Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment ...schedules, might enhance efficacy.
To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs).
Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4% vs 35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics.
Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.
Cancer Research UK, Medical Research Council.
Water-soluble metalla-cages were used to deliver hydrophobic porphin molecules to cancer cells. After internalization, the photosensitizer was photoactivated, significantly increasing the ...cytotoxicity in cells. During the transport, the photosensitizer remains nonreactive to light, offering a new strategy to tackle overall photosensitization, a limitation often encountered in photodynamic therapy.
Abstract Introduction Discriminating between placentally-mediated fetal growth restriction and constitutionally-small fetuses is a challenge in obstetric practice. Placental growth factor (PlGF), ...measurable in the maternal circulation, may have this discriminatory capacity. Methods Plasma PlGF was measured in women presenting with suspected fetal growth restriction (FGR; ultrasound fetal abdominal circumference <10th percentile for gestational age) at sites in Canada, New Zealand and the United Kingdom. When available, placenta tissue underwent histopathological examination for lesions indicating placental dysfunction, blinded to PlGF and clinical outcome. Lesions were evaluated according to pre-specified severity criteria and an overall severity grade was assigned (0–3, absent to severe). Low PlGF (concentration <5th percentile for gestational age) to identify placental FGR (severity grade ≥2) was assessed and compared with routine parameters for fetal assessment. For all cases, the relationship between PlGF and the sampling-to-delivery interval was determined. Results Low PlGF identified placental FGR with an area under the receiver-operator characteristic curve of 0.96 95% CI 0.93–0.98, 98.2% 95% CI 90.5–99.9 sensitivity and 75.1% 95% CI 67.6–81.7 specificity. Negative and positive predictive values were 99.2% 95% CI 95.4–99.9 and 58.5% 95% CI 47.9–68.6, respectively. Low PlGF outperformed gestational age, abdominal circumference and umbilical artery resistance index in predicting placental FGR. Very low PlGF (<12 pg/mL) was associated with shorter sampling-to-delivery intervals than normal PlGF (13 vs. 29.5 days, P<0.0001). Discussion Low PlGF identifies small fetuses with significant underlying placental pathology and is a promising tool for antenatal discrimination of FGR from fetuses who are constitutionally-small.
Improving materials used to make qubits is crucial to further progress in quantum information processing. Of particular interest are semiconductor-superconductor heterostructures that are expected to ...form the basis of topological quantum computing. We grew semiconductor indium antimonide nanowires that were coated with shells of tin of uniform thickness. No interdiffusion was observed at the interface between Sn and InSb. Tunnel junctions were prepared by in situ shadowing. Despite the lack of lattice matching between Sn and InSb, a 15-nanometer-thick shell of tin was found to induce a hard superconducting gap, with superconductivity persisting in magnetic field up to 4 teslas. A small island of Sn-InSb exhibits the two-electron charging effect. These findings suggest a less restrictive approach to fabricating superconducting and topological quantum circuits.
Key points
Muscle glycogen and intramuscular triglycerides (IMTG, stored in lipid droplets) are important energy substrates during prolonged exercise.
Exercise‐induced changes in lipid droplet (LD) ...morphology (i.e. LD size and number) have not yet been studied under nutritional conditions typically adopted by elite endurance athletes, that is, after carbohydrate (CHO) loading and CHO feeding during exercise.
We report for the first time that exercise reduces IMTG content in both central and peripheral regions of type I and IIa fibres, reflective of decreased LD number in both fibre types whereas reductions in LD size were exclusive to type I fibres.
Additionally, CHO feeding does not alter subcellular IMTG utilisation, LD morphology or muscle glycogen utilisation in type I or IIa/II fibres.
In the absence of alterations to muscle fuel selection, CHO feeding does not attenuate cell signalling pathways with regulatory roles in mitochondrial biogenesis.
We examined the effects of carbohydrate (CHO) feeding on lipid droplet (LD) morphology, muscle glycogen utilisation and exercise‐induced skeletal muscle cell signalling. After a 36 h CHO loading protocol and pre‐exercise meal (12 and 2 g kg–1, respectively), eight trained males ingested 0, 45 or 90 g CHO h–1 during 180 min cycling at lactate threshold followed by an exercise capacity test (150% lactate threshold). Muscle biopsies were obtained pre‐ and post‐completion of submaximal exercise. Exercise decreased (P < 0.01) glycogen concentration to comparable levels (∼700 to 250 mmol kg–1 DW), though utilisation was greater in type I (∼40%) versus type II fibres (∼10%) (P < 0.01). LD content decreased in type I (∼50%) and type IIa fibres (∼30%) (P < 0.01), with greater utilisation in type I fibres (P < 0.01). CHO feeding did not affect glycogen or IMTG utilisation in type I or II fibres (all P > 0.05). Exercise decreased LD number within central and peripheral regions of both type I and IIa fibres, though reduced LD size was exclusive to type I fibres. Exercise induced (all P < 0.05) comparable AMPKThr172 (∼4‐fold), p53Ser15 (∼2‐fold) and CaMKIIThr268 phosphorylation (∼2‐fold) with no effects of CHO feeding (all P > 0.05). CHO increased exercise capacity where 90 g h–1 (233 ± 133 s) > 45 g h–1 (156 ± 66 s; P = 0.06) > 0 g h–1 (108 ± 54 s; P = 0.03). In conditions of high pre‐exercise CHO availability, we conclude CHO feeding does not influence exercise‐induced changes in LD morphology, glycogen utilisation or cell signalling pathways with regulatory roles in mitochondrial biogenesis.
