Durvalumab significantly improves overall survival for patients with unresectable stage III non-small-cell lung cancer and no progression after concurrent chemoradiotherapy (cCRT). Building upon that ...standard of care, COAST is a phase II study of durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab or anti-NKG2A monoclonal antibody monalizumab as consolidation therapy in this setting.
Patients with unresectable stage III non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and no progression after cCRT were randomly assigned 1:1:1, ≤ 42 days post-cCRT, to durvalumab alone or combined with oleclumab or monalizumab for up to 12 months, stratified by histology. The primary end point was investigator-assessed confirmed objective response rate (ORR; RECIST v1.1).
Between January 2019 and July 2020, 189 patients were randomly assigned. At this interim analysis (data cutoff, May 17, 2021), median follow-up was 11.5 months (range, 0.4-23.4 months; all patients). Confirmed ORR was numerically higher with durvalumab plus oleclumab (30.0%; 95% CI, 18.8 to 43.2) and durvalumab plus monalizumab (35.5%; 95% CI, 23.7 to 48.7) versus durvalumab (17.9%; 95% CI, 9.6 to 29.2). Progression-free survival (PFS) was prolonged with both combinations versus durvalumab (plus oleclumab: hazard ratio, 0.44; 95% CI, 0.26 to 0.75; and plus monalizumab: hazard ratio, 0.42; 95% CI, 0.24 to 0.72), with higher 12-month PFS rates (plus oleclumab: 62.6% 95% CI, 48.1 to 74.2 and plus monalizumab: 72.7% 95% CI, 58.8 to 82.6
durvalumab alone: 33.9% 95% CI, 21.2 to 47.1). All-cause grade ≥ 3 treatment-emergent adverse events occurred in 40.7%, 27.9%, and 39.4% with durvalumab plus oleclumab, durvalumab plus monalizumab, and durvalumab, respectively.
Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was similar across arms with no new or significant safety signals identified with either combination. These data support their further evaluation in a phase III trial.
Let
P
∈
Z
X
,
Y
be a given square-free polynomial of total degree
d
with integer coefficients of bitsize less than
τ
, and let
V
R
(
P
)
:
=
{
(
x
,
y
)
∈
R
2
∣
P
(
x
,
y
)
=
0
}
be the real ...planar algebraic curve implicitly defined as the vanishing set of
P
. We give a deterministic algorithm to compute the topology of
V
R
(
P
)
in terms of a simple straight-line planar graph
G
that is isotopic to
V
R
(
P
)
. The upper bound on the bit complexity of our algorithm is in
O
~
(
d
5
τ
+
d
6
)
(The expression “the complexity is in
O
~
(
f
(
d
,
τ
)
)
” with
f
a polynomial in
d
,
τ
is an abbreviation for the expression “there exists a positive integer
c
such that the complexity is in
O
(
(
log
d
log
τ
)
c
f
(
d
,
τ
)
)
”); which matches the current record bound for the problem of computing the topology of a planar algebraic curve. However, compared to existing algorithms with comparable complexity, our method does not consider any change of coordinates, and more importantly the returned simple planar graph
G
yields the cylindrical algebraic decomposition information of the curve in the original coordinates. Our result is based on two main ingredients: First, we derive amortized quantitative bounds on the roots of polynomials with algebraic coefficients as well as adaptive methods for computing the roots of bivariate polynomial systems that actually exploit this amortization. The results we obtain are more general that the previous literature. Our second ingredient is a novel approach for the computation of the local topology of the curve in a neighborhood of all singular points.
The pH-dependent partitioning of chemotherapeutic drugs is a fundamental yet understudied drug distribution mechanism that may underlie the low success rates of current approaches to counter ...multidrug resistance (MDR). This mechanism is influenced by the hypoxic tumour microenvironment and results in selective trapping of weakly basic drugs into acidified compartments such as the extracellular environment. Here we report that hypoxia not only leads to acidification of the tumour microenvironment but also induces endosome hyperacidification. The acidity of the vesicular lumen, together with the alkaline pH of the cytoplasm, gives rise to a strong intracellular pH gradient that drives intravesicular drug trapping and chemoresistance. Endosome hyperacidification is due to the relocalization of the Na
/H
exchanger isoform 6 (NHE6) from endosomes to the plasma membrane, an event that involves binding of NHE6 to the activated protein kinase C-receptor for activated C kinase 1 complex. These findings reveal a novel mechanism of hypoxia-induced MDR that involves the aberrant intracellular distribution of NHE6.
