Background
Peripheral neuropathy is the dose‐limiting toxicity of many oncology drugs, including paclitaxel. There is large interindividual variability in the neuropathy, and several risk factors ...have been proposed; however, many have not been replicated. Here we present a comprehensive study aimed at identifying treatment and physiopathology‐related paclitaxel‐induced neuropathy risk factors in a large cohort of well‐characterized patients.
Patients and Methods
Analyses included 503 patients with breast or ovarian cancer who received paclitaxel treatment. Paclitaxel dose modifications caused by the neuropathy were extracted from medical records and patients self‐reported neuropathy symptoms were collected. Multivariate logistic regression analyses were performed to identify concomitant medications and comorbidities associated with paclitaxel‐induced neuropathy.
Results
Older patients had higher neuropathy: for each increase of 1 year of age, the risk of dose modifications and grade 3 neuropathy increased 4% and 5%, respectively. Cardiovascular drugs increased the risk of paclitaxel dose reductions (odds ratio OR, 2.51; p = .006), with a stronger association for beta‐adrenergic antagonists. The total number of concomitant medications also showed an association with dose modifications (OR, 1.25; p = .012 for each concomitant drug increase). A dose modification predictive model that included the new identified factors gave an area under the curve of 0.74 (p = 1.07 × 10−10). Preexisting nerve compression syndromes seemed to increase neuropathy risk.
Conclusion
Baseline characteristics of the patients, including age and concomitant medications, could be used to identify individuals at high risk of neuropathy, personalizing chemotherapy treatment and reducing the risk of severe neuropathy.
Implications for Practice
Peripheral neuropathy is a common adverse effect of many cancer drugs, including chemotherapeutics, targeted therapies, and immune checkpoint inhibitors. About 40% of survivors of cancer have functional deficits caused by this toxicity, some of them irreversible. Currently, there are no effective treatments to prevent or treat this neuropathy. This study, performed in a large cohort of well‐characterized patients homogenously treated with paclitaxel, identified concomitant medications, comorbidities, and demographic factors associated with peripheral neuropathy. These factors could serve to identify patients at high risk of severe neuropathy for whom alternative non‐neurotoxic alternatives may be considered.
Peripheral neuropathy is a common adverse effect of many cancer drugs, including chemotherapeutics, targeted therapies, and immune checkpoint inhibitors. This article reports results of a study designed to identify treatment and physiopathology‐related paclitaxel‐inducd neuropathy risk factors in a cohort of ore than 500 patients.
Oxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60-80% of the ...patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin.
Blood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: "cases" developed oxaliplatin-induced grade 3-4 neuropathy (n = 48), and "controls" (n = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria (NCI-CTC), Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and Total Neuropathy score (TNS). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated.
We found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16-0.96; p = 0.041). Multivariate analysis adjusting for diabetes provided similar results (p = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673.
SCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.
After the launch of the Surface Water and Ocean Topography (SWOT) satellite planned for 2022, the region around the Balearic Islands (western Mediterranean Sea) will be the target of several
in situ
...sampling campaigns aimed at validating the first available tranche of SWOT data. In preparation for this validation, the PRE-SWOT cruise in 2018 was conceived to explore the three-dimensional (3D) circulation at scales of 20 km that SWOT aims to resolve, included in the fine-scale range (1–100 km) as defined by the altimetric community. These scales and associated variability are not captured by contemporary nadir altimeters. Temperature and salinity observations reveal a front that separates local Atlantic Water in the northeast from recent Atlantic Water in the southeast, and extends from the surface to ~150 m depth with maximum geostrophic velocities of the order of 0.20 m s
−1
and a geostrophic Rossby number that ranges between −0.24 and 0.32. This front is associated with a 3D vertical velocity field characterized by an upwelling cell surrounded by two downwelling cells, one to the east and the other to the west. The upwelling cell is located near an area with high nitrate concentrations, possibly indicating a recent inflow of nutrients. Meanwhile, subduction of chlorophyll-a in the western downwelling cell is detected in glider observations. The comparison of the altimetric geostrophic velocity with the CTD-derived geostrophic velocity, the ADCP horizontal velocity, and drifter trajectories, shows that the present-day resolution of altimetric products precludes the representation of the currents that drive the drifter displacement. The Lagrangian analysis based on these velocities demonstrates that the study region has frontogenetic dynamics not detected by altimetry. Our results suggest that the horizontal component of the flow is mainly geostrophic down to scales of 20 km in the study region and during the period analyzed, and should therefore be resolvable by SWOT and other future satellite-borne altimeters with higher resolutions. In addition, fine-scale features have an impact on the physical and biochemical spatial variability, and multi-platform
in situ
sampling with a resolution similar to that expected from SWOT can capture this variability.
Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, ...the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.
We sequenced the coding region of 4
genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment.
Gene-based analysis identified
as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in
were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for
low-frequency nonsynonymous variant carriers HR, 14.60; 95% confidence interval (CI), 2.33-91.62;
= 0.0042, and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77;
= 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31;
= 9.1 × 10
).
This first study sequencing
genes revealed that low-frequency variants in
, and
contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs.
.
Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been ...suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a whole-exome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy.
Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes.
WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4*20 allele) and a novel missense variant (CYP3A4*25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4*20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4*8 and the novel CYP3A4*27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2- and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P = 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7- and 3-fold higher risk for loss-of-function and missense variants, respectively, P = 5.9 × 10(-5)).
