ontrolled vocabularies are a common component in applications of linked data in order to connect digital resources. There are applications in the Humanities and digital editions, too. Two scenarios are described in some detail. The first concerns the analysis of annotations on manuscripts of Aristotle’s De interpretatione. In conjunction with transcriptions, the usage of authority files in metadata as well of domain specific vocabularies helps in this example to find stemmatological relations between glosses and diagrams in some of the manuscripts. The second example is not about a text-critical application but about the creation of the thesaurus for a commentary on Michael Maier’s Atalanta fugiens, that is a multimodal, figurative and dense written book by today’s standards. The question is raised as to what extent a controlled vocabulary with its concepts and the implicit semantics of the relations between them can be of a heuristic value for the reconstruction of this historical, alchemical concepts in its dynamics and alterity.View less
Archaeological narratives have traditionally associated the rise of social and political ‘complexity’ with the emergence of agricultural societies. However, this framework neglects the innovations of the hunter-gatherer populations occupying the Siberian taiga 8000 years ago, including the construction of some of the oldest-known fortified sites in the world. Here, the authors present results from the fortified site of Amnya in western Siberia, reporting new radiocarbon dates as the basis for a re-evaluation of the chronology and settlement organisation. Assessed within the context of the changing social and environmental landscape of the taiga, Amnya and similar fortified sites can be understood as one facet of a broader adaptive strategy.View less
The thalamus is primarily known as a relay for sensory information; however, it also critically contributes to higher-order cortical processing and coordination. Thalamocortical hyperconnectivity is associated with hallucinatory phenomena that occur in various psychopathologies (e.g., psychosis, migraine aura) and altered states of consciousness (ASC; e.g., induced by psychedelic drugs). However, the exact functional contribution of thalamocortical hyperconnectivity in forming hallucinatory experiences is unclear. Flicker light stimulation (FLS) can be used as an experimental tool to induce transient visual hallucinatory phenomena in healthy participants. Here, we use FLS in combination with fMRI to test how FLS modulates thalamocortical connectivity between specific thalamic nuclei and visual areas. We show that FLS induces thalamocortical hyperconnectivity between lateral geniculate nucleus (LGN), early visual areas, and proximal upstream areas of the ventral visual stream (e.g., hV4, VO1). Further, an exploratory analysis indicates specific higher-order thalamic nuclei, such as anterior and mediodorsal nuclei, to be strongly affected by FLS. Here, the connectivity changes to upstream cortical visual areas directly reflect a frequency-dependent increase in experienced visual phenomena. Together, these findings contribute to the identification of specific thalamocortical interactions in the emergence of visual hallucinations.View less
Background: We evaluated the role of radiomics applied to contrast-enhanced computed tomography (CT) in the detection of lymph node (LN) metastases in patients with known lung cancer compared to 18F-fluorodeoxyglucose positron emission tomography (PET)/CT as a reference.
Methods: This retrospective analysis included 381 patients with 1,799 lymph nodes (450 malignant, 1,349 negative). The data set was divided into a training and validation set. A radiomics analysis with 4 filters and 6 algorithms resulting in 24 different radiomics signatures and a bootstrap algorithm (Bagging) with 30 bootstrap iterations was performed. A decision curve analysis was applied to generate a net benefit to compare the radiomics signature to two expert radiologists as one-by-one and as a prescreening tool in combination with the respective radiologist and only the radiologists.
Results: All 24 modeling methods showed good and reliable discrimination for malignant/benign LNs (area under the curve 0.75-0.87). The decision curve analysis showed a net benefit for the least absolute shrinkage and selection operator (LASSO) classifier for the entire probability range and outperformed the expert radiologists except for the high probability range. Using the radiomics signature as a prescreening tool for the radiologists did not improve net benefit.
