julilili42/papers huggingface dataset:
Chemotherapy-induced cognitive impairment and its long-term development in patients with breast cancer: results from the observational CICARO study
2024-10-14

Abstract Background Chemotherapy-induced cognitive impairment (CICI) is a well-recognized side effect of breast cancer treatment. However, prospective long-term evaluations of CICI using standardized neuropsychological tests are scarce. Patients and Methods This prospective longitudinal cohort study investigated cognitive dysfunction and its impact on quality of life and everyday functioning in patients with breast cancer receiving first-line chemotherapy compared to patients with breast cancer without chemotherapy. Assessment occurred prior to chemotherapy, postchemotherapy (median 6 months), and 2-3 years later. We used standardized neuropsychological tests, questionnaires, and scales to assess patients’ quality of life and functioning. Additionally, serum analysis for neurodegenerative markers and autoantibodies was conducted. Results We included n = 53 patients. Overall cognitive function declined statistically significantly (P = .046) postchemotherapy compared to control patients, mostly driven by a reduced figural memory (P = .011). Patients who received chemotherapy showed a greater reduction in quality of life (increased fatigue symptoms, P = .023; reduced Karnofsky index, P &amp;lt; .001); however, without a statistically significant effect on cognitive decline. The neurodegenerative markers Neurofilament light chain (NfL) and phosphorylated Neurofilament heavy chain (pNfH) increased statistically significantly (P &amp;lt; .001) postchemotherapy and pNfH correlated with overall cognitive function. After 2-3 years, both cognitive performance and quality of life were comparable between chemotherapy-treated and control patients. Conclusion Our findings suggest that chemotherapy statistically significantly contributes to overall cognitive dysfunction in patients with breast cancer, which disappears after 2-3 years, indicating a recovery in both objectively measurable cognitive function and subjective quality of life. Future research should examine larger sample sizes and explore screening indicators, particularly pNfH.
AML-VAC-XS15-01: protocol of a first-in-human clinical trial to evaluate the safety, tolerability and preliminary efficacy of a multi-peptide vaccine based on leukemia stem cell antigens in acute myeloid leukemia patients
2024-10-14

Introduction Acute myeloid leukemia (AML) has a dismal prognosis, mostly due to minimal residual disease-driven relapse, making an elimination of persisting therapy-resistant leukemia progenitor/stem cells (LPCs) the main goal for novel therapies. Peptide-based immunotherapy offers a low-side-effect approach aiming to induce T cell responses directed against human leukocyte antigen (HLA) presented tumor antigens on malignant cells by therapeutic vaccination. Mass spectrometry-based analysis of the naturally presented immunopeptidome of primary enriched LPC and AML samples enabled the selection of antigens exclusively expressed on LPC/AML cells, which showed de novo induction and spontaneous memory T cell responses in AML patients, and whose presentation and memory T cell recognition was associated with improved disease outcome. Methods Based on these data the therapeutic vaccine AML-VAC-XS15 was designed, comprising two mutated HLA class I-restricted peptides from the common AML-specific mutation in NPM1 and seven HLA class II-restricted peptides (six non-mutated high-frequent AML/LPC-associated antigens and one mutated peptide from the AML-specific mutation R140Q in IDH2), adjuvanted with the toll like receptor 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. A phase I open label clinical trial investigating AML-VAC-XS15 was designed, recruiting AML patients in complete cytological remission (CR) or CR with incomplete blood count recovery. Patients are vaccinated twice with a six-week interval, with an optional booster vaccination four months after 2nd vaccination, and are then followed up for two years. The trial’s primary objectives are the assessment of the vaccine’s immunogenicity, safety and toxicity, secondary objectives include characterization of vaccine-induced T cell responses and assessment of preliminary clinical efficacy. Ethics and dissemination The AML-VAC-XS15-01 study was approved by the Ethics Committee of the Bavarian State medical association and the Paul-Ehrlich Institut (P01392). Clinical trial results will be published in peer-reviewed journals.
A novel orf virus vector-based COVID-19 booster vaccine shows cross-neutralizing activity in the absence of anti-vector neutralizing immunity
2024-10-14

