Loss of the multifunctional RNA-binding protein RBM47 as a source of selectable metastatic traits in breast cancer.

The mechanisms through which cancer cells lock in altered transcriptional programs in support of metastasis remain largely unknown. Through integrative analysis of clinical breast cancer gene expression datasets, cell line models of breast cancer progression, and mutation data from cancer genome resequencing studies, we identified RNA binding motif protein 47 (RBM47) as a suppressor of breast cancer progression and metastasis. RBM47 inhibited breast cancer re-initiation and growth in experimental models. Transcriptome-wide HITS-CLIP analysis revealed widespread RBM47 binding to mRNAs, most prominently in introns and 3'UTRs. RBM47 altered splicing and abundance of a subset of its target mRNAs. Some of the mRNAs stabilized by RBM47, as exemplified by dickkopf WNT signaling pathway inhibitor 1, inhibit tumor progression downstream of RBM47. Our work identifies RBM47 as an RNA-binding protein that can suppress breast cancer progression and demonstrates how the inactivation of a broadly targeted RNA chaperone enables selection of a pro-metastatic state

Can Long-Term Regular Practice of Physical Exercises Including Taichi Improve Finger Tapping of Patients Presenting With Mild Cognitive Impairment?

Background: Mild cognitive impairment (MCI) is a brain disease with both anatomical and functional alterations. There is clear evidence that individuals that are diagnosed with MCI have a high risk to develop dementia in the next 2–5 years compared to an age-matched population with a non-MCI diagnosis. The present study aimed to investigate whether the finger tapping frequency of patients with MCI was different from that of healthy individuals without MCI, and whether Tai Chi, a traditional Chinese movement discipline, could improve the finger tapping frequency of MCI patients.Methods: The study population consisted of subjects of ≥50 years of age. Group one included 40 subjects without exercise habits from communities of Yangpu District in Shanghai, and group two included 60 subjects from a Tai Chi class in Shanghai Elderly University of Huangpu District. The Montreal Cognitive Assessment (MoCA) and a finger tapping test were conducted to assess the finger tapping frequency of all subjects.Results: The MoCA score of MCI subjects was significantly lower compared to subjects without MCI (P < 0.01), and was not influenced by age, weight, or height. The finger tapping frequency of MCI subjects’ left hands was significantly lower compared to that of healthy subjects without MCI (P < 0.01), and a similar trend was observed for the subjects’ right hand. The MoCA score of MCI subjects in the Tai Chi class was significantly lower than that of healthy subjects without MCI (P < 0.01), which was not influenced by age, weight or height. The finger tapping frequency of MCI subjects’ right hands was lower compared to that of healthy subjects in the Tai Chi class without MCI (P < 0.05), but no significant difference regarding the finger tapping frequency of the left hand was observed.Conclusion: These findings suggested that finger tapping frequency of MCI subjects was significantly lower compared to normal subjects without MCI, and long-term Tai Chi exercise could reduce this significant difference. Moreover, there was no significant difference between groups for the subjects’ non-dominant (left) hand

JIEYUANSHEN DECOCTION EXERTS ANTIDEPRESSANT EFFECTS ON DEPRESSIVE RAT MODEL VIA REGULATING HPA AXIS AND THE LEVEL OF AMINO ACIDS NEUROTRANSMITTER

Background: Jieyuanshen decoction (JYAS-D) - a traditional Chinese medicine was invented by Professor Nie based on classic formulas, chaihu jia longgu muli decoction has been proved as having favorable curative effects on depression in clinical practices. The aim of this study was to investigate the antidepressant effects and its molecular mechanism of JYAS-D. Materials and Methods: The model of depression was established by Chronic Unpredictable Stress. Different doses (8.2 g/kg, 16.3 g/kg, 32.7 g/kg) of JYAS-D was orally administered; Fluoxetine was orally administered with 10mg/kg. All treatments lasted for 28 days. Sucrose preference and open-field tests were adopted to observe the behavior of rats. OPA (ortho-phthalaldehyde) derivatization method was used to detect the contents of amino acid neurotransmitter. RIA (Radiation immunity analysis) method was used to measure the serum concentrations of CORT (Corticosterone), ACTH (Adrenocorticotropic hormone) and CRH (Corticotropin-releasing hormone). ELISA (Enzyme linked immunosorbent assay) method was adopted to examine the contents of Glucocorticoid receptor (GR) and Mineralocorticoid receptor (MR) in hippocampus. Results: Compared with the model group, sucrose preference was increased in all treatment groups. The concentration of serum CORT was reduced in the middle dose of JYAS-D and control groups; the concentration of serum ACTH was reduced in the low and high-dose of JYAS-D; the concentration of serum CRH was reduced in the middle and high-dose of JYAS-D. The content of hippocampus GR was increased in the middle and high-dose of JYAS-D; the content of hippocampus Glu (Glutamic acid) was reduced among the low, middle and high-dose of JYAS-D and fluoxetine group, the ratio of Glu/γ-GABA (γ-aminobutyric acid was reduced in the low and high-dose of JYAS-D. Conclusion: JYAS-D had a significant antidepressant-like effect on rat model through regulating serum concentration of CORT, ACTH and CRH, increasing the content of hippocampus GR and regulating the equilibrium of amino acids neurotransmitter

A modified ‘skeleton/skin’ strategy for designing CoNiP nanosheets arrayed on graphene foam for on/off switching of NaBH4_{4} hydrolysis

