The Ki-67 antigen is used to evaluate the proliferative activity of breast cancer (BC); however, Ki-67's role as a prognostic marker in BC is still undefined. In order to better define the prognostic ...value of Ki-67/MIB-1, we performed a meta-analysis of studies that evaluated the impact of Ki-67/MIB-1 on disease-free survival (DFS) and/or on overall survival (OS) in early BC. Sixty-eight studies were identified and 46 studies including 12 155 patients were evaluable for our meta-analysis; 38 studies were evaluable for the aggregation of results for DFS, and 35 studies for OS. Patients were considered to present positive tumours for the expression of Ki-67/MIB-1 according to the cut-off points defined by the authors. Ki-67/MIB-1 positivity is associated with higher probability of relapse in all patients (HR=1.93 (95% confidence interval (CI): 1.74-2.14); P<0.001), in node-negative patients (HR=2.31 (95% CI: 1.83-2.92); P<0.001) and in node-positive patients (HR=1.59 (95% CI: 1.35-1.87); P<0.001). Furthermore, Ki-67/MIB-1 positivity is associated with worse survival in all patients (HR=1.95 (95% CI: 1.70-2.24; P<0.001)), node-negative patients (HR=2.54 (95% CI: 1.65-3.91); P<0.001) and node-positive patients (HR=2.33 (95% CI: 1.83-2.95); P<0.001). Our meta-analysis suggests that Ki-67/MIB-1 positivity confers a higher risk of relapse and a worse survival in patients with early BC.
The dynein-2 motor complex drives retrograde intraflagellar transport (IFT), playing a pivotal role in the assembly and functions of cilia. However, the mechanisms that regulate dynein-2 motility ...remain poorly understood. Here, we identify the Caenorhabditis elegans WDR60 homologue, WDR-60, and dissect the roles of this intermediate chain using genome editing and live imaging of endogenous dynein-2/IFT components. We find that loss of WDR-60 impairs dynein-2 recruitment to cilia and its incorporation onto anterograde IFT trains, reducing retrograde motor availability at the ciliary tip. Consistent with this, we show that fewer dynein-2 motors power WDR-60-deficient retrograde IFT trains, which move at reduced velocities and fail to exit cilia, accumulating on the distal side of the transition zone. Remarkably, disrupting the transition zone's NPHP module almost fully restores ciliary exit of underpowered retrograde trains in wdr-60 mutants. This work establishes WDR-60 as a major contributor to IFT, and the NPHP module as a roadblock to dynein-2 passage through the transition zone.
Monte Carlo codes are a standard tool for studying energetic particle propagation, secondary production, and radiation in astrophysical settings. In magnetised plasmas such as those found in solar ...active regions, the enormous disparity between particle gyroradii and system scales proves to be a major computational obstacle. To address this problem we have written a new module in Geant4 using the guiding centre (GC) approach in which the particle motion is averaged over a gyrofrequency. We describe the formulation and implementation of this method in particular dealing with the uncertainty in gyrophase so that particle velocities are well-defined for input to the modules handling reactions. As far as feasible, we compare the propagation and slowing down of primary protons, secondary particle production, and run times in the GC limit with the Newton–Lorentz approach, finding very good agreement between the two methods and orders of magnitude improvement in run times in the GC case. Finally, we present an illustrative solar physics application involving two interacting dipoles, which is only achievable using the GC approach.
We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in ...patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial.
This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome.
Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 95% confidence interval (CI) 0.48-0.80 and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS hazard ratio (95% CI) for pembrolizumab versus chemotherapy was observed regardless of STK11 STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05); KEAP1 KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99), or KRAS KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18) mutation status.
tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.
•Pembrolizumab monotherapy is a standard first-line treatment of patients with PD-L1-positive advanced/metastatic NSCLC.•We assessed clinical utility of potential biomarkers among patients receiving pembrolizumab versus chemotherapy.•tTMB ≥175 mutations/exome was associated with improved outcomes among patients receiving pembrolizumab versus chemotherapy.•tTMB has potential clinical utility as a biomarker for pembrolizumab in first-line PD-L1-positive advanced/metastatic NSCLC.•Pembrolizumab improved overall survival versus chemotherapy regardless of STK11, KEAP1, or KRAS mutation status.
In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified ...exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data.
PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis.
At date cut-off of 24 March 2017, median follow-up was 31 months (range 23–41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 95% confidence interval (CI): 0.57, 0.77. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival 0.63 (95% CI: 0.45, 0.89) and newly collected samples 0.53 (95% CI: 0.38, 0.72). In patients with TPS ≥1%, PFS HRs were similar across archival 0.82 (95% CI: 0.66, 1.02) and newly collected samples 0.83 (95% CI: 0.68, 1.02).
Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples.
ClinicalTrials.gov: NCT01905657.