Next-generation COVID-19 vaccines are being developed to expand the breadth of coverage against existing and future variants and to extend the duration of protection. Prime-2-CoV_Beta is an orf virus (ORFV) based multi-antigen COVID-19 vaccine that co-expresses Spike (S) and Nucleocapsid (N) antigens. The safety and immunogenicity of Prime-2-CoV_Beta is investigated in a phase 1 first-in-human (FIH) dose-finding trial (ORFEUS study, ClinicalTrials.gov: NCT05367843). Participants of two age groups (18–55 and 65–85 years) who previously completed at least two doses of mRNA vaccines were enrolled and sequentially assigned to different dose groups to receive one intramuscular dose of 3 × 10<sup>5</sup>, 3 × 10<sup>6</sup>, 1.5 × 10<sup>7</sup>, or 3 × 10<sup>7</sup> plaque-forming units (PFU) of Prime-2-CoV_Beta on day 1 and a second dose on day 29. Here, we report safety and immunogenicity data collected up to 6 months after the first study vaccination. Prime-2-CoV_Beta is safe and well tolerated and elicits immune responses at higher dose levels in participants aged 18–55. A single dose of 3 × 10<sup>7</sup> PFU boosted binding and cross-neutralizing antibody responses that are maintained through 6 months after the first booster vaccination. Polyfunctional S-specific CD4+ and CD8+ T cell responses are observed after vaccination. No pre-existing or vaccine-induced neutralizing anti-vector antibodies are detected. Our findings highlight the potential of the ORFV vector as a safe platform for future vaccine design, which provides the ability to deliver multiple antigens and allows for repeat immunization.
Markers of consciousness in infants: Towards a ‘cluster‐based’ approach
2024-10-14

Abstract As recently as the 1980s, it was not uncommon for paediatric surgeons to operate on infants without anaesthesia. Today, the same omission would be considered criminal malpractice, and there is an increased concern with the possibility of consciousness in the earliest stage of human infancy. This concern reflects a more general trend that has characterised science since the early 1990s of taking consciousness seriously. While this attitude shift has opened minds towards the possibility that our earliest experiences predate our first memories, convincing demonstrations of infant consciousness remain challenging given that infants cannot report on their experiences. Furthermore, while many behavioural and neural markers of consciousness that do not rely on language have been validated in adults, no one specific marker can be confidently translated to infancy. For this reason, we have proposed the ‘cluster‐based’ approach, in which a consensus of evidence across many markers, all pointing towards the same developmental period, could be used to argue convincingly for the presence of consciousness. Conclusion We review the most promising markers for early consciousness, arguing that consciousness is likely to be in place by 5 months of age if not earlier.
Emergence of lineage ST150 and linezolid resistance in Enterococcus faecalis: a molecular epidemiology study of UTIs in Tehran, Iran
2024-10-14

Background Urinary tract infections (UTIs) represent one of the most prevalent bacterial infections, with Enterococcus species now recognized as the second leading cause of these infections. This study focused on symptomatic UTI cases to investigate the risk factors associated with Enterococcus faecalis clinical isolates in patients from Tehran, Iran. Methods Urine samples were collected from patients presenting with symptomatic UTIs. The identification of E. faecalis isolates was performed using standard microbiological techniques, with confirmation via polymerase chain reaction (PCR). Antibiotic susceptibility testing was conducted using the Kirby–Bauer disc diffusion method. The presence of virulence genes was determined through PCR, and biofilm formation was assessed using the microtiter plate method. Additionally, multi-locus sequence typing (MLST) was utilized to genotype linezolid-resistant isolates. Results Out of 300 UTI cases , E. faecalis was identified as the causative agent in 160 instances. Notably, a high proportion of these isolates exhibited resistance to tetracycline (83.8%) and minocycline (82.5%). Linezolid resistance was observed in 1.3% ( n = 2) of the isolates. Conversely, the highest susceptibility rates were observed for vancomycin, penicillin G, ampicillin, and nitrofurantoin, each demonstrating a 98.8% susceptibility rate. Biofilm formation was detected in 25% of the E. faecalis isolates. A significant majority (93.8%) of the isolates harbored the efbA and ace genes, with varying frequencies of esp (72.5%), asa1 (61.2%), cylA (52.5%), and gelE (88.8%) genes. MLST analysis demonstrated that both linezolid-resistant isolates, characterized by strong biofilm formation and the presence of virulence genes, were assigned to the ST150 lineage, which has not been previously documented in clinical settings. Conclusion The emergence of the ST150 clonal lineage, underscores its clinical significance, particularly in relation to linezolid resistance in E. faecalis . This study adds to the growing body of evidence linking specific clonal lineages with antibiotic resistance, highlighting the critical need for ongoing surveillance and molecular characterization of resistant pathogens.
Exome Sequencing of Consanguineous Pashtun Families With Familial Epilepsy Reveals Causative and Candidate Variants in TSEN54, MOCS2, and OPHN1
2024-10-14