CoNiP nanosheet array catalysts were successfully prepared on three-dimensional (3D) graphene foam using hydrothermal synthesis. These catalysts were prepared using 3D Ni–graphene foam (Ni/GF), comprising nickel foam as the ‘skeleton’ and reduced graphene oxide as the ‘skin’. This unique continuous modified ‘skeleton/skin’ structure ensure that the catalysts had a large surface area, excellent conductivity, and sufficient surface functional groups, which promoted in situ CoNiP growth, while also optimizing the hydrolysis of sodium borohydride. The nanosheet arrays were fully characterized and showed excellent catalytic performance, as supported by density functional theory calculations. The hydrogen generation rate and activation energy are 6681.34 mL min$_{−1}$ g$_{−1}$ and 31.2 kJ mol$_{−1}$, respectively, outperforming most reported cobalt-based catalysts and other precious metal catalysts. Furthermore, the stability of mockstrawberry-like CoNiP catalyst was investigated, with 74.9% of the initial hydrogen generation rate remaining after 15 cycles. The catalytic properties, durability, and stability of the catalyst were better than those of other catalysts reported previously

Prognostic Value of Inflammatory Mediators in 1-Year Outcome of Acute Ischemic Stroke with Middle Cerebral Artery Stenosis

Background and Purpose. Inflammation exists in inception, progression, and reperfusion of acute ischemic stroke. Insightful understanding of correlation in inflammatory mediators and stroke severity with intracranial artery stenosis may improve rational stroke therapy. Methods. We prospectively recruited 977 patients with acute noncardioembolic ischemic stroke with MCA stenosis by MRA as none to mild (<50%), moderate (50–69%), severe (70–99%), or occlusive (100%). The peripheral levels of WBC, homocysteine (HCY), and high sensitivity C-reactive protein (hs-CRP) were recorded. All patients were assessed of 1-year outcome by mRS as favorable (0–2) or poor (3–6). Results. The levels of WBC, HCY, and hs-CRP had no significant differences in patients with categorized MCA stenosis (all P > 0.05). Higher levels of WBC, HCY, and hs-CRP were found in patients with 1-year poor outcome (all P < 0.05), but only hs-CRP is an independent predictor (OR 1.06, 95% CI 1.027–1.093, P = 0.0003). The combination of any two of increased hs-CRP (>3 mg/L), WBC (>6.91 × 10(9)/L), and HCY (>15 μmol/L) had higher power in predicting 1-year poor outcome than the single elevated mediator. Conclusions. Elevated hs-CRP independently predicts 1-year poor outcome in acute stroke. The combination of increased hs-CRP, WBC, or HCY had a stronger predictive value in poor outcome than individual elevated mediator

Ferroptosis in health and disease

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.Fil: Berndt, Carsten. Heinrich-Heine University; AlemaniaFil: Alborzinia, Hamed. Heidelberg Institute for Stem Cell Technology and Experimental Medicine; AlemaniaFil: Amen, Vera Skafar. University of Würzburg; AlemaniaFil: Ayton, Scott. University of Melbourne; AustraliaFil: Barayeu, Uladzimir. Heidelberg University; Alemania. German Cancer Research Center; Alemania. Tohoku University Graduate School of Medicine; JapónFil: Bartelt, Alexander. Ludwig Maximilians Universitat; AlemaniaFil: Bayir, Hülya. Columbia University; Estados UnidosFil: Bebber, Christina M.. University of Cologne; AlemaniaFil: Birsoy, Kivanc. The Rockefeller University; Estados UnidosFil: Böttcher, Jan P.. Universitat Technical Zu Munich; AlemaniaFil: Brabletz, Simone. Friedrich-Alexander University of Erlangen-Nürnberg; AlemaniaFil: Brabletz, Thomas. Friedrich-Alexander University of Erlangen-Nürnberg; AlemaniaFil: Brown, Ashley R.. Columbia University; Estados UnidosFil: Brunner Bernhardt, Mauricio Andrés. Goethe Universitat Frankfurt; AlemaniaFil: Bulli, Giorgia. Ludwig Maximilians Universitat; AlemaniaFil: Bruneau, Alix. Goethe Universitat Frankfurt; AlemaniaFil: Chen, Quan. Nankai University; ChinaFil: DeNicola, Gina M.. Moffitt Cancer Center; Estados UnidosFil: Dick, Tobias P.. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Distefano, Ayelen Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Biológicas. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; ArgentinaFil: Dixon, Scott J.. University of Stanford; Estados UnidosFil: Engler, Jan B.. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Pagnussat, Gabriela Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Biológicas. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; ArgentinaFil: Wilhelm, Christoph. Universitat Bonn; AlemaniaFil: Wölk, Michele. University Hospital Carl Gustav Carus; AlemaniaFil: Wu, Katherine. University of New York; Estados UnidosFil: Yang, Xin. Columbia University; Estados UnidosFil: Yu, Fan. Nankai University; ChinaFil: Zou, Yilong. Westlake University; ChinaFil: Conrad, Marcus. Helmholtz Center Munich; Alemani

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may b

Therapy-induced tumour secretomes promote resistance and tumour progression.

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.DG is supported by the EU-FP7-SUPPRESSTEM project. SN-Z is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is a Wellcome Beit Fellow. For more information, please visit the publisher's website