown. This work found that decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells. This effect was associated with a decrease in total β-catenin protein levels and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional activity. Moreover, TRPM4 silencing increases the Ser33/Ser37/Thr41 β-catenin phosphorylated population and reduces the phosphorylation of GSK-3β at Ser9, suggesting an increase in β-catenin degradation as the underlying mechanism. Conversely, TRPM4 overexpression in LNCaP cells increases the Ser9 inhibitory phosphorylation of GSK-3β and the total levels of β-catenin and its nonphosphorylated form. Finally, PC3 cells with reduced levels of TRPM4 showed a decrease in basal and stimulated phosphoactivation of Akt1, which is likely responsible for the decrease in GSK-3β activity in these cells. Our results also suggest that the effect of TRPM4 on Akt1 is probably mediated by an alteration in the calcium/calmodulin-EGFR axis, linking TRPM4 activity with the observed effects in β-catenin-related signaling pathways. These results suggest a role for TRPM4 channels in β-catenin oncogene signaling and underlying mechanisms, highlighting this ion channel as a new potential target for future therapies in prostate cancer.https://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1878-0261.1210
Estrogen receptor mutations and splice variants determined in liquid biopsies from metastatic breast cancer patients

Mutations and splice variants in the estrogen receptor (ER) gene, ESR1, may yield endocrine resistance in metastatic breast cancer (MBC) patients. These putative endocrine resistance markers are likely to emerge during treatment, and therefore, its detection in liquid biopsies, such as circulating tumor cells (CTCs) and cell-free DNA (cfDNA), is of great interest. This research aimed to determine whether ESR1 mutations and splice variants occur more frequently in CTCs of MBC patients progressing on endocrine treatment. In addition, the presence of ESR1 mutations was evaluated in matched cfDNA and compared to CTCs. CellSearch-enriched CTC fractions (≥5/7.5 mL) of two MBC cohorts were evaluated, namely (a) patients starting first-line endocrine therapy (n = 43, baseline cohort) and (b) patients progressing on any line of endocrine therapy (n = 40, progressing cohort). ESR1 hotspot mutations (D538G and Y537S/N/C) were evaluated in CTC-enriched DNA using digital PCR and compared with matched cfDNA (n = 18 baseline cohort; n = 26 progressing cohort). Expression of ESR1 full-length and 4 of its splice variants ((increment)5, (increment)7, 36 kDa, and 46 kDa) was evaluated in CTC-enriched mRNA. It was observed that in the CTCs, the ESR1 mutations were not enriched in the progressing cohort (8%), when compared with the baseline cohort (5%) (P = 0.66). In the cfDNA, however, ESR1 mutations were more prevalent in the progressing cohort (42%) than in the baseline cohort (11%) (P = 0.04). Three of the same mutations were observed in both CTCs and cfDNA, 1 mutation in CTCs only, and 11 in cfDNA only. Only the (increment)5 ESR1 splice variant was CTC-specific expressed, but was not enriched in the progressing cohort. In conclusion, sensitivity for detecting ESR1 mutations in CTC-enriched fractions was lower than for cfDNA. ESR1 mutations detected in cfDNA, rarely present at the start of first-line endocrine therapy, were enriched at progression, strongly suggesting a role in conferring endocrine resistance in MBC
Glacier velocities and dynamic ice discharge from the Queen Elizabeth Islands, Nunavut, Canada

Recent studies indicate an increase in glacier mass loss from the Canadian Arctic Archipelago as a result of warmer summer air temperatures. However, no complete assessment of dynamic ice discharge from this region exists. We present the first complete surface velocity mapping of all ice masses in the Queen Elizabeth Islands and show that these ice masses discharged ~2.6 ± 0.8 Gt a−1 of ice to the oceans in winter 2012. Approximately 50% of the dynamic discharge was channeled through non surge-type Trinity and Wykeham Glaciers alone. Dynamic discharge of the surge-type Mittie Glacier varied from 0.90 ± 0.09 Gt a−1 during its 2003 surge to 0.02 ± 0.02 Gt a−1 during quiescence in 2012, highlighting the importance of surge-type glaciers for interannual variability in regional mass loss. Queen Elizabeth Islands glaciers currently account for ~7.5% of reported dynamic discharge from Arctic ice masses outside Greenland.We thank NSERC, Canada Foundation for Innovation, Ontario Research Fund, ArcticNet,
Ontario Graduate Scholarship, University of Ottawa and the NSERC Canada Graduate Scholarship for funding. RADARSAT-2 data were provided by MacDonald, Dettwiler and
Associates under the RADARSAT-2 Government Data Allocation administrated by the Canadian Space Agency. Support to DB is provided through the Climate Change Geosciences Program, Earth Sciences Sector, Natural Resources Canada (ESS Contribution #20130293). We also acknowledge support from U.K NERC for grants R3/12469 and NE/K004999 to JAD.This is the accepted version of an article published in Geophysical Research Letters. An edited version of this paper was published by AGU. Copyright (2014) American Geophysical Union. The final version is available at http://onlinelibrary.wiley.com/doi/10.1002/2013GL058558/abstract;jsessionid=6A3AD907C4383DA5D4E20C4924D6EC18.f02t02
Wave activity at ionospheric heights above the Andes Mountains detected from FORMOSAT-3/COSMIC GPS radio occultation data

