Cyclin G1 regulates the outcome of taxane-induced mitotic checkpoint arrest

Anti-mitotic chemotherapeutic agents such as taxanes activate the spindle assembly checkpoint (SAC) to arrest anaphase onset, but taxane-exposed cells eventually undergo slippage to exit mitosis. The therapeutic efficacy of taxanes depends on whether slippage after SAC arrest culminates in continued cell survival, or in death by apoptosis. However, the mechanisms that determine these outcomes remain unclear. Here, we identify a novel role for cyclin G1 (CCNG1), an atypical cyclin. Increased CCNG1 expression accompanies paclitaxel-induced, SAC-mediated mitotic arrest, independent of p53 integrity or signaling through the SAC component, BUBR1. CCNG1 overexpression promotes cell survival after paclitaxel exposure. Conversely, CCNG1 depletion by RNA interference delays slippage and enhances paclitaxel-induced apoptosis. Consistent with these observations, CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds. Collectively, our findings implicate CCNG1 in regulating slippage and the outcome of taxane-induced mitotic arrest, with potential implications for cancer therapy

Aerobic exercise in obese diabetic patients with chronic kidney disease: a randomized and controlled pilot study

<p>Abstract</p> <p>Background</p> <p>Patients with obesity, diabetes, and chronic kidney disease (CKD) are generally physically inactive, have a high mortality rate, and may benefit from an exercise program.</p> <p>Methods</p> <p>We performed a 24-week randomized controlled feasibility study comparing aerobic exercise plus optimal medical management to medical management alone in patients with type 2 diabetes, obesity (body mass index [BMI] > 30 kg/m²), and stage 2-4 CKD (estimated glomerular filtration rate [eGFR] 15-90 mL/min/1.73 m²with persistent proteinuria). Subjects randomized to exercise underwent thrice weekly aerobic training for 6 followed by 18 weeks of supervised home exercise. The primary outcome variable was change in proteinuria.</p> <p>Results</p> <p>Seven subjects randomized to exercise and 4 control subjects completed the study. Exercise training resulted in an increase in exercise duration during treadmill testing, which was accompanied by slight but insignificant decreases in resting systolic blood pressure and 24-hour proteinuria. Exercise did not alter GFR, hemoglobin, glycated hemoglobin, serum lipids, or C-reactive protein (CRP). Caloric intake and body weight and composition also did not change with exercise training.</p> <p>Conclusion</p> <p>Exercise training in obese diabetic patients with CKD is feasible and may have clinical benefits. A large-scale randomized controlled trial to determine the effects of exercise on renal functions, cardiovascular fitness, inflammation, and oxidative stress in diabetic patients with CKD is planned.</p

Characterisation of human kallikrein 6/protease M expression in ovarian cancer

Kallikrein 6 (hK6, also known as protease M/zyme/neurosin) is a member of the human kallikrein gene family. We have previously cloned the cDNA for this gene by differential display and shown the overexpression of the mRNA in breast and ovarian primary tumour tissues and cell lines. To thoroughly characterise the expression of this kallikrein in ovarian cancer, we have developed a novel monoclonal antibody specific to hK6 and employed it in immunohistochemistry with a wide range of ovarian tumour samples. The expression was found elevated in 67 of 80 cases of ovarian tumour samples and there was a significant difference in the expression levels between normal and benign ovarian tissues and the borderline and invasive tumours (P&lt;0.001). There was no difference of expression level between different subtypes of tumours. More significantly, high level of kallikrein 6 expression was found in many early-stage and low-grade tumours, and elevated hK6 proteins were found in benign epithelia coexisting with borderline and invasive tissues, suggesting that overexpression of hK6 is an early phenomenon in the development of ovarian cancer. Quantitative real-time reverse transcription-polymerase chain reactions also showed elevated kallikrein 6 mRNA expression in ovarian tumours. Genomic Southern analysis of 19 ovarian tumour samples suggested that gene amplification is one mechanism for the overexpression of hK6 in ovarian cancer

