Miracle-dz/UniFAR-FTUs huggingface dataset:
Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.
High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.
3D Spatial Distribution of Nanoparticles in Mice Brain Metastases by X-ray Phase-Contrast Tomography

Characterizing nanoparticles (NPs) distribution in multiple and complex metastases is of fundamental relevance for the development of radiological protocols based on NPs administration. In the literature, there have been advances in monitoring NPs in tissues. However, the lack of 3D information is still an issue. X-ray phase-contrast tomography (XPCT) is a 3D label-free, non-invasive and multi-scale approach allowing imaging anatomical details with high spatial and contrast resolutions. Here an XPCT qualitative study on NPs distribution in a mouse brain model of melanoma metastases injected with gadolinium-based NPs for theranostics is presented. For the first time, XPCT images show the NPs uptake at micrometer resolution over the full brain. Our results revealed a heterogeneous distribution of the NPs inside the melanoma metastases, bridging the gap in spatial resolution between magnetic resonance imaging and histology. Our findings demonstrated that XPCT is a reliable technique for NPs detection and can be considered as an emerging method for the study of NPs distribution in organs.
A Prospective Investigation of Bispecific CD19/22 CAR T Cell Therapy in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma

Background The use of T cells expressing chimeric antigen receptor (CAR T) engineered to target CD19 constitutes breakthrough treatment for relapsed or refractory B cell non-Hodgkin lymphoma (R/R B-NHL). Despite improved outcomes, high relapse rate remains a challenge to overcome. Here, we report the clinical results and the pharmacokinetics of bispecific CD19/22 CAR T in patients with R/R B-NHL. Methods We performed a prospective, single-arm study of bispecific CD19/22 CAR T cells in R/R B-NHL. We analyzed the safety and efficacy and investigated the kinetic profiles of the CAR T cells. CAR transgene levels were measured using quantitative polymerase chain reaction, and correlation analyses of pharmacodynamic markers and product characteristics, disease conditions, clinical efficacy and adverse events were performed. Results From August 2017 to September 2020, a total of 32 patients with CD19/22 CAR T administration were analyzed. The overall response rate was 79.3%, and the complete response rate was 34.5%. The progression-free survival (PFS) and overall survival (OS) rates at 12 months were 40.0% and 63.3%, respectively. Among patients who had a CR at 3 months, the PFS and OS rates at 12 months were 66.7% and 100%, respectively. Severe cytokine release syndrome (sCRS) (grade 3 and higher) occurred in nine patients (28.1%). Grade 3 or higher neurologic events occurred in four patients (12.5%). One patient died from irreversible severe CRS-associated acute kidney injury. Long-term CAR T cells persistence correlated with clinical efficacy (133 days vs 22 days, P = 0.004). Patients treated with more than three prior therapies and presenting extranodal organ involvement had lower maximal concentration (Cmax) values than other patients. Responders had higher Cmax and area under the curve values than non-responders. Tumour burden and Cmax were potentially associated with the severity of CRS. Conclusions This study demonstrates the safety and potential clinical efficacy of bispecific CD19/22 CAR T cells in patients with R/R B-NHL and highlights the importance of measuring kinetic parameters in PB to predict efficacy and safety in clinical applications of CAR T cell therapy. Clinical Trial Registration https://www.clinicaltrials. gov/ct2/show/NCT03196830, identifier NCT03196830.
Effects of Flower-Enriched Ecological Focus Areas on Functional Diversity Across Scales

Ecological Focus Areas (EFAs) to benefit biodiversity became mandatory in intensively farmed landscapes after the reform of the European Common Agricultural Policy (CAP) in 2013. The implementation of EFAs as uncropped field margins has been criticized as ineffective but created a window of opportunity to test if augmenting them with annual flower strips can benefit biodiversity. In this study, we investigated if annual flower strips on EFAs benefited functional biodiversity in intensively farmed landscapes. To this end we established eleven annual flower strips with a seed mixture targeted for both natural enemies and pollinators, on areas were farmers had planned for EFAs. We determined effects on aphids and their natural enemies in cereal fields close to six of the flower strips, and for solitary bees and wasp close to and in the surroundings of all eleven flower strips. We found that annual flower strips benefited the abundance of hoverfly larvae and possibly also that of solitary bees. However, there were neither any significant effects on natural enemies (other than hoverfly larvae), nor any difference in natural pest control as shown by lack of differences in aphid numbers and parazitation rates. Abundances of solitary bees and wasps in the surrounding landscapes were unaffected, although there was a tendency for more solitary bee cells closer to the strips. We suggest that the critical issue leading to the mostly negative results is the lack of permanent structures to sustain populations of arthropods that in turn can benefit from annual flower strips. Hence, future agri-environmental policies need to carefully consider if and how annual agri-environmental measures should be implemented in intensively managed agricultural landscapes, e.g., by combining them with more permanent structures.
Knowledge and Information Exposure About Family Planning Among Women of Reproductive Age in Informal Settlements of Kira Municipality, Wakiso District, Uganda