ABSTRACT Next‐generation sequencing is advancing in low‐ and middle‐income countries, but accessibility remains limited. In Pakistan, many members of the Pashtun population practice familial marriage and maintain distinct socio‐cultural traditions, isolating them from other ethnic groups. As a result, they may harbor genetic variants that could unveil new gene‐disease associations. To investigate the genetic basis of epilepsy in the Pashtun community we recently established a collaboration between Bannu University and the University of Tuebingen. Here we report our first results of exome sequencing of four families with presumed monogenetic epilepsy and Mendelian inheritance pattern. In Family #201, we identified distinct disease‐causing variants. One had a homozygous pathogenic missense variant in TSEN54 (c.919G &gt; T, p.(Ala307Ser)), linked to Pontocerebellar Hypoplasia Type 2A. The second individual had a homozygous class IV missense variant in MOCS2 (c.226G &gt; A, p.(Gly76Arg)) which is associated with Molybdenum cofactor deficiency. In family EP02, one affected individual carried a heterozygous class III variant in OPHN1 (c.1490G &gt; A, p.(Arg497Gln)), related to syndromic X‐linked intellectual disability with epilepsy. Our small study demonstrates the promise of next‐generation sequencing in genetic epilepsies among the Pashtun population. Diagnostic next‐generation sequencing should be established in Pakistan as soon as possible, and if not feasible, genetic research projects may pioneer this path.
Passive sampling of polycyclic aromatic hydrocarbons with low-density polyethylene: Equilibration limitations in aqueous suspensions
2024-10-14

Abstract Polyethylene (PE) and other polymers are widely and successfully used as passive samplers for organic pollutants in the environment. This study provides high-resolution experimental data from batch shaking tests on the uptake, reversibility, and linear equilibrium partitioning of polycyclic aromatic hydrocarbons (PAHs) using two different PE sheets of 30 μm and 80 μm thickness. Kinetics for phenanthrene are well described by a mechanistic first-order model with mass transfer limited by an aqueous boundary layer (with a mean thickness of 170 μm). Equilibration in laboratory batch systems during uptake and desorption is very rapid with characteristic times of 1–2 h but this depends on the boundary condition, e.g., the ratio of PE mass to water volume. Therefore, equilibration of PE in other setups, e.g., in soil slurries or sediment suspensions, may take orders of magnitude longer because the boundary condition for PE changes from finite to infinite bath conditions (soil or sediment particles may keep the concentration in water almost constant). Solid precipitates for high molecular weight PAHs explain partition coefficients below expected values because of kinetic limitations in such a system. Nevertheless, passive sampling can be employed safely if such limitations are considered; furthermore, partition coefficients can be estimated accurately by empirical relationships (e.g., within 0.1 log unit) based on molecular weight, octanol/water partition coefficients, or subcooled liquid solubilities.
The 2024 Public Health Emergency of International Concern: A Global Failure to Control Mpox
2024-10-15

ABSTRACT. On August 14, 2024, following a regional declaration by the Africa Centres for Disease Control and Prevention, the World Health Organization declared mpox a Public Health Emergency of International Concern, marking the second such declaration in two years. A series of outbreaks involving the more virulent clade I virus (compared to clade II, which caused a global outbreak in 2022), has now spread in 13 African countries, exposing the inadequacies of the public health infrastructure in these settings. There was significant investment during the 2022 global outbreak, but these efforts failed to address vaccine access and treatment in the Global South. Regulatory delays, unequal access to vaccines, and a lack of compassionate use treatments for severe cases have resulted in preventable cases and deaths, especially among vulnerable populations such as pregnant women, children, and the immunocompromised. The current outbreak also underscores critical knowledge gaps in our understanding of mpox, including its transmission, pathogenesis, and viral evolution. We join intensified calls for global solidarity and action to control mpox, emphasizing immediate containment measures and long-term local and international investment in African public health systems, to prevent future epidemics.
General purpose genotypes and evolution of higher plasticity in clonality underlie knotweed invasion
2024-10-15

