Prolonged Unilateral Disuse Osteopenia 14 Years Post External Fixator Removal: A Case History and Critical Review

Disuse osteopenia is a complication of immobilisation, with reversal generally noted upon remobilisation. This case report focuses on a patient who was seen 18 years following a road traffic collision when multiple fractures were sustained. The patient had an external fixator fitted for a tibia and fibula fracture, which remained in situ for a period of 4 years. Following removal, the patient was mobilised but, still required a single crutch to aid walking. Fourteen years post removal of the fixator, the patient had a DXA scan which, demonstrated a T-score 2.5 SD lower on the affected hip. This places the patient at an increased risk of hip fracture on this side, which requires monitoring. There appear to be no current studies investigating prolonged disuse-osteopenia in patients following removal of long-term external fixators. Further research is required to quantify unilateral long-term effects to bone health and fracture risk in this population

Collateral-resistance to estrogen and HER-activated growth is associated with modified AKT, ERα and cell-cycle signaling in a breast cancer model

These studies were supported by grants from Cancer Research UK (C503/A5010 and C1938/A6769).Aim : A model of progressively endocrine-resistant breast cancer was investigated to identify changes that can occur in signaling pathways after endocrine manipulation. Methods : The MCF7 breast cancer model is sensitive to estrogens and anti-estrogens while variant lines previously derived from wild-type MCF7 are either relatively 17β-estradiol (E2)-insensitive (LCC1) or fully resistant to estrogen and anti-estrogens (LCC9). Results : In LCC1 and LCC9 cell lines, loss of estrogen sensitivity was accompanied by loss of growth response to transforming growth factor alpha (TGFα), heregulin-beta and pertuzumab. LCC1 and LCC9 cells had enhanced AKT phosphorylation relative to MCF7 which was reflected in downstream activation of phospho-mechanistic target of rapamycin (mTOR), phospho-S6, and phospho-estrogen receptor alpha Ser167 [ERα(Ser167)]. Both AKT2 and AKT3 were phosphorylated in the resistant cell lines, but siRNA knockdown suggested that all three AKT isoforms contributed to growth response. ERα(Ser118) phosphorylation was increased by E2 and TGFα in MCF7, by E2 only in LCC1, but by neither in LCC9 cells. Multiple alterations in E2-mediated cell cycle control were identified in the endocrine-resistant cell lines including increased expression of MYC, cyclin A1, cyclin D1, cyclin-dependent kinase 1 (CDK1), CDK2, and hyperphosphorylated retinoblastoma protein (ppRb), whereas p21 and p27 were reduced. Estrogen modulated expression of these regulators in MCF7 and LCC1 cells but not in LCC9 cells. Seliciclib inhibited CDK2 activation in MCF7 cells but not in resistant variants; in all lines, it reduced ppRb, increased p53 associated responses including p21, p53 up-regulated modulator of apoptosis (PUMA), and p53 apoptosis-inducing protein 1 (p53AIP1), inhibited growth, and produced G2/M block and apoptosis. Conclusions : Multiple changes occur with progression of endocrine resistance in this model with AKT activation contributing to E2 insensitivity and loss of ERα(Ser118) phosphorylation being associated with full resistance. Cell cycle regulation is modified in endocrine-resistant breast cancer cells, and seliciclib is effective in both endocrine-sensitive and resistant diseases.Publisher PDFPeer reviewe

Stochastically-modulated inter-pulse intervals to increase the efficiency of functional electrical stimulation cycling

Introduction: Functional electrical stimulation cycling has various health benefits, but the mechanical power output and efficiency are very low compared to volitional muscle activation. Stimulation with variable frequency showed significantly higher power output values in experiments with a knee dynamometer. The aim of the present work was to compare stochastic modulation of inter-pulse interval to constant inter-pulse interval stimulation during functional electrical stimulation cycling. Methods: Seventeen able-bodied subjects participated (n = 17). Quadriceps and hamstring muscle groups were stimulated with two activation patterns: P1-constant frequency, P2-stochastic inter-pulse interval. Power output was measured on functional electrical stimulation ergometer. Results: Overall, mean power output with the stochastically modulated pattern P2 was lower than with P1 (12.57 ± 3.74 W vs. 11.44 ± 3.81 W, P1 vs. P2, p = 0.022), but no significant differences during the first 30 s and the last 30 s were observed. Conclusions: This study showed that stimulation strategies that use randomized modulation of inter-pulse intervals can negatively affect power output generation during functional electrical stimulation cycling. To minimise voluntary contractions, power measurement and assessment should be focused on the periods where only the quadriceps are stimulated.ISSN:2055-668

ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling

ISG15 is an ubiquitin-like modifier that is associated with reduced survival rates in breast cancer patients. The mechanism by which ISG15 achieves this however remains elusive. We demonstrate that modification of Rab GDP-Dissociation Inhibitor Beta (GDI2) by ISG15 (ISGylation) alters endocytic recycling of the EGF receptor (EGFR) in non-interferon stimulated cells using CRISPR-knock out models for ISGylation. By regulating EGFR trafficking, ISGylation enhances EGFR recycling and sustains Akt-signalling. We further show that Akt signalling positively correlates with levels of ISG15 and its E2-ligase in basal breast cancer cohorts, confirming the link between ISGylation and Akt signalling in human tumours. Persistent and enhanced Akt activation explains the more aggressive tumour behaviour observed in human breast cancers. We show that ISGylation can act as a driver of tumour progression rather than merely being a bystander.</p

A lower to middle Eocene astrochronology for the Mentelle Basin (Australia) and its implications for the geologic time scale

The geologic time scale for the Cenozoic Era has been notably improved over the last decades by virtue of integrated stratigraphy, combining high-resolution astrochronologies, biostratigraphy and magnetostratigraphy with high-precision radioisotopic dates. However, the middle Eocene remains a weak link. The so-called “Eocene time scale gap” reflects the scarcity of suitable study sections with clear astronomically-forced variations in carbonate content, primarily because large parts of the oceans were starved of carbonate during the Eocene greenhouse. International Ocean Discovery Program (IODP) Expedition 369 cored a carbonate-rich sedimentary sequence of Eocene age in the Mentelle Basin (Site U1514, offshore southwest Australia). The sequence consists of nannofossil chalk and exhibits rhythmic clay content variability. Here, we show that IODP Site U1514 allows for the extraction of an astronomical signal and the construction of an Eocene astrochronology, using 3-cm resolution X-Ray fluorescence (XRF) core scans. The XRF-derived ratio between calcium and iron content (Ca/Fe) tracks the lithologic variability and serves as the basis for our U1514 astrochronology. We present a 16 million-year-long (40-56 Ma) nearly continuous history of Eocene sedimentation with variations paced by eccentricity and obliquity. We supplement the high-resolution XRF data with low-resolution bulk carbon and oxygen isotopes, recording the long-term cooling trend from the Paleocene-Eocene Thermal Maximum (PETM – ca. 56 Ma) into the middle Eocene (ca. 40 Ma). Our early Eocene astrochronology corroborates existing chronologies based on deep-sea sites and Italian land sections. For the middle Eocene, the sedimentological record at U1514 provides a single-site geochemical backbone and thus offers a further step towards a fully integrated Cenozoic geologic time scale at orbital resolution

The Time-Domain Spectroscopic Survey: Understanding the Optically Variable Sky with SEQUELS in SDSS-III

The Time-Domain Spectroscopic Survey (TDSS) is an SDSS-IV eBOSS subproject primarily aimed at obtaining identification spectra of ~220,000 optically-variable objects systematically selected from SDSS/Pan-STARRS1 multi-epoch imaging. We present a preview of the science enabled by TDSS, based on TDSS spectra taken over ~320 deg^2 of sky as part of the SEQUELS survey in SDSS-III, which is in part a pilot survey for eBOSS in SDSS-IV. Using the 15,746 TDSS-selected single-epoch spectra of photometrically variable objects in SEQUELS, we determine the demographics of our variability-selected sample, and investigate the unique spectral characteristics inherent in samples selected by variability. We show that variability-based selection of quasars complements color-based selection by selecting additional redder quasars, and mitigates redshift biases to produce a smooth quasar redshift distribution over a wide range of redshifts. The resulting quasar sample contains systematically higher fractions of blazars and broad absorption line quasars than from color-selected samples. Similarly, we show that M-dwarfs in the TDSS-selected stellar sample have systematically higher chromospheric active fractions than the underlying M-dwarf population, based on their H-alpha emission. TDSS also contains a large number of RR Lyrae and eclipsing binary stars with main-sequence colors, including a few composite-spectrum binaries. Finally, our visual inspection of TDSS spectra uncovers a significant number of peculiar spectra, and we highlight a few cases of these interesting objects. With a factor of ~15 more spectra, the main TDSS survey in SDSS-IV will leverage the lessons learned from these early results for a variety of time-domain science applications.Comment: 17 pages, 14 figures, submitted to Ap