Key points
Muscle glycogen and intramuscular triglycerides (IMTG, stored in lipid droplets) are important energy substrates during prolonged exercise.
Exercise‐induced changes in lipid droplet (LD) morphology (i.e. LD size and number) have not yet been studied under nutritional conditions typically adopted by elite endurance athletes, that is, after carbohydrate (CHO) loading and CHO feeding during exercise.
We report for the first time that exercise reduces IMTG content in both central and peripheral regions of type I and IIa fibres, reflective of decreased LD number in both fibre types whereas reductions in LD size were exclusive to type I fibres.
Additionally, CHO feeding does not alter subcellular IMTG utilisation, LD morphology or muscle glycogen utilisation in type I or IIa/II fibres.
In the absence of alterations to muscle fuel selection, CHO feeding does not attenuate cell signalling pathways with regulatory roles in mitochondrial biogenesis.
Our knowledge of the factors mediating ethylene-dependent ripening of climacteric fruit remains limited. The transcription of ethylene-regulated genes is mediated by ethylene response factors (ERFs), ...but mutants providing information on the specific role of the ERFs in fruit ripening are still lacking, likely due to functional redundancy among this large multigene family of transcription factors. We present here a comprehensive expression profiling of tomato (Solanum lycopersicum) ERFs in wild-type and tomato ripening-impaired tomato mutants (Never-ripe Nr, ripening-inhibitor rin, and non-ripening nor), indicating that out of the 77 ERFs present in the tomato genome, 27 show enhanced expression at the onset of ripening while 28 display a ripening-associated decrease in expression, suggesting that different ERFs may have contrasting roles in fruit ripening. Among the 19 ERFs exhibiting the most consistent up-regulation during ripening, the expression of 11 ERFs is strongly down-regulated in rin, nor, and Nr tomato ripening mutants, while only three are consistently up-regulated. Members of subclass E, SlERF.E1, SlERF.E2, and SlERF.E4, show dramatic down-regulation in the ripening mutants, suggesting that their expression might be instrumental in fruit ripening. This study illustrates the high complexity of the regulatory network connecting RIN and ERFs and identifies subclass E members as the most active ERFs in ethylene- and RIN/NOR-dependent ripening.
A broad range of scientific and industrial disciplines require precise optical measurements at very low light levels. Single-photon detectors combining high efficiency and high time resolution are ...pivotal in such experiments. By using relatively thick films of NbTiN (8–11 nm) and improving the pattern fidelity of the nanostructure of the superconducting nanowire single-photon detectors (SNSPD), we fabricated devices demonstrating superior performance over all previously reported detectors in the combination of efficiency and time resolution. Our findings prove that small variations in the nanowire width, in the order of a few nanometers, can lead to a significant penalty on their temporal response. Addressing these issues, we consistently achieved high time resolution (best device 7.7 ps, other devices ∼10–16 ps) simultaneously with high system detection efficiencies (80–90%) in the wavelength range of 780–1000 nm, as well as in the telecom bands (1310–1550 nm). The use of thicker films allowed us to fabricate large-area multipixel devices with homogeneous pixel performance. We first fabricated and characterized a 100 × 100 μm2 16-pixel detector and showed there was little variation among individual pixels. Additionally, to showcase the power of our platform, we fabricated and characterized 4-pixel multimode fiber-coupled detectors and carried out photon-correlation experiments on a nanowire quantum dot resulting in g 2(0) values lower than 0.04. The multipixel detectors alleviate the need for beamsplitters and can be used for higher order correlations with promising prospects not only in the field of quantum optics, but also in bioimaging applications, such as fluorescence microscopy and positron emission tomography.
Abstract
The bZIP transcription factor (TF) SlTGA2.2 was previously highlighted as a possible hub in a network regulating fruit growth and transition to ripening (maturation phase). It belongs to a ...clade of TFs well known for their involvement in the regulation of the salicylic acid–dependent systemic acquired resistance. To investigate if this TGA TF plays a role in tomato fruit growth and maturation, we took advantage of the fruit-specific SlPPC2 promoter (PPC2pro) to target the expression of a SlTGA2.2-SRDX chimeric repressor in a developmental window restricted to early fruit growth and maturation. Here, we show that this SlTGA2.2-SRDX repressor alters early fruit development and metabolism, including chloroplast number and structure, considerably extends the time necessary to reach the mature green stage and slows down fruit ripening. RNA sequencing and plant hormone analyses reveal that PPC2pro:SlTGA2.2-SRDX fruits are maintained in an immature stage as long as PPC2pro is active, through early modifications of plant hormonal signaling and down-regulation of MADS-RIN and NAC-NOR ripening regulators. Once PPC2pro becomes inactive and therefore SlTGA2.2-SRDX expression is reduced, ripening can proceed, albeit at a slower pace than normal. Altogether, this work emphasizes the developmental continuum between fruit growth, maturation and ripening and provides a useful tool to alter and study the molecular bases of tomato fruit transition to ripening.
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