Abstract Many widespread invasive plant species express high phenotypic variation across novel environments, providing a unique opportunity to examine ecological and evolutionary dynamics under global change. However, biogeographical studies often lack information about the origin of introduced populations, limiting our understanding of post-introduction evolution of introduced species in the new range. Here, we assessed the responses of Reynoutria japonica from 128 populations spanning three latitudinal transects in the native ranges of China and Japan, and the introduced ranges of North America and Europe. When grown in two common gardens in the native range, plants from introduced populations in North America and Europe differed in almost all traits from those from native Chinese populations, but were similar to plants from native Japanese populations. Compared to Chinese populations, North American, European and Japanese populations expressed lower trait values and plasticity in most traits. However, plants from both introduced ranges and from Japanese populations expressed higher clonality and plasticity in clonality than plants from Chinese populations. In addition, introduced populations expressed higher plasticity in clonality but lower plasticity in basal diameter compared to Japanese populations. Our study showed heritable differences in phenotypes between plants from the native ranges of Japan and China, and those from the introduced ranges were similar to the putative source of origin in Japan. However, we found that introduced populations may have evolved higher plasticity in clonal growth. Our findings emphasize the critical role of clonality and plasticity in invasion success, demonstrating the importance of discriminating between source and non-source native populations to identify ecological and evolutionary responses of invasive plants to novel environments.
Longitudinal Analysis of Natural History Progression of Rare and Ultra‐Rare Cerebellar Ataxias Using Item Response Theory
2024-10-15

Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra‐rare genetic diseases. While disease‐modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real‐world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix–Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~ 0.98 SARA points/year at SARA = 20) and very low in COQ8A ataxia (~ 0.003 SARA points/year at SARA = 20). Smaller trial sizes were required in case of faster progression, longer trials (~ 75–90% less with 5 years vs. 2 years), and larger drug effects (~ 70–80% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well‐controlled type I error, compared to total score models or end‐of‐treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra‐rare genetic ataxias.
Effects of mesenchymal stromal cells and human recombinant Nerve Growth Factor delivered by bioengineered human corneal lenticule on an innovative model of diabetic retinopathy
2024-10-15

Introduction Diabetic retinopathy (DR) is a microvascular complication of diabetes in which neurodegeneration has been recently identified as a driving force. In the last years, mesenchymal stromal cells (MSCs) and neurotrophins like Nerve Growth Factor (NGF), have garnered significant attention as innovative therapeutic approaches targeting DR-associated neurodegeneration. However, delivering neurotrophic factors directly in the eye remains a challenge. Hence, this study evaluated the effects of MSCs from human amniotic fluids (hAFSCs) and recombinant human NGF (rhNGF) delivered by human corneal lenticule (hCL) on a high glucose (HG) induced ex vivo model simulating the molecular mechanisms driving DR. Methods Porcine neuroretinal explants exposed to HG (25 mM for four days) were used to mimic DR ex vivo . hCLs collected from donors undergoing refractive surgery were decellularized using 0.1% sodium dodecyl sulfate and then bioengineered with hAFSCs, microparticles loaded with rhNGF (rhNGF-PLGA-MPs), or both simultaneously. Immunofluorescence (IF) and scanning electron microscopy (SEM) analyses were performed to confirm the hCLs bioengineering process. To assess the effects of hAFSCs and rhNGF, bioengineered hCLs were co-cultured with HG-treated neuroretinal explants and following four days RT-PCR and cytokine array experiments for inflammatory, oxidative, apoptotic, angiogenic and retinal cells markers were performed. Results Data revealed that HG-treated neuroretinal explants exhibit a characteristic DR-phenotype, including increased level of NF-kB, NOS2, NRF2 GFAP, VEGFA, Bax/Bcl2 ratio and decreased expression of TUBB3 and Rho. Then, the feasibility to bioengineer decellularized hCLs with hAFSCs and rhNGF was demonstrated. Interestingly, co-culturing hAFSCs- and rhNGF- bioengineered hCLs with HG-treated neuroretinal explants for four days significantly reduced the expression of inflammatory, oxidative, apoptotic, angiogenic and increased retinal markers. Conclusion Overall, we found for the first time that hAFSCs and rhNGF were able to modulate the molecular mechanisms involved in DR and that bioengineered hCLs represents a promising ocular drug delivery system of hAFSCs and rhNGF for eye diseases treatment. In addition, results demonstrated that porcine neuroretinal explants treated with HG is a useful model to reproduce ex vivo the DR pathophysiology.
Who owns the wind? Understanding wind energy production through a property chains perspective
2024-10-15

In this article, we argue that the resourcification of wind is based on a specific entanglement of different property objects - in particular wind, land and wind turbines - and property holders. We depart from an understanding of property as a social phenomenon that is enacted through social practices and thereby becomes relevant within an arrangement of different entities (human, non-human and material) by structuring the relations between these entities. We propose a practice theoretical approach based on Theodore Schatzki's concept of practice-arrangement constellations for understanding how property becomes relevant through socio-material relations which enable the resourcification of wind. Based on this theoretical approach, we show how different entities and practices bring about chains of property objects that enable the transformation of wind into electricity. With our conceptual considerations concerning property chains we hope to deepen the discussion around the significance of property in the resourcification of renewable energy sources.