Expression of steroid receptor coactivator 3 in ovarian epithelial cancer is a poor prognostic factor and a marker for platinum resistance

BACKGROUND: Steroid receptor coactivator 3 (SRC3) is an important coactivator of a number of transcription factors and is associated with a poor outcome in numerous tumours. Steroid receptor coactivator 3 is amplified in 25% of epithelial ovarian cancers (EOCs) and its expression is higher in EOCs compared with non-malignant tissue. No data is currently available with regard to the expression of SRC-3 in EOC and its influence on outcome or the efficacy of treatment. METHODS: Immunohistochemistry was performed for SRC3, oestrogen receptor-α, HER2, PAX2 and PAR6, and protein expression was quantified using automated quantitative immunofluorescence (AQUA) in 471 EOCs treated between 1991 and 2006 with cytoreductive surgery followed by first-line treatment platinum-based therapy, with or without a taxane. RESULTS: Steroid receptor coactivator 3 expression was significantly associated with advanced stage and was an independent prognostic marker. High expression of SRC3 identified patients who have a significantly poorer survival with single-agent carboplatin chemotherapy, while with carboplatin/paclitaxel treatment such a difference was not seen. CONCLUSION: Steroid receptor coactivator 3 is a poor prognostic factor in EOCs and appears to identify a population of patients who would benefit from the addition of taxanes to their chemotherapy regimen, due to intrinsic resistance to platinum therapy

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.

Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common 'metastatic precursor'. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination

Changes in muscle contractile characteristics and jump height following 24 days of unilateral lower limb suspension

We measured changes in maximal voluntary and electrically evoked torque and rate of torque development because of limb unloading. We investigated whether these changes during single joint isometric muscle contractions were related to changes in jump performance involving dynamic muscle contractions and several joints. Six healthy male subjects (21 ± 1 years) underwent 3 weeks of unilateral lower limb suspension (ULLS) of the right limb. Plantar flexor and knee extensor maximal voluntary contraction (MVC) torque and maximal rate of torque development (MRTD), voluntary activation, and maximal triplet torque (thigh; 3 pulses at 300 Hz) were measured next to squat jump height before and after ULLS. MVC of plantar flexors and knee extensors (MVCke) and triplet torque decreased by 12% (P = 0.012), 21% (P = 0.001) and 11% (P = 0.016), respectively. Voluntary activation did not change (P = 0.192). Absolute MRTD during voluntary contractions decreased for plantar flexors (by 17%, P = 0.027) but not for knee extensors (P = 0.154). Absolute triplet MRTD decreased by 17% (P = 0.048). The reduction in MRTD disappeared following normalization to MVC. Jump height with the previously unloaded leg decreased significantly by 28%. No significant relationships were found between any muscle variable and jump height (r < 0.48), but decreases in torque were (triplet, r = 0.83, P = 0.04) or tended to be (MVCke r = 0.71, P = 0.11) related to decreases in jump height. Thus, reductions in isometric muscle torque following 3 weeks of limb unloading were significantly related to decreases in the more complex jump task, although torque in itself (without intervention) was not related to jump performance

Conventionally assessed voluntary activation does not represent relative voluntary torque production