This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization.
Introduction:
Elevated plasma α-klotho (αKl) protects against several ageing phenotypes and has been proposed as a biomarker of a good prognosis for different diseases. The beneficial health effects ...of elevated plasma levels of soluble αKl (SαKl) have been likened to the positive effects of exercise on ageing and chronic disease progression. It has also been established that molecular responses and adaptations differ according to exercise dose. The aim of this study is to compare the acute SαKl response to different exercise interventions, cardiorespiratory, and strength exercise in healthy, physically active men and to examine the behavior of SαKl 72h after acute strength exercise.
Methods:
In this quasi-experimental study, plasma SαKl was measured before and after a cardiorespiratory exercise session (CR) in 43 men, and strength exercise session (ST) in 39 men. The behavior of SαKl was also examined 24, 48, and 72h after ST.
Results:
Significant differences (time×group) were detected in SαKl levels (
p
=0.001;
d
=0.86) between CR and ST. After the ST intervention, SαKl behavior varied significantly (
p
=0.009;
d
=0.663) in that levels dropped between pre- and post-exercises (
p
=0.025;
d
=0.756) and were also significantly higher compared to pre ST values at 24h (
p
=0.033;
d
=0.717) and at 48h (
p
=0.015;
d
=0.827).
Conclusions:
SαKl levels increased in response to a single bout of cardiorespiratory exercise; while they decreased immediately after strength exercise, levels were elevated after 24h indicating different klotho protein responses to different forms of exercise.
We present the stellar kinematic maps of a large sample of galaxies from the integral-field spectroscopic survey CALIFA. The sample comprises 300 galaxies displaying a wide range of morphologies ...across the Hubble sequence, from ellipticals to late-type spirals. This dataset allows us to homogeneously extract stellar kinematics up to several effective radii. In this paper, we describe the level of completeness of this subset of galaxies withrespect to the full CALIFA sample, as well as the virtues and limitations of the kinematic extraction compared to other well-known integral-field surveys. In addition, we provide averaged integrated velocity dispersion radial profiles for different galaxy types, which are particularly useful to apply aperture corrections for single aperture measurements or poorly resolved stellar kinematics of high-redshift sources. The work presented in this paper sets the basis for the study of more general properties of galaxies that will be explored in subsequent papers of the survey.
Context. According to numerical simulations, stars are not always kept at their birth galactocentric distances but they have a tendency to migrate. The importance of this radial migration in shaping ...galactic light distributions is still unclear. However, if radial migration is indeed important, galaxies with different surface brightness (SB) profiles must display differences in their stellar population properties. Aims. We investigate the role of radial migration in the light distribution and radial stellar content by comparing the inner colour, age, and metallicity gradients for galaxies with different SB profiles. We define these inner parts, avoiding the bulge and bar regions and up to around three disc scale lengths (type I, pure exponential) or the break radius (type II, downbending; type III, upbending). Methods. We analysed 214 spiral galaxies from the CALIFA survey covering different SB profiles. We made use of GASP2D and SDSS data to characterise the light distribution and obtain colour profiles of these spiral galaxies. The stellar age and metallicity profiles were computed using a methodology based on full-spectrum fitting techniques (pPXF, GANDALF, and STECKMAP) to the Integral Field Spectroscopic CALIFA data. Results. The distributions of the colour, stellar age, and stellar metallicity gradients in the inner parts for galaxies displaying different SB profiles are unalike as suggested by Kolmogorov-Smirnov and Anderson-Darling tests. We find a trend in which type II galaxies show the steepest profiles of all, type III show the shallowest, and type I display an intermediate behaviour. Conclusions. These results are consistent with a scenario in which radial migration is more efficient for type III galaxies than for type I systems, where type II galaxies present the lowest radial migration efficiency. In such a scenario, radial migration mixes the stellar content, thereby flattening the radial stellar properties and shaping different SB profiles. However, in light of these results we cannot further quantify the importance of radial migration in shaping spiral galaxies, and other processes, such as recent star formation or satellite accretion, might play a role.
We estimate the current extinction-corrected H star formation rate (SFR) of the different morphological components that shape galaxies (bulges, bars, and disks). We use a multicomponent photometric ...decomposition based on Sloan Digital Sky Survey imaging to Calar Alto Legacy Integral Field Area Integral Field Spectroscopy (IFS) datacubes for a sample of 219 galaxies. This analysis reveals an enhancement of the central SFR and specific SFR (sSFR = SFR/M ) in barred galaxies. Along the main sequence, we find that more massive galaxies in total have undergone efficient suppression (quenching) of their star formation, in agreement with many studies. We discover that more massive disks have had their star formation quenched as well. We evaluate which mechanisms might be responsible for this quenching process. The presence of type 2 AGNs plays a role at damping the sSFR in bulges and less efficiently in disks. Also, the decrease in the sSFR of the disk component becomes more noticeable for stellar masses around for bulges, it is already present at . The analysis of the line-of-sight stellar velocity dispersions ( ) for the bulge component and of the corresponding Faber-Jackson relation shows that AGNs tend to have slightly higher values than star-forming galaxies for the same mass. Finally, the impact of environment is evaluated by means of the projected galaxy density, 5. We find that the SFR of both bulges and disks decreases in intermediate- to high-density environments. This work reflects the potential of combining IFS data with 2D multicomponent decompositions to shed light on the processes that regulate the SFR.
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