The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development ...of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient’s tumor.
In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, and the ability to profile circulating tumor fractions. Integrating these insights promises to continually advance the precision oncology field, fostering better patient outcomes.
Cancer biomarkers have transformed oncology, enabling treatments tailored to each tumor’s unique profile. This review highlights the field’s progress due to advancements in understanding cancer biology, testing methods, and understanding of the immune microenvironment to advance precision oncology for improved patient outcomes.
•OLDA inhibition mechanisms were investigated by polarization curves and Electrochemical Impedance Spectroscopy (EIS) measurements.•OLDA acts as a mixed inhibitor by blocking both the anodic and ...cathodic sites of the carbon steel surface.•Under conditions for which the corrosion is limited, the OLDA adsorption kinetics is temperature independent (25 °C – 50 °C).•The OLDA response on the impedance spectra is exacerbated in the presence of corrosion products.•Polarization Modulation Infrared Reflection Absorption Spectroscopy (PM-IRRAS) analyses revealed the formation of an OLDA monolayer in the absence of corrosion products.
In the present study, the inhibition mechanisms and the adsorption kinetics of a film-forming amine (N-oleyl-1,3-propanediamine, OLDA) were investigated on a carbon steel surface in various corrosive environments, relevant to industrial water/steam circuits. In situ electrochemical characterizations including Electrochemical Impedance Spectroscopy (EIS) and polarization curves were combined with ex situ surface analysis, such as Polarization Modulation Infrared Reflection Absorption Spectroscopy (PM-IRRAS) and Raman Spectroscopy. OLDA acts as a mixed inhibitor for all the studied conditions. In a deaerated medium, OLDA adsorption is temperature-independent (25 °C–50 °C) and PM-IRRAS analyses reveal the formation of a monolayer (thickness of about 1.6 nm) on the steel surface. In aerated media, mixed OLDA/corrosion products layers are formed exceeding the monolayer thickness (about 20 nm). Finally, the presence of a well-defined time constant in the high frequency range in impedance spectra is correlated with the accumulation of OLDA molecules with corrosion products.
The isolation and analysis of circulating cell-free tumor DNA in plasma is a powerful tool with considerable potential to improve clinical outcomes across multiple cancer types, including NSCLC. ...Assays of this nature that use blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of innovative platforms have been recently developed that improve not only the fidelity of the molecular analysis but also the number of tests performed on a single specimen. Circulating tumor DNA assays for detection of both EGFR sensitizing and resistance mutations have already entered clinical practice and many other molecular tests — such as detection of resistance mutations for Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase rearrangements — are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology was convened by the International Association for the Study of Lung Cancer to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs. In summary, the panel concluded that liquid biopsy approaches have significant potential to improve patient care, and immediate implementation in the clinic is justified in a number of therapeutic settings relevant to NSCLC.
A facile and rapid photochemical method for preparing supported silver nanoparticles (Ag-NPs) in a suspension of faujasite type (FAU) zeolite nanocrystals is described. Silver cations are introduced ...by ion exchange into the zeolite and subsequently irradiated with a Xe–Hg lamp (200 W) in the presence of a photoactive reducing agent (2-hydroxy-2-methylpropiophenone). UV–vis characterization indicates that irradiation time and intensity (I 0) influence significantly the amount of silver cations reduced. The full reduction of silver cations takes place after 60 s of a polychromatic irradiation, and a plasmon band of Ag-NPs appears at 380 nm. Transmission electron microscopy combined with theoretical calculation of the plasmon absorbance band using Mie theory shows that the Ag-NPs, stabilized in the micropores and on the external surface of the FAU zeolite nanocrystals, have an almost spheroidal shape with diameters of 0.75 and 1.12 nm, respectively. Ag-NPs, with a homogeneous distribution of size and morphology, embedded in a suspension of FAU zeolites are very stable (∼8 months), even without stabilizers or capping agents.