Conclusions: Radiomics showed good discrimination power irrespective of the modeling technique in detecting LN metastases in patients with known lung cancer. The LASSO classifier was a suitable diagnostic tool and even outperformed the expert radiologists, except for high probabilities. Radiomics failed to improve clinical benefit as a prescreening tool.View less
Background: In radiomics studies, differences in the volume of interest (VOI) are often inevitable and may confound the extracted features. We aimed to correct this confounding effect of VOI variability by applying parametric maps with a fixed voxel size.
Methods: Ten scans of a cup filled with sodium chloride solution were scanned using a multislice computed tomography (CT) unit. Sphere-shaped VOIs with different diameters (4, 8, or 16 mm) were drawn centrally into the phantom. A total of 93 features were extracted conventionally from the original images using PyRadiomics. Using a self-designed and pretested software tool, parametric maps for the same 93 features with a fixed voxel size of 4 mm3 were created. To retrieve the feature values from the maps, VOIs were copied from the original images to preserve the position. Differences in feature quantities between the VOI sizes were tested with the Mann-Whitney U-test and agreement with overall concordance correlation coefficients (OCCC).
Results: Fifty-five conventionally extracted features were significantly different between the VOI sizes, and none of the features showed excellent agreement in terms of OCCCs. When read from the parametric maps, only 8 features showed significant differences, and 3 features showed an excellent OCCC (≥ 0.85). The OCCCs for 89 features substantially increased using the parametric maps.
Conclusions: This phantom study shows that converting CT images into parametric maps resolves the confounding effect of VOI variability and increases feature reproducibility across VOI sizes.View less
Background: Multisegment reconstruction (MSR) was introduced to shorten the temporal reconstruction window of computed tomography (CT) and thereby reduce motion artefacts. We investigated whether MSR of myocardial CT perfusion (CTP) can improve diagnostic performance in detecting obstructive coronary artery disease (CAD) compared with halfscan reconstruction (HSR).
Methods: A total of 134 patients (median age 65.7 years) with clinical indication for invasive coronary angiography and without cardiac surgery prospectively underwent static CTP. In 93 patients with multisegment acquisition, we retrospectively performed both MSR and HSR and searched both reconstructions for perfusion defects. Subgroups with known (n = 68) or suspected CAD (n = 25) and high heart rate (n = 30) were analysed. The area under the curve (AUC) was compared applying DeLong approach using >= 50% stenosis on invasive coronary angiography as reference standard.
Results: Per-patient analysis revealed the overall AUC of MSR (0.65 [95% confidence interval 0.53, 0.78]) to be inferior to that of HSR (0.79 [0.69, 0.88]; p = 0.011). AUCs of MSR and HSR were similar in all subgroups analysed (known CAD 0.62 [0.45, 0.79] versus 0.72 [0.57, 0.86]; p = 0.157; suspected CAD 0.80 [0.63, 0.97] versus 0.89 [0.77, 1.00]; p = 0.243; high heart rate 0.46 [0.19, 0.73] versus 0.55 [0.33, 0.77]; p = 0.389). Median stress radiation dose was higher for MSR than for HSR (6.67 mSv versus 3.64 mSv, p < 0.001).
Conclusions: MSR did not improve diagnostic performance of myocardial CTP imaging while increasing radiation dose compared with HSR.View less
Introduction: Intramedullary (IM) fixation is the dominant treatment for pertrochanteric and femoral shaft fractures. In comparison to plate osteosynthesis (PO), IM fixation offers greater biomechanical stability and reduced non-union rates. Due to the minimally invasive nature, IM fixations are less prone to approach-associated complications, such as soft-tissue damage, bleeding or postoperative infection, but they are more prone to fat embolism. A rare but serious complication, however, is implant failure. Thus, the aim of this study was to identify possible risk factors for intramedullary fixation (IMF) and plate osteosynthesis (PO) failure.