HER2 testing in breast cancer: Opportunities and challenges

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-25% of breast cancers, usually as a result of HER2 gene amplification. Positive HER2 status is considered to be an adverse prognostic factor. Recognition of the role of HER2 in breast cancer growth has led to the development of anti-HER2 directed therapy, with the humanized monoclonal antibody trastuzumab (Herceptin (R)) having been approved for the therapy of HER2-positive metastatic breast cancer. Clinical studies have further suggested that HER2 status can provide important information regarding success or failure of certain hormonal therapies or chemotherapies. As a result of these developments, there has been increasing demand to perform HER2 testing on current and archived breast cancer specimens. This article reviews the molecular background of HER2 function, activation and inhibition as well as current opinions concerning its role in chemosensitivity and interaction with estrogen receptor biology. The different tissue-based assays used to detect HER2 amplification and overexpression are discussed with respect to their advantages and disadvantages, when to test (at initial diagnosis or pre-treatment), where to test (locally or centralized) and the need for quality assurance to ensure accurate and valid testing results

On the origin of [Ne II] emission in young stars: mid-infrared and optical observations with the Very Large Telescope

{Abridged version for ArXiv}. We provide direct constraints on the origin of the [Ne II] emission in 15 young stars using high-spatial and spectral resolution observations with VISIR at the VLT that allow us to study the kinematics of the emitting gas. In addition we compare the [Ne II] line with optical forbidden lines observed for three stars with UVES. The [Ne II] line was detected in 7 stars, among them the first confirmed detection of [Ne II] in a Herbig Be star, V892 Tau. In four cases, the large blueshifted lines indicate an origin in a jet. In two stars, the small shifts and asymmetric profiles indicate an origin in a photo-evaporative wind. CoKu Tau 1, seen close to edge-on, shows a spatially unresolved line centered at the stellar rest velocity, although cross-dispersion centroids move within 10 AU from one side of the star to the other as a function of wavelength. The line profile is symmetric with wings extending up to about +-80 km/s. The origin of the [Ne II] line could either be due to the bipolar jet or to the disk. For the stars with VLT-UVES observations, in several cases, the optical forbidden line profiles and shifts are very similar to the profile of the [Ne II] line, suggesting that the lines are emitted in the same region. A general trend observed with VISIR is a lower line flux when compared with the fluxes obtained with Spitzer. We found no correlation between the line full-width at half maximum and the line peak velocity. The [Ne II] line remains undetected in a large part of the sample, an indication that the emission detected with Spitzer in those stars is likely extended.Comment: Accepted for publication in Astronomy & Astrophysics; revised version: corrected minor typos, corrected center values (col 3) for CoKuTau1 in Table

The semisynthetic flavonoid monoHER sensitises human soft tissue sarcoma cells to doxorubicin-induced apoptosis via inhibition of nuclear factor-κB

Background:Despite therapeutic advances, the prognosis of patients with metastatic soft tissue sarcoma (STS) remains extremely poor. The results of a recent clinical phase II study, evaluating the protective effects of the semisynthetic flavonoid 7-mono-O-(beta-hydroxyethyl)-rutoside (monoHER) on doxorubicin-induced cardiotoxicity, suggest that monoHER enhances the antitumour activity of doxorubicin in STSs.Methods:To molecularly explain this unexpected finding, we investigated the effect of monoHER on the cytotoxicity of doxorubicin, and the potential involvement of glutathione (GSH) depletion and nuclear factor-kappaB (NF-kappaB) inactivation in the chemosensitising effect of monoHER.Results:MonoHER potentiated the antitumour activity of doxorubicin in the human liposarcoma cell line WLS-160. Moreover, the combination of monoHER with doxorubicin induced more apoptosis in WLS-160 cells compared with doxorubicin alone. MonoHER did not reduce intracellular GSH levels. On the other hand, monoHER pretreatment significantly reduced doxorubicin-induced NF-kappaB activation.Conclusion:These results suggest that reduction of doxorubicin-induced NF-kappaB activation by monoHER, which sensitises cancer cells to apoptosis, is involved in the chemosensitising effect of monoHER in human liposarcoma cells