An estimation of the ionospheric wave activity, derived from 4 years of FORMOSAT-3/ COSMIC GPS (Taiwan's Formosa Satellite Mission 3/Constellation Observing System for Meteorology—Global Positioning System) radio occultation electron density data, is presented. A systematic enhancement at the eastern side of the Andes range with respect to the western side is observed. A fitting method to remove the wavelike component from each measured profile and estimate the wave activity is described. The differential effect introduced by the action of orography on the generation, to the eastern side of the Andes, of mountain waves, deep convection waves, or even secondary waves aloft after momentum deposition in the middle atmosphere, is suggested.Fil: de la Torre, Alejandro. Universidad Austral. Facultad de Ingeniería; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alexander, Pedro Manfredo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Llamedo Soria, Pablo Martin. Universidad Austral. Facultad de Ingeniería; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hierro, Rodrigo Federico. Universidad Austral. Facultad de Ingeniería; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Nava, B.. The Abdus Salam; ItaliaFil: Radicella, S.. The Abdus Salam; ItaliaFil: Schmidt, T.. Helmholtz Centre Potsdam; AlemaniaFil: Wickert, J.. Helmholtz Centre Potsdam; Alemani
On the relationship between lightning peak current\ud
and early VLF perturbations

Lightning strokes are known to cause direct heating and ionization of the D region, some of which are detected via scattering of VLF transmitter signals and are known as Early VLF events. The disturbed ionosphere typically recovers in many tens of seconds. New experimental evidence is presented demonstrating that the scattering pattern and onset amplitude of Early VLF events are strongly related to both the magnitude and polarity of causative lightning peak current. Observations of Early VLF events at nine Stanford VLF receiver sites across the continental United States are combined with lightning geolocation data from the National Lightning Detection Network (NLDN). During January and March 2011, NLDN recorded 7769 intense lightning discharges with high peak currents (>100 kA) generating 1250 detected Early VLF events. We show that the size of the scattered field due to the ionospheric disturbance increases with the peak current intensity of the causative lightning discharge. The most intense peak currents of >+200 and <−250 kA disturb VLF transmitter signals as far as ∼400 km away from the lightning stroke. Early VLF event detection probability also increases rapidly with peak current intensity. On the other hand, the observed VLF amplitude change is not significantly dependent on the peak current intensity. Stroke polarity is also important, with positive strokes being ∼5 times more likely to generate Early VLF disturbances than negative strokes of the same intensity. Intense positive cloud-to-ground lightning discharges, especially when occurring over the sea, are also more likely to produce Early VLF events with long recovery (many minutes)
Low - mid latitude D region ionospheric perturbations associated with 22 July 2009 total solar eclipse: wave -like signatures inferred from VLF observations

We present first report on the periodic wave-like signatures (WLS) in the D region ionosphere during\ud
22 July 2009 total solar eclipse using JJI, Japan, very low frequency (VLF) navigational transmitter signal (22.2 kHz) observations at stations, Allahabad, Varanasi and Nainital in Indian Sector, Busan in Korea, and Suva in Fiji. The signal amplitude increased on 22 July by about 6 and 7 dB at Allahabad and Varanasi and decreased by about 2.7, 3.5, and 0.5 dB at Nainital, Busan, and Suva, respectively, as compared to 24 July 2009 (normal day). The increase/decrease in the amplitude can be understood in terms of modal interference at the sites of modes\ud
converted at the discontinuity created by the eclipse intercepting the different transmitter-receiver great\ud
circle paths. The wavelet analysis shows the presence of WLS of period ~16–40 min at stations under total eclipse\ud
and of period ~30–80 min at stations under partial eclipse (~85–54% totality) with delay times between ~50\ud
and 100 min at different stations. The intensity of WLS was maximum for paths in the partially eclipsed region\ud
and minimum in the fully eclipsed region. The features of WLS on eclipse day seem almost similar to WLS observed in the nighttime of normal days (e.g., 24 July 2009). The WLS could be generated by sudden cutoff of the photo-ionization creating nighttime like conditions in the D region ionosphere and solar eclipse induced gravity waves coming to ionosphere from below and above. The present observations shed additional light on the current understanding of gravity waves induced D region ionospheric perturbations