In tropical regions, most primary ecosystems have been replaced by mosaic landscapes in which species must cope with a large shift in the distribution of their habitat and associated food resources. ...Primates are particularly vulnerable to habitat modifications. Most species persist in small fragments surrounded by complex human-mediated matrices whose structure and connectivity may strongly influence their dispersal and feeding behavior. Behavioral plasticity appears to be a crucial parameter governing the ability of organisms to exploit the resources offered by new matrix habitats and thus to persist in fragmented habitats. In this study, we were interested in the dietary plasticity of the golden-crowned sifaka (Propithecus tattersalli), an endangered species of lemur, found only in the Daraina region in north-eastern Madagascar. We used a DNA-based approach combining the barcoding concept and Illumina next-generation sequencing to (i) describe the species diet across its entire range and (ii) evaluate the influence of landscape heterogeneity on diet diversity and composition. Faeces from 96 individuals were sampled across the entire species range and their contents were analyzed using the trnL metabarcoding approach. In parallel, we built a large DNA reference database based on a checklist of the plant species of the Daraina region. Our results suggest that golden-crowned sifakas exhibit remarkable dietary diversity with at least 130 plant species belonging to 80 genera and 49 different families. We highlighted an influence of both habitat type and openness on diet composition suggesting a high flexibility of foraging strategies. Moreover, we observed the presence of numerous cultivated and naturalized plants in the faeces of groups living in forest edge areas. Overall, our findings support our initial expectation that P. tattersalli is able to cope with the current level of alteration of the landscape and confirm our previous results on the distribution and the dispersal ability of this species.
Computational fragment-based approaches are widely used in drug design and discovery. One of their limitations is the lack of performance of docking methods, mainly the scoring functions. With the ...emergence of fragment-based approaches for single-stranded RNA ligands, we analyze the performance in docking and screening powers of an MCSS-based approach. The performance is evaluated on a benchmark of protein–nucleotide complexes where the four RNA residues are used as fragments. The screening power can be considered the major limiting factor for the fragment-based modeling or design of sequence-selective oligonucleotides. We show that the MCSS sampling is efficient even for such large and flexible fragments. Hybrid solvent models based on some partial explicit representations improve both the docking and screening powers. Clustering of the n best-ranked poses can also contribute to a lesser extent to better performance. A detailed analysis of molecular features suggests various ways to optimize the performance further.
•EIS is used to follow the OLDA adsorption kinetic onto carbon steel surface from 2 min to 140 min of immersion.•OLDA adsorption and corrosion processes occur simultaneously from the beginning of ...immersion.•OLDA preferentially adsorbed on the corrosion products.•For short immersion time, the barrier layer thickness is around 10-20 nm.•With increasing temperature, corrosion and, as a consequence, barrier layer thickness increases.
N-oleyl-1, 3-propanediamine (OLDA) is one of the most used film-forming amines (FFAs) for the corrosion protection of carbon steel circuits of a wide range of industrial plants. The present work focused on the study of OLDA adsorption kinetics onto the carbon steel surface by electrochemical impedance spectroscopy (EIS). The diagrams were obtained in a 200 mg.kg−1 NaCl with and without OLDA for immersion times ranging from 2 min to 140 min and for two temperatures (25°C and 50°C). It was shown that, from the beginning of immersion (2 min), OLDA adsorption and corrosion occurred simultaneously on the carbon steel surface. With increasing immersion time, a dynamic and competitive process between both phenomena was established until a steady-state was reached and the corrosion was slowed down. Ex situ Raman spectroscopy analyses revealed a heterogeneous distribution of the OLDA molecules on the surface with a preferential adsorption on the corrosion products, mainly γ-FeOOH. Ex situ Polarization Modulation Infrared Reflection Absorption Spectroscopy (PM-IRRAS) analyses confirmed the formation of mixed barrier layers (OLDA molecules/corrosion products) whose thickness increased with time and temperature.
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