The ability to voluntarily activate a muscle is commonly assessed by some variant of the twitch interpolation technique (ITT), which assumes that the stimulated force increment decreases linearly as voluntary force increases. In the present study, subjects (n = 7) with exceptional ability for maximal voluntary activation (VA) of the knee extensors were used to study the relationship between superimposed and voluntary torque. This includes very high contraction intensities (90–100%VA), which are difficult to consistently obtain in regular healthy subjects (VA of ∼90%). Subjects were tested at 30, 60, and 90° knee angles on two experimental days. At each angle, isometric knee extensions were performed with supramaximal superimposed nerve stimulation (triplet: three pulses at 300 Hz). Surface EMG signals were obtained from rectus femoris, vastus lateralis, and medialis muscles. Maximal VA was similar and very high across knee angles: 97 ± 2.3% (mean ± SD). At high contraction intensities, the increase in voluntary torque was far greater than would be expected based on the decrement of superimposed torque. When voluntary torque increased from 79.6 ± 6.1 to 100%MVC, superimposed torque decreased from 8.5 ± 2.6 to 2.8 ± 2.3% of resting triplet. Therefore, an increase in VA of 5.7% (from 91.5 ± 2.6 to 97 ± 2.3%) coincided with a much larger increase in voluntary torque (20.4 ± 6.1%MVC) and EMG (33.9 ± 6.6%max). Moreover, a conventionally assessed VA of 91.5 ± 2.6% represented a voluntary torque of only 79.6 ± 6.1%MVC. In conclusion, when maximal VA is calculated to be ∼90% (as in regular healthy subjects), this probably represents a considerable overestimation of the subjects’ ability to maximally drive their quadriceps muscles

Daily 30-min exposure to artificial gravity during 60 days of bed rest does not maintain aerobic exercise capacity but mitigates some deteriorations of muscle function: results from the AGBRESA RCT

Purpose: Spaceflight impairs physical capacity. Here we assessed the protective effect of artificial gravity (AG) on aerobic exercise capacity and muscle function during bed rest, a spaceflight analogue. Methods: 24 participants (33 ± 9 years, 175 ± 9 cm, 74 ± 10 kg, 8 women) were randomly allocated to one of three groups: continuous AG (cAG), intermittent AG (iAG) or control (CTRL). All participants were subjected to 60 days of six-degree head-down tilt bed rest, and subjects of the intervention groups completed 30 min of centrifugation per day: cAG continuously and iAG for 6 × 5 min, with an acceleration of 1g at the center of mass. Physical capacity was assessed before and after bed rest via maximal voluntary contractions, cycling spiroergometry, and countermovement jumps. Results: AG had no significant effect on aerobic exercise capacity, flexor muscle function and isometric knee extension strength or rate of force development (RFD). However, AG mitigated the effects of bed rest on jumping power (group * time interaction of the rmANOVA p < 0.001; iAG − 25%, cAG − 26%, CTRL − 33%), plantar flexion strength (group * time p = 0.003; iAG − 35%, cAG − 31%, CTRL − 48%) and plantar flexion RFD (group * time p = 0.020; iAG − 28%, cAG − 12%, CTRL − 40%). Women showed more pronounced losses than men in jumping power (p < 0.001) and knee extension strength (p = 0.010). Conclusion: The AG protocols were not suitable to maintain aerobic exercise capacity, probably due to the very low cardiorespiratory demand of this intervention. However, they mitigated some losses in muscle function, potentially due to the low-intensity muscle contractions during centrifugation used to avoid presyncope

Head-down tilt bed rest with or without artificial gravity is not associated with motor unit remodeling

© 2020, The Author(s). Purpose: The objective of this study was to assess whether artificial gravity attenuates any long-duration head-down 60 bed rest (HDBR)-induced alterations in motor unit (MU) properties. Methods: Twenty-four healthy participants (16 men; 8 women; 26–54 years) underwent 60-day HDBR with (n = 16) or without (n = 8) 30 min artificial gravity daily induced by whole-body centrifugation. Compound muscle action potential (CMAP), MU number (MUNIX) and MU size (MUSIX) were estimated using the method of Motor Unit Number Index in the Abductor digiti minimi and tibialis anterior muscles 5 days before (BDC-5), and during day 4 (HDT4) and 59 (HDT59) of HDBR. Results: The CMAP, MUNIX, and MUSIX at baseline did not change significantly in either muscle, irrespective of the intervention (p > 0.05). Across groups, there were no significant differences in any variable during HDBR, compared to BDC-5. Conclusion: Sixty days of HDBR with or without artificial gravity does not induce alterations in motor unit number and size in the ADM or TA muscles in healthy individuals

Conformational differences between lgGs from autoimmune and non-auto-immune serum aare detected by LLPC

Abstract from the 29th Annual Meeting of the Scandinavian Society of Immunolog