Materials: and methods We searched our trauma surgery database for implant failure, intramedullary and plate osteosynthesis, after proximal-pertrochanteric, subtrochanteric-or femoral shaft fractures between 2011 and 2019. Implant failures in both the IMF and PO groups were included. Demographic data, fracture type, quality of reduction, duration between initial implantation and nail or plate failure, the use of cerclages, intraoperative microbiological samples, sonication, and, if available, histology were collected.
Results: A total of 24 femoral implant failures were identified: 11 IMFs and 13 POs. The average age of patients in the IM group was 68.2 +/- 13.5 years and in the PO group was 65.6 +/- 15.0 years, with men being affected in 63.6% and 39.5% of cases, respectively. A proximal femoral nail (PFN) anti-rotation was used in 7 patients, a PFN in one and a gamma nail in two patients. A total of 6 patients required cerclage wires for additional stability. A combined plate and intramedullary fixation was chosen in one patient. Initially, all intramedullary nails were statically locked. Failures were observed 34.1 weeks after the initial surgery on average. Risk factors for implant failure included the application of cerclage wires at the level of the fracture (n = 5, 21%), infection (n = 2, 8%), and the use of an additional sliding screw alongside the femoral neck screw (n = 3, 13%). In all patients, non-union was diagnosed radiographically and clinically after 6 months (n = 24, 100%). In the event of PO failure, the placement of screws within all screw holes, and interprosthetic fixation were recognised as the major causes of failure.
Conclusion: Intramedullary or plate osteosynthesis remain safe and reliable procedures in the treatment of proximal femoral fractures (pertrochanteric, subtrochanteric and femoral shaft fractures). Nevertheless, the surgeon needs to be aware of several implant-related limitations causing implant breakage. These may include the application of tension band wiring which can lead to a too rigid fixation, or placement of cerclage wires at the fracture site.View less
Background: The radiometal gallium-68 (Ga-68) is increasingly used in diagnostic positron emission tomography (PET), with Ga-68-labeled radiopharmaceuticals developed as potential higher-resolution imaging alternatives to traditional Tc-99m agents. In precision medicine, PET applications of Ga-68 are widespread, with Ga-68 radiolabeled to a variety of radiotracers that evaluate perfusion and organ function, and target specific biomarkers found on tumor lesions such as prostate-specific membrane antigen, somatostatin, fibroblast activation protein, bombesin, and melanocortin.
Main body: These Ga-68 radiopharmaceuticals include agents such as [Ga-68]Ga-macroaggregated albumin for myocardial perfusion evaluation, [Ga-68]Ga-PLED for assessing renal function, [Ga-68]Ga-t-butyl-HBED for assessing liver function, and [Ga-68]Ga-PSMA for tumor imaging. The short half-life, favourable nuclear decay properties, ease of radiolabeling, and convenient availability through germanium-68 (Ge-68) generators and cyclotron production routes strongly positions Ga-68 for continued growth in clinical deployment. This progress motivates the development of a set of common guidelines and standards for the Ga-68 radiopharmaceutical community, and recommendations for centers interested in establishing Ga-68 radiopharmaceutical production.
Conclusion: This review outlines important aspects of Ga-68 radiopharmacy, including Ga-68 production routes using a Ge-68/Ga-68 generator or medical cyclotron, standardized Ga-68 radiolabeling methods, quality control procedures for clinical Ga-68 radiopharmaceuticals, and suggested best practices for centers with established or upcoming Ga-68 radiopharmaceutical production. Finally, an outlook on Ga-68 radiopharmaceuticals is presented to highlight potential challenges and opportunities facing the community.View less
Context. The TOI-178 system consists of a nearby late K-dwarf transited by six planets in the super-Earth to mini-Neptune regime, with radii ranging from ~1.1 to 2.9 R⊕ and orbital periods between 1.9 and 20.7 days. All planets but the innermost one form a chain of Laplace resonances. Mass estimates derived from a preliminary radial velocity (RV) dataset suggest that the planetary densities do not decrease in a monotonic way with the orbital distance to the star, contrary to what one would expect based on simple formation and evolution models.
