Separation of breast cancer and organ microenvironment transcriptomes in metastases

Background: The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis. Methods: In these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability. Results: The experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids. Conclusions: These studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression

Towards a unified theory of Sobolev inequalities

We discuss our work on pointwise inequalities for the gradient which are connected with the isoperimetric profile associated to a given geometry. We show how they can be used to unify certain aspects of the theory of Sobolev inequalities. In particular, we discuss our recent papers on fractional order inequalities, Coulhon type inequalities, transference and dimensionless inequalities and our forthcoming work on sharp higher order Sobolev inequalities that can be obtained by iteration.Comment: 39 pages, made some changes to section 1

Star cluster formation and star formation: the role of environment and star-formation efficiencies

“The original publication is available at www.springerlink.com”. Copyright Springer. DOI: 10.1007/s10509-009-0088-5By analyzing global starburst properties in various kinds of starburst and post-starburst galaxies and relating them to the properties of the star cluster populations they form, I explore the conditions for the formation of massive, compact, long-lived star clusters. The aim is to determine whether the relative amount of star formation that goes into star cluster formation as opposed to field star formation, and into the formation of massive long-lived clusters in particular, is universal or scales with star-formation rate, burst strength, star-formation efficiency, galaxy or gas mass, and whether or not there are special conditions or some threshold for the formation of star clusters that merit to be called globular clusters a few billion years later.Peer reviewe

Clinical implications of serum neurofilament in newly diagnosed MS patients: a longitudinal multicentre cohort study

BACKGROUND: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients. METHODS: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up. FINDINGS: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels. INTERPRETATION: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions

Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German National early MS cohort (KKNMS)

BACKGROUND: Cognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors predicting CI and progression after initial diagnosis. METHODS: Neuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes. RESULTS: At baseline, 22% of patients had CI (impairment in ≥2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year. CONCLUSIONS: Identification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction

The SPECTRA Collaboration OMERACT Special Interest Group: Current Research and Future Directions

Objective High-resolution peripheral quantitative computed tomography (HR-pQCT) has the potential to improve radiographic progression determination in clinical trials and longitudinal observational studies. The goal of this work was to describe the current state of research presented at Outcome Measures in Rheumatology (OMERACT) 2016 and ensuing future directions outlined during discussion among attendees. Methods At OMERACT 2016, SPECTRA (Study grouP for xtrEme-Computed Tomography in Rheumatoid Arthritis) introduced efforts to (1) validate the HR-pQCT according to OMERACT guidelines, focusing on rheumatoid arthritis (RA), and (2) find alternatives for automated joint space width (JSW) analysis. The Special Interest Group (SIG) was presented to patient research partners, physicians/researchers, and SIG leaders followed by a 40-min discussion on future directions. Results A consensus definition for RA erosion using HR-pQCT was demonstrated through a systematic literature review and a Delphi exercise. Histopathology and perfusion studies were presented that analyzed the true characteristics of cortical breaks in HR-pQCT images, and to provide criterion validity. Results indicate that readers were able to discriminate between erosion and small vascular channels. Moderate reliability (ICC 0.206–0.871) of direct erosion size measures was shown, which improved (> 0.9) only when experienced readers were considered. Quantification of erosion size was presented for scoring, direct measurement, and volumetric approaches, as well as a reliability exercise for direct measurement. Three methods for JSW measurement were compared, all indicating excellent reproducibility with differences at the extremes (i.e., near-zero and joint edge thickness). Conclusion Initial reports on HR-pQCT are promising; however, to consider its use in clinical trials and longitudinal observational studies, it is imperative to assess the responsiveness of erosion measurement quantification

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The mechanism of inhibition by fluoride of mitochondrial fatty acid oxidation

The following evidence is presented in favour of the old hypothesis that F− inhibition of fatty acid oxidation in intact, coupled rat-liver mitochondria is due to an accumulation of pyrophosphate in the mitochondrial matrix: 1. 1.Addition of fatty acid to mitochondria oxidizing malate in the presence of F− initially causes an increased rate of O2 uptake, followed by a gradual decrease, indicating the accumulation of an inhibitor as a result of fatty acid oxidation. 2. 2. This inhibition is only found when the fatty acid substrate is activated in the mitochondrial matrix. 3. 3. The matrix acyl-CoA synthetase (acid:CoA ligase (AMP), EC 6.2.1.3) is strongly inhibited by pyrophosphate. 4. 4. Mitochondrial pyrophosphatase (pyrophosphate phosphohydrolase, EC 3.6.1.1) is inhibited by F− and is localized mainly in the matrix. 5. 5. The mitochondrial inner membrane is impermeable to pyrophosphate. 6. 6. Pyrophosphate accumulates in mitochondria oxidizing fatty acid in the presence of fluoride. Oxidation of fatty acids by uncoupled mitochondria in the absence of inorganic phosphate also leads to pyrophosphate accumulation when F− is added, showing that under these conditions too, an ATP-dependent acyl-CoA synthetase is active

Glycogen metabolism in Schistosoma mansoni worms after their isolation from the host

Adult Schistosoma mansoni worms rapidly degrade their endogenous glycogen stores immediately after isolation from the host. In NCTC 109 or in a diphasic culture medium the glycogen levels slowly recovered again after the initial decrease. The rapid degradation of glycogen could be prevented, even in a simple salt medium, if 100 mM glucose and 1% bovine serum albumin were present. Incubations with 14C-labelled glucose under different conditions revealed that the degradation of glycogen was induced by the limited catabolism of external glucose. Conditions are described which induce glycogen degradation or resynthesis by S. mansoni. The physiological function of the glycogen stores is probably to provide substrate during periods of insufficient supply of external glucose. It is speculated that such periods occur when the worm pair moves into the small mesenteric veins of the host. This hypothesis explains the remarkable wandering behaviour of the parasite in the mesenteric veins, since the schistosomes would have return to larger vessels when their endogenous glycogen stores are exhausted