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.
A previous study found that the capacitive behavior of nanoparticles fed to the silkworm can be delivered to carbonized silk fibers, which can be used to fabricate electrodes for the construction of ...flexible supercapacitors. However, the tendency of nanoparticles to aggregate decreases the quantity of nanoparticles that enter the silk and therefore reduces the capacitance performance of the prepared carbonized silk. Here, we sprayed ammonium molybdate tetrahydrate (AMT) on the surface of mulberry leaves used for feeding silkworms and investigated the effect of feeding AMT on the growth of silkworms and the properties of spun silk. The precursor incorporated into the silk was converted into scattered MoO
2
NPs, which were embedded within the carbonized silk fiber (CSF)
via
carbothermal reduction. The specific capacitance of CSF obtained from silkworms fed with an aqueous solution of AMT-treated mulberry leaves reached up to 298 F/g at 0.2 g/A, which is much higher than that of the control group (102 F/g). Since AMT is highly water-soluble, and its concentration can be easily modulated, we believe that the proposed strategy is feasible for the large-scale fabrication of CSF with enhanced capacitive performance.
We examine the influences of a set of early life conditions (ELCs) on all-cause and cause-specific mortality among elderly individuals, with special attention to one of the most dramatic early events ...in a child's, adolescent's, or even young adult's life, the death of a parent. The foremost question is, once controlling for prevailing (and potentially confounding) conditions early in life (family history of longevity, paternal characteristics (SES, age at time of birth, sibship size, and religious affiliation)), is a parental death associated with enduring mortality risks after age 65? The years following parental death may initiate new circumstances through which the adverse effects of paternal death operate. Here we consider the offspring's marital status (whether married; whether and when widowed), adult socioeconomic status, fertility, and later life health status. Adult health status is based on the Charlson Co-Morbidity Index, a construct that summarizes nearly all serious illnesses afflicting older individuals that relies on Medicare data. The data are based on linkages between the Utah Population Database and Medicare claims that hold medical diagnoses data. We show that offspring whose parents died when they were children, but especially when they were adolescents/young adults, have modest but significant mortality risks after age 65. What are striking are the weak mediating influences of later-life comorbidities, marital status, fertility and adult socioeconomic status since controls for these do little to alter the overall association. No beneficial effects of the surviving parent's remarriage were detected. Overall, we show the persistence of the effects of early life loss on later-life mortality and indicate the difficulties in addressing challenges at young ages.
•Excess adult (age 65+) mortality was associated with early parental death.•Sons were affected more by parental deaths in early adulthood while for daughters it is parental deaths in childhood.•Adult comorbidities do not mediate the mortality effects of early parental death.•Mortality risk attributable to early parental death is greatest for heart disease.
•More information about interventions for homeless smokers is needed.•Increase in positive affect post-quit is associated with fewer CPD.•Time by affect effects on post-quit CPD support the need for ...early intervention.
Cigarette smoking disproportionately affects homeless individuals, who have a higher smoking prevalence, fewer resources, and increased stressors compared to domiciled smokers. Little is known about how to facilitate smoking cessation among this population although some findings support focusing efforts on affective variables as well as alternate outcomes in order to optimize interventions for this group.
Participants were homeless adults recruited from a Dallas, TX, shelter (N = 57, 61.4% male, Mage = 48.8 ± 9.0) to participate in tobacco cessation classes using an American Cancer Society-based therapy and support group with nicotine replacement therapy. Moment-to-moment changes in affect e.g., negative affect (NA), positive affect (PA), and stress were recorded via Ecological Momentary Assessments to assess whether they were associated with concurrent changes in cigarettes smoked per day (CPD) following a specific quit attempt. Separate generalized linear models (GLM) were evaluated for each predictor to examine the associations between affective variables and CPD in covariate-adjusted analyses.
Significant interaction effects of time and affect were found for all variables (NA: p = 0.0011, PA: p = 0.0006, stress: p = 0.0259), whereby the association of affect and CPD were significant in the early part of the week but the effects faded as time progressed. With regard to main effects, only increases in PA during the post-quit week significantly predicted fewer CPD (adjusted incidence rate ratio = 0.924, SE = 0.027, p = 0.0032).
Homeless smokers may be more likely to decrease their cigarette consumption during periods of greater PA throughout the post-quit week. Relationship between positive affect and reduction in CPD suggest focus on affective variables with homeless smokers may be an effective avenue for change in smoking behaviors, particularly in the days immediately following a quit attempt. Time effects should be further investigated to determine when these interventions might best be implemented.
We developed a microarray hybridization-based method, 'comparative genome sequencing' (CGS), to find mutations in bacterial genomes and used it to study metronidazole resistance in H. pylori. CGS ...identified mutations in several genes, most likely affecting metronidazole activation, and produced no false positives in analysis of three megabases. We conclude that CGS identifies mutations in bacterial genomes efficiently, should enrich understanding of systems biology and genome evolution, and help track pathogens during outbreaks.