Aims. To improve the characterisation of this key system and prepare for future studies (in particular with JWST), we performed a detailed photometric study based on 40 new CHEOPS visits, one new TESS sector, and previously published CHEOPS, TESS, and NGTS data.
Methods. First we updated the parameters of the host star using the new parallax from Gaia EDR3. We then performed a global analysis of the 100 transits contained in our data to refine the physical and orbital parameters of the six planets and study their transit timing variations (TTVs). We also used our extensive dataset to place constraints on the radii and orbital periods of potential additional transiting planets in the system.
Results. Our analysis significantly refines the transit parameters of the six planets, most notably their radii, for which we now obtain relative precisions of ≲3%, with the exception of the smallest planet, b, for which the precision is 5.1%. Combined with the RV mass estimates, the measured TTVs allow us to constrain the eccentricities of planets c to g, which are found to be all below 0.02, as expected from stability requirements. Taken alone, the TTVs also suggest a higher mass for planet d than that estimated from the RVs, which had been found to yield a surprisingly low density for this planet. However, the masses derived from the current TTV dataset are very prior-dependent, and further observations, over a longer temporal baseline, are needed to deepen our understanding of this iconic planetary system.View less
The Sun is magnetically active and often produces eruptive events on different energetic and temporal scales. Until recently, the upper limit of such events was unknown and believed to be roughly represented by direct instrumental observations. However, two types of extreme events were discovered recently: extreme solar energetic particle events on the multi-millennial time scale and super-flares on sun-like stars. Both discoveries imply that the Sun might rarely produce events, called extreme solar events (ESE), whose energy could be orders of magnitude greater than anything we have observed during recent decades. During the years following these discoveries, great progress has been achieved in collecting observational evidence, uncovering new events, making statistical analyses, and developing theoretical modelling. The ESE paradigm lives and is being developed. On the other hand, many outstanding questions still remain open and new ones emerge. Here we present an overview of the current state of the art and the forming paradigm of ESE from different points of view: solar physics, stellar–solar projections, cosmogenic-isotope data, modelling, historical data, as well as terrestrial, technological and societal effects of ESEs. Special focus is paid to open questions and further developments. This review is based on the joint work of the International Space Science Institute (ISSI) team #510 (2020–2022).View less
Large-scale classical dust cycle models, developed more than two decades ago, assume for simplicity that the Earth's land surface is devoid of vegetation, reduce dust emission estimates using a vegetation cover complement, and calibrate estimates to observed atmospheric dust optical depth (DOD). Consequently, these models are expected to be valid for use with dust-climate projections in Earth System Models. We reveal little spatial relation between DOD frequency and satellite observed dust emission from point sources (DPS) and a difference of up to 2 orders of magnitude. We compared DPS data to an exemplar traditional dust emission model (TEM) and the albedo-based dust emission model (AEM) which represents aerodynamic roughness over space and time. Both models overestimated dust emission probability but showed strong spatial relations to DPS, suitable for calibration. Relative to the AEM calibrated to the DPS, the TEM overestimated large dust emission over vast vegetated areas and produced considerable false change in dust emission. It is difficult to avoid the conclusion that calibrating dust cycle models to DOD has hidden for more than two decades, these TEM modeling weaknesses. The AEM overcomes these weaknesses without using masks or vegetation cover data. Considerable potential therefore exists for ESMs driven by prognostic albedo, to reveal new insights of aerosol effects on, and responses to, contemporary and environmental change projections.View less