Global Warming: Forecasts by Scientists versus Scientific Forecasts

In 2007, the Intergovernmental Panel on Climate Change’s Working Group One, a panel of experts established by the World Meteorological Organization and the United Nations Environment Programme, issued its Fourth Assessment Report. The Report included predictions of dramatic increases in average world temperatures over the next 92 years and serious harm resulting from the predicted temperature increases. Using forecasting principles as our guide we asked: Are these forecasts a good basis for developing public policy? Our answer is “no”. To provide forecasts of climate change that are useful for policy-making, one would need to forecast (1) global temperature, (2) the effects of any temperature changes, and (3) the effects of feasible alternative policies. Proper forecasts of all three are necessary for rational policy making. The IPCC WG1 Report was regarded as providing the most credible long-term forecasts of global average temperatures by 31 of the 51 scientists and others involved in forecasting climate change who responded to our survey. We found no references in the 1056-page Report to the primary sources of information on forecasting methods despite the fact these are conveniently available in books, articles, and websites. We audited the forecasting processes described in Chapter 8 of the IPCC’s WG1 Report to assess the extent to which they complied with forecasting principles. We found enough information to make judgments on 89 out of a total of 140 forecasting principles. The forecasting procedures that were described violated 72 principles. Many of the violations were, by themselves, critical. The forecasts in the Report were not the outcome of scientific procedures. In effect, they were the opinions of scientists transformed by mathematics and obscured by complex writing. Research on forecasting has shown that experts’ predictions are not useful in situations involving uncertainly and complexity. We have been unable to identify any scientific forecasts of global warming. Claims that the Earth will get warmer have no more credence than saying that it will get colder

Clinical and genetic spectrum of SCN2A-associated episodic ataxia

Background: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.Peer reviewe

The Far-Ultraviolet "Continuum" in Protoplanetary Disk Systems II: CO Fourth Positive Emission and Absorption

We exploit the high sensitivity and moderate spectral resolution of the $HST$-Cosmic Origins Spectrograph to detect far-ultraviolet spectral features of carbon monoxide (CO) present in the inner regions of protoplanetary disks for the first time. We present spectra of the classical T Tauri stars HN Tau, RECX-11, and V4046 Sgr, representative of a range of CO radiative processes. HN Tau shows CO bands in absorption against the accretion continuum. We measure a CO column density and rotational excitation temperature of N(CO) = 2 +/- 1 $\times$ 10$^{17}$ cm$^{-2}$ and T_rot(CO) 500 +/- 200 K for the absorbing gas. We also detect CO A-X band emission in RECX-11 and V4046 Sgr, excited by ultraviolet line photons, predominantly HI LyA. All three objects show emission from CO bands at $\lambda$ $>$ 1560 \AA, which may be excited by a combination of UV photons and collisions with non-thermal electrons. In previous observations these emission processes were not accounted for due to blending with emission from the accretion shock, collisionally excited H$_{2}$, and photo-excited H2; all of which appeared as a "continuum" whose components could not be separated. The CO emission spectrum is strongly dependent upon the shape of the incident stellar LyA emission profile. We find CO parameters in the range: N(CO) 10$^{18-19}$ cm$^{-2}$, T_{rot}(CO) > 300 K for the LyA-pumped emission. We combine these results with recent work on photo- and collisionally-excited H$_{2}$ emission, concluding that the observations of ultraviolet-emitting CO and H2 are consistent with a common spatial origin. We suggest that the CO/H2 ratio in the inner disk is ~1, a transition between the much lower interstellar value and the higher value observed in solar system comets today, a result that will require future observational and theoretical study to confirm.Comment: 12 pages, 7 figures, 3 tables. ApJ - accepte