Abstract Aim To use published literature and experts’ opinion to investigate the clinical meaning and magnitude of changes in the Quality of Life (QOL) of groups of patients measured with the ...European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Methods An innovative method combining systematic review of published studies, expert opinions and meta-analysis was used to estimate large, medium, and small mean changes over time for QLQ-C30 scores. Results Nine hundred and eleven papers were identified, leading to 118 relevant papers. One thousand two hundred and thirty two mean changes in QOL over time were combined in the meta-analysis, with timescales ranging from four days to five years. Guidelines were produced for trivial, small, and medium size classes, for each subscale and for improving and declining scores separately. Estimates for improvements were smaller than respective estimates for declines. Conclusions These guidelines can be used to aid sample size calculations and interpretation of mean changes over time from groups of patients. Observed mean changes in the QLQ-C30 scores are generally small in most clinical situations, possibly due to response shift. Careful consideration is needed when planning studies where QOL changes over time are of primary interest; the timing of follow up, sample attrition, direction of QOL changes, and subscales of primary interest are key considerations.
Solar observations in the infrared domain can bring important clues on the response of the low solar atmosphere to primary energy released during flares. At present, the infrared continuum has been ...detected at 30 THz (10 μm) in only a few flares. SOL2012-03-13, which is one of these flares, has been presented and discussed in Kaufmann
et al.
(
Astrophys. J.
768
, 134,
2013
). No firm conclusions were drawn on the origin of the mid-infrared radiation. In this work we present a detailed multi-frequency analysis of the SOL2012-03-13 event, including observations at radio-millimeter and submillimeter wavelengths, in hard X-rays (HXR), gamma-rays (GR),
H
α
, and white light. The HXR/GR spectral analysis shows that SOL2012-03-13 is a GR line flare and allows estimating the numbers of and energy contents in electrons, protons, and
α
particles produced during the flare. The energy spectrum of the electrons producing the HXR/GR continuum is consistent with a broken power-law with an energy break at
∼
800
keV
. We show that the high-energy part (above
∼
800
keV
) of this distribution is responsible for the high-frequency radio emission (
>
20
GHz
) detected during the flare. By comparing the 30 THz emission expected from semi-empirical and time-independent models of the quiet and flare atmospheres, we find that most (
∼
80
%
) of the observed 30 THz radiation can be attributed to thermal free–free emission of an optically thin source. Using the F2 flare atmospheric model (Machado
et al.
in
Astrophys. J.
242
, 336,
1980
), this thin source is found to be at temperatures T
∼
8000
K
and is located well above the minimum temperature region. We argue that the chromospheric heating, which results in 80 % of the 30 THz excess radiation, can be due to energy deposition by nonthermal flare-accelerated electrons, protons, and
α
particles. The remaining 20 % of the 30 THz excess emission is found to be radiated from an optically thick atmospheric layer at T
∼
5000
K
, below the temperature minimum region, where direct heating by nonthermal particles is insufficient to account for the observed infrared radiation.
There is no agreement regarding which solvent is more suitable to obtain sol–gel–derived titania (TiO
2
) samples with an enhanced photocatalytic behavior. Furthermore, the solvent effect on the ...preparation of TiO
2
-RGO (reduced graphene oxide) nanocomposites has not been published yet and could be an attractive experimental strategy to modulate structure and properties. On the basis of these observations, TiO
2
-RGO nanocomposites were fabricated in this study. It was evaluated for the influence of using either isopropyl (IsoprOH) or ethyl (EtOH) alcohol on the textural and photocatalytic properties of the prepared materials. The use of IsoprOH led to samples with smaller crystallite size, narrower apparent band gap, smaller isoelectric point, larger adsorption capacity, and higher photocatalytic activity. In addition, the incorporation of RGO into TiO
2
greatly improved the adsorption capacity and photocatalytic activity of the latter. However, the optimal loading of RGO to prepare composites with enhanced photocatalytic activities was 1 wt%. This finding can be related to the stacking of RGO sheets when concentrations above 1 wt% are used, which could prevent UV light to reach the TiO
2
particles and also decrease the photocatalytic capacity of the composites. Moreover, materials with RGO concentration above 1 wt% could exhibit a highly negatively charged surface, which may decrease the separation of the generated electron–hole pairs and lead to faster recombination rates of charge carriers.
Cilia assembly and function require intraflagellar transport (IFT), a mechanism that uses “trains” to transport cargoes into and out of cilia. While much has been learned about IFT in the past ...decades, IFT train assembly, loading of cargo and transport regulation have remained poorly understood. In a recent study, Hesketh, Mukhopadhyay and colleagues obtained the complete structure of the IFT-A complex, a key element of IFT trains. By modelling IFT-A into anterograde trains and performing structure-guided mutagenesis, the authors uncover how the IFT-A complex polymerizes and forms carriages to accomplish its distinctive functions.
A number of cancer therapy agents are cleared by the kidney and may affect renal function, including cytotoxic chemotherapy agents, molecular targeted therapies, analgesics, antibiotics, ...radiopharmaceuticals and radiation therapy, and bone-targeted therapies. Many of these agents can be nephrotoxic, including targeted cancer therapies. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here, we review the renal effects associated with a selection of currenty approved targeted cancer therapies, directed to vascular endothelial growth factor or VEGF receptor(s) (VEGF/VEGFR), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor2 (HER2), BRAF, anaplastic lymphoma kinase (ALK), programmed cell death protein-1 or its ligand (PD-1/PDL-1), receptor activator of nuclear factor kappa-B ligand (RANKL), and mammalian target of rapamycin (mTOR). The early diagnosis and prompt treatment of these renal alterations are essential in the daily practice where molecular targeted therapies have a definitive role in the armamentarium used in many cancers.
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