The mobility of transposable elements (TEs) contributes to evolution of genomes. Their uncontrolled activity causes genomic instability; therefore, expression of TEs is silenced by host genomes. TEs are marked with DNA and H3K9 methylation, which are associated with silencing in flowering plants, animals, and fungi. However, in distantly related groups of eukaryotes, TEs are marked by H3K27me3 deposited by the Polycomb repressive complex 2 (PRC2), an epigenetic mark associated with gene silencing in flowering plants and animals. The direct silencing of TEs by PRC2 has so far only been shown in one species of ciliates. To test if PRC2 silences TEs in a broader range of eukaryotes, we generated mutants with reduced PRC2 activity and analyzed the role of PRC2 in extant species along the lineage of Archaeplastida and in the diatom P. tricornutum. In this diatom and the red alga C. merolae, a greater proportion of TEs than genes were repressed by PRC2, whereas a greater proportion of genes than TEs were repressed by PRC2 in bryophytes. In flowering plants, TEs contained potential cis-elements recognized by transcription factors and associated with neighbor genes as transcriptional units repressed by PRC2. Thus, silencing of TEs by PRC2 is observed not only in Archaeplastida but also in diatoms and ciliates, suggesting that PRC2 deposited H3K27me3 to silence TEs in the last common ancestor of eukaryotes. We hypothesize that during the evolution of Archaeplastida, TE fragments marked with H3K27me3 were selected to shape transcriptional regulation, controlling networks of genes regulated by PRC2.View less
The evolution of endothermy in vertebrates is a major research topic in recent decades that has been tackled by a myriad of research disciplines including paleontology, anatomy, physiology, evolutionary and developmental biology. The ability of most mammals to maintain a relatively constant and high body temperature is considered a key adaptation, enabling them to successfully colonize new habitats and harsh environments. It has been proposed that in mammals the anterior nasal cavity, which houses the maxilloturbinal, plays a pivotal role in body temperature maintenance, via a bony system supporting an epithelium involved in heat and moisture conservation. The presence and the relative size of the maxilloturbinal has been proposed to reflect the endothermic conditions and basal metabolic rate in extinct vertebrates. We show that there is no evidence to relate the origin of endothermy and the development of some turbinal bones by using a comprehensive dataset of µCT-derived maxilloturbinals spanning most mammalian orders. Indeed, we demonstrate that neither corrected basal metabolic rate nor body temperature significantly correlate with the relative surface area of the maxilloturbinal. Instead, we identify important variations in the relative surface area, morpho-anatomy, and complexity of the maxilloturbinal across the mammalian phylogeny and species ecology.View less
Soils provide essential ecosystem functions that are threatened by climate change and intensified land use. We explore how climate and land use impact multiple soil function simultaneously, employing two datasets: (1) observational – 456 samples from the European Land Use/Land Cover Area Frame Survey; and (2) experimental – 80 samples from Germany’s Global Change Experimental Facility. We aim to investigate whether manipulative field experiment results align with observable climate, land use, and soil multifunctionality trends across Europe, measuring seven ecosystem functions to calculate soil multifunctionality. The observational data showed Europe-wide declines in soil multifunctionality under rising temperatures and dry conditions, worsened by cropland management. Our experimental data confirmed these relationships, suggesting that changes in climate will reduce soil multifunctionality across croplands and grasslands. Land use changes from grasslands to croplands threaten the integrity of soil systems, and enhancing soil multifunctionality in arable systems is key to maintain multifunctionality in a changing climate.View less
Introduction: Despite the wealth of studies dealing with the invasions of alien plants, invasions of alien genotypes of native species (cryptic invasions) have been vastly neglected. The impact of cryptic invasions on the biodiversity of plant communities can, however, be significant. Inland saline habitats and halophytes (i.e., salt-tolerant plant species) are especially threatened by this phenomenon as they inhabit fragmented remnants of largely destroyed habitats, but at the same time some of these halophytic species are rapidly spreading along salt-treated roads. To study potential cryptic invasion of halophytes, the patterns of genome size and ploidy variation in the Puccinellia distans complex (Poaceae), the most rapidly spreading roadside halophyte in Central Europe, were investigated.
Methods: DNA flow cytometry with confirmatory chromosome counts were employed to assess ploidy levels of 1414 individuals from 133 populations of the P. distans complex. In addition, climatic niche modelling was used to predict the distributions of selected cytotypes.