Sea anemone venom is rich in bioactive compounds, including peptides containing multiple disulfide bridges. In a transcriptomic study on Oulactis sp., we identified the putative 36-residue peptide, ...OspTx2b, which is an isoform of the KV channel blocker OspTx2a (Sunanda P et al. 2018 Identification, chemical synthesis, structure and function of a new KV1 channel blocking peptide from Oulactis sp. Peptide Science, in press). As OspTx2b contains a ShK/BgK-like cysteine framework, with high amino acid sequence similarity to BgK, we were interested to investigate its structure and function. The solution structure of OspTx2b was determined using nuclear magnetic resonance spectroscopy. OspTx2b does indeed possess a BgK-like scaffold, with the same disulfide bond connectivities. The orientation of the Lys-Tyr dyad in OspTx2b is more similar to that in ShK than in BgK. However, it failed to show against a range of voltage-gated potassium channels in Xenopus oocytes and human T lymphocytes. OspTx2b also showed no growth inhibitory activity against several strains of bacteria and fungi. Having a BgK-like fold with the Lys-Tyr dyad but no BgK-like activity highlights the importance of key amino acid residues in BgK that are missing in OspTx2b. The lack of activity against the KV channels assessed in this study emphasises that the ShK/BgK scaffold is capable of supporting functional activity beyond potassium channel blockade.
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•OspTx2b, from the sea anemone Oulactis sp, is a new member of the ShKT family of peptides and proteins.•OspTx2b has a similar solution structure to that of BgK.•Despite having both a BgK-like structure and a Lys-Tyr dyad, OspTx2b is not active against KV1 channels.•Lack of activity against KV1 channels implies that OspTx2b may have evolved to function through other ion channels or receptors.
Recent subsalt petroleum discoveries associated with rifted‐margin salt basins have piqued interest in the presalt geology of the Gulf of Mexico margin. Available subsurface data does not uniquely ...constrain the subsalt geometry, so creating an interpretation of the crustal architecture requires the application of geological models for crustal extension and breakup. However, published interpretations of the nature of the transition from continental rifting to seafloor spreading range from magma‐rich to magma‐poor. To address this uncertainty, we present 2D forward kinematic models for crustal configurations generated by diverse models (symmetric extension, depth‐dependent extension, and volcanic extension). Through a series of conceptual balanced cross‐sections grounded in a ~600 km 2D seismic line from the NE Gulf of Mexico, we demonstrate the implications of each model for the limit of oceanic crust, basement morphology, crustal architecture, and hydrocarbon prospectivity. We discuss evidence for the dominant crustal processes, including geodynamic factors and structural and stratigraphic observations. Based on our observations and the geologic history, we favour an asymmetric, magma‐poor to ‐intermediate margin interpretation for the NE Gulf of Mexico, but suggest that the degree of volcanic input and width of the ocean‐continent transition zone may vary along strike. The along‐strike variability highlights the importance of understanding all potential presalt crustal configurations, their key features, and their implications. With increased data availability on the presalt geology in the Gulf of Mexico the relevance of these scenarios can be assessed, allowing development of comprehensive geodynamic and tectonic models of the margin and consideration of petroleum system elements in the presalt sequence.
This paper defends Flatland—the view that there exist neither determination nor dependence relations, and that everything is therefore fundamental—from the objection from explanatory inefficacy. ...According to that objection, Flatland is unattractive because it is unable to explain either the appearance as of there being determination relations, or the appearance as of there being dependence relations. We show how the Flatlander can meet the first challenge by offering four strategies—reducing, eliminating, untangling and omnizing—which, jointly, explain the appearance as of determination relations where no such relations obtain. Since, plausibly, dependence relations just are asymmetric determination relations, we argue that once we come mistakenly to believe that there exist determination relations, the existence of other asymmetries (conceptual and temporal) explains why it appears that there are dependence relations.
Care teams are increasingly expected to attend to the needs of patient's personal caregivers (e.g., family members). Improving communication among oncologists, patients with advanced cancer, and ...their personal caregivers might enhance caregivers' experiences of end-of-life (EoL) cancer care and bereavement outcomes.
To explore the effects of the Values and Options in Cancer Care intervention on caregivers' experiences of EoL care and bereavement outcomes.
We developed a brief behavioral intervention to improve communication among oncologists, patients with advanced cancer, and their personal caregivers. The intervention was designed to help patients/caregivers ask questions, express concerns, and help oncologists respond effectively. We randomly assigned oncologists (and their patients/caregivers) to the intervention or usual care.
Medical oncologists in NY and CA; patients/personal caregivers with advanced cancer.
Two months after the patient's death, caregivers completed three instruments assessing their experiences of EoL care. Seven months after the patient's death, caregivers completed the Prolonged Grief Disorder-13 (PG-13; primary prespecified outcome), the Purpose-in-Life scale, and scales assessing mental health function, depression, and anxiety.
The intervention did not significantly improve caregivers' scores on the PG-13 (
= 0.21), mental health function, depression, or anxiety, but it did improve purpose-in-life scores (
= 0.018). Cohen's
(95% confidence interval) for all three experiences of EoL care outcomes were promising, ranging from 0.22 (-0.19 to 0.63) to 0.39 (-0.07 to 0.86) although none was statistically significant.
Preliminary findings show promise that scalable interventions in cancer care settings may improve caregiver experiences with cancer care and some bereavement outcomes.
Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis ...to develop a molecular predictor of the length of survival.
Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens.
Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells.
The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.
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