Results: Eight groups differing in ploidy level and/or genome size were discovered, one diploid (2x; 2n = 14), two tetraploid (4xA, 4xB; 2n = 28), one pentaploid (5x; 2n = 35), three hexaploid (6xA, 6xB, 6xC; 2n = 42), and one heptaploid (7x; 2n = 49). The hexaploids (mostly the 6xC cytotype) were widespread through the study area, spreading intensively in both anthropogenic and natural habitats and probably hybridizing with the natural habitat dwelling tetraploids. In contrast, the non-hexaploid cytotypes rarely spread and were predominantly confined to natural habitats.
Discussion: The extensive spread of the hexaploid cytotypes along roadsides has most likely facilitated their incursion into natural habitats. The colonization of new natural habitats by the hexaploids may pose a threat to the indigenous Puccinellia populations by compromising their genetic integrity and/or by outcompeting them.View less
Volcanoes that deposit eruptive products into the ocean can trigger phytoplankton blooms near the deposition area. Phytoplankton blooms impact the global carbon cycle, but the specific conditions and mechanisms that facilitate volcanically triggered blooms are not well understood, especially in low nutrient ocean regions. We use satellite remote sensing to analyze the chlorophyll response to an 8-month period of explosive and effusive activity from Nishinoshima volcano, Japan. Nishinoshima is an ocean island volcano in a low nutrient low chlorophyll region of the Northern Pacific Ocean. From June to August 2020, during explosive activity, satellite-derived chlorophyll-a was detectable with amplitudes significantly above the long-term climatological value. After the explosive activity ceased in mid-August 2020, these areas of heightened chlorophyll concentration decreased as well. In addition, we used aerial observations and satellite imagery to demonstrate a spatial correlation between blooms and ash plume direction. Using a sun-induced chlorophyll-a fluorescence satellite product, we confirmed that the observed chlorophyll blooms are phytoplankton blooms. Based on an understanding of the nutrients needed to supply blooms, we hypothesize that blooms of nitrogen-fixing phytoplankton led to a 1010–1012 g drawdown of carbon. Thus, the bloom could have significantly mediated the output of carbon from the explosive phase of the eruption but is a small fraction of anthropogenic CO2 stored in the ocean or the global biological pump. Overall, we provide a case study of fertilization of a nutrient-poor ocean with volcanic ash and demonstrate a scenario where multi-month scale deposition triggers continuous phytoplankton blooms across 1,000s of km2.View less
Intervertebral cage subsidence is a common complication in treating disc-associated cervical spondylomyelopathy in dogs. The mechanical stability of the vertebral endplate in contact with the cage is crucial to preventing subsidence. This study aims to assess subchondral bone mineral density (sBMD) in the canine vertebral endplate (specifically, the C6-C7 vertebral motion unit) as a measure of its mechanical stability. The sBMD distribution was mapped for the C6 caudal and C7 cranial vertebral endplates in 15 middle- to large-breed dogs using computed tomography osteoabsorptiometry. The sBMD distribution in the canine C6 and C7 vertebral endplates exhibited a heterogeneous pattern, with lower density observed in the central and dorsal contact areas of the nucleus pulposus, where common subsidence occurs. Our results suggest a potential need to redesign intervertebral cages to ensure that contact areas align with regions of higher bone density. A broad-based design extending toward the lateral and dorsal aspects of the annulus fibrosus contact area may enhance stability.View less
Non-O1 and non-O139 Vibrio cholerae (NOVC) can cause gastrointestinal infections in humans. Contaminated food, especially seafood, is an important source of human infections. In this study, the virulence potential of 63 NOVC strains isolated from retail seafood were characterized at the genotypic and phenotypic levels. Although no strain encoded the cholera toxin (CTX) and the toxin-coregulated pilus (TCP), several virulence factors, including the HlyA hemolysin, the cholix toxin ChxA, the heat-stable enterotoxin Stn, and genes coding for the type 3 and type 6 secretion systems, were detected. All strains showed hemolytic activity against human and sheep erythrocytes: 90% (n = 57) formed a strong biofilm, 52% (n = 33) were highly motile at 37 °C, and only 8% (n = 5) and 14% (n = 9) could resist ≥60% and ≥40% human serum, respectively. Biofilm formation and toxin regulation genes were also detected. cgMLST analysis demonstrated that NOVC strains from seafood cluster with clinical NOVC strains. Antimicrobial susceptibility testing (AST) results in the identification of five strains that developed non-wildtype phenotypes (medium and resistant) against the substances of the classes of beta-lactams (including penicillin, carbapenem, and cephalosporin), polymyxins, and sulphonamides. The phenotypic resistance pattern could be partially attributed to the acquired resistance determinants identified via in silico analysis. Our results showed differences in the virulence potential of the analyzed NOVC isolated from retail seafood products, which may be considered for further pathogenicity evaluation and the risk assessment of NOVC isolates in future seafood monitoring.View less
Rare gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and PDGFRA genes. Avapritinib (BLU-285) is a targeted selective inhibitor for mutated KIT and PDGFRA receptors that can be used to treat these tumors. However, there are subtypes of GISTs that exhibit resistance against BLU-285 and thus require other treatment strategies. This can be addressed by employing a drug delivery system that transports a combination of drugs with distinct cell targets. In this work, we present the synthesis of esterase-responsive polyglycerol-based nanogels (NGs) to overcome drug resistance in rare GISTs. Using inverse nanoprecipitation mediated with inverse electron-demand Diels–Alder cyclizations (iEDDA) between dPG-methyl tetrazine and dPG-norbornene, multi-drug-loaded NGs were formed based on a surfactant-free encapsulation protocol. The obtained NGs displayed great stability in the presence of fetal bovine serum (FBS) and did not trigger hemolysis in red blood cells over a period of 24 h. Exposing the NGs to Candida Antarctica Lipase B (CALB) led to the degradation of the NG network, indicating the capability of targeted drug release. The bioactivity of the loaded NGs was tested in vitro on various cell lines of the GIST-T1 family, which exhibit different drug resistances. Cell internalization with comparable uptake kinetics of the NGs could be confirmed by confocal laser scanning microscopy (CLSM) and flow cytometry for all cell lines. Cell viability and live cell imaging studies revealed that the loaded NGs are capable of intracellular drug release by showing similar IC50 values to those of the free drugs. Furthermore, multi-drug-loaded NGs were capable of overcoming BLU-285 resistance in T1-α-D842V + G680R cells, demonstrating the utility of this carrier system.View less
In oncology, longitudinal biomarkers reflecting the patient’s status and disease evolution can offer reliable predictions of the patient’s response to treatment and prognosis. By leveraging clinical data in patients with advanced non-small-cell lung cancer receiving first-line chemotherapy, we aimed to develop a framework combining anticancer drug exposure, tumor dynamics (RECIST criteria), and C-reactive protein (CRP) concentrations, using nonlinear mixed-effects models, to evaluate and quantify by means of parametric time-to-event models the significance of early longitudinal predictors of progression-free survival (PFS) and overall survival (OS). Tumor dynamics was characterized by a tumor size (TS) model accounting for anticancer drug exposure and development of drug resistance. CRP concentrations over time were characterized by a turnover model. An x-fold change in TS from baseline linearly affected CRP production. CRP concentration at treatment cycle 3 (day 42) and the difference between CRP concentration at treatment cycles 3 and 2 were the strongest predictors of PFS and OS. Measuring longitudinal CRP allows for the monitoring of inflammatory levels and, along with its reduction across treatment cycles, presents a promising prognostic marker. This framework could be applied to other treatment modalities such as immunotherapies or targeted therapies allowing the timely identification of patients at risk of early progression and/or short survival to spare them unnecessary toxicities and provide alternative treatment decisions.View less