Introduction: A high unmet need for family planning (FP) prevails in sub-Saharan Africa. Knowledge, awareness creation, and ensuring accessibility are frequently used to increase FP uptake. However, evidence on knowledge or information dissemination about FP among marginalized populations in urban settings in Africa is limited. This study explored the knowledge of FP methods, media exposure, and contact with FP providers among women from an informal settlement in Uganda. Methods: Using a cross-sectional study design, we interviewed 626 women aged 15–49 years living in informal settlements of Kira municipality, selected through multistage sampling. Using a standard questionnaire, data was collected on socioeconomic characteristics, knowledge of FP methods, and access to media FP messages among others. Binomial log-linear regression was used to assess disparities in exposure to media FP messages or provider information. Data were analyzed using STATA version 14, at a 5% level of statistical significance. Results: Nearly all women in the survey were aware of FP methods (99.7%). On average, each woman was aware of 10 FP methods. The most commonly known methods were male condoms (98.2%), injectables (97.4%), and the oral contraceptive pill (95.2%). Use of any contraceptive was found among 42.7% of respondents. Exposure to media was found in 70.6% of the respondents, mostly through television (58.5%) and radio (58.3%). Discussing FP with a provider was significantly associated with media exposure (aPR 1.4, 95% CI: 1.24–1.56). Less than 50% of women who were not using FP had contact with an FP provider. Women in union (aPR 1.6, 95% CI: 1.01–2.68) and those with access to media messages (aPR 2.5, 95% CI: 1.37–4.54) were more likely to have contact with a provider to discuss FP. Conclusion: There is high general awareness about FP methods and media exposure, but method use was low. Further exploration of women's understanding of FP methods and the fit between existing education programs and FP knowledge needs in this urban setting should be conducted. The potential for mobile health solutions in this urban population should be explored. Future studies should focus on the knowledge and understanding of FP among unmarried and nulliparous women and those with no access to media information.
Surface Mass Balance Models Vs. Stake Observations: A Comparison in the Lake Vostok Region, Central East Antarctica

The surface mass balance (SMB) is very low over the vast East Antarctic Plateau, for example in the Vostok region, where the mean SMB is on the order of 20–35 kg m-2 a-1. The observation and modeling of spatio-temporal SMB variations are equally challenging in this environment. Stake measurements carried out in the Vostok region provide SMB observations over half a century (1970–2019). This unique data set is compared with SMB estimations of the regional climate models RACMO2.3p2 (RACMO) and MAR3.11 (MAR). We focus on the SMB variations over time scales from months to decades. The comparison requires a rigorous assessment of the uncertainty in the stake observations and the spatial scale dependence of the temporal SMB variations. Our results show that RACMO estimates of annual and multi-year SMB agree well with the observations. The regression slope between modelled and observed temporal variations is close to 1.0 for this model. SMB simulations by MAR are affected by a positive bias which amounts to 6 kg m-2 a-1 at Vostok station and 2 kg m-2 a-1 along two stake profiles between Lake Vostok and Ridge B. None of the models is capable to reproduce the seasonal distributions of SMB and precipitation. Model SMB estimates are used in assessing the ice-mass balance and sea-level contribution of the Antarctic Ice Sheet by the input-output method. Our results provide insights into the uncertainty contribution of the SMB models to such assessments.
The Cyclophilin ROC3 Regulates ABA-Induced Stomatal Closure and the Drought Stress Response of Arabidopsis thaliana

Drought causes a major constraint on plant growth, development, and crop productivity. Drought stress enhances the synthesis and mobilization of the phytohormone abscisic acid (ABA). Enhanced cellular levels of ABA promote the production of reactive oxygen species (ROS), which in turn induce anion channel activity in guard cells that consequently leads to stomatal closure. Although Cyclophilins (CYPs) are known to participate in the biotic stress response, their involvement in guard cell ABA signaling and the drought response remains to be established. The Arabidopsis thaliana gene ROC3 encodes a CYP. Arabidopsis roc3 T-DNA mutants showed a reduced level of ABA-activated S-type anion currents, and stomatal closure than wild type (WT). Also, roc3 mutants exhibited rapid loss of water in leaf than wild type. Two complementation lines of roc3 mutants showed similar stomatal response to ABA as observed for WT. Both complementation lines also showed similar water loss as WT by leaf detached assay. Biochemical assay suggested that ROC3 positively regulates ROS accumulation by inhibiting catalase activity. In response to ABA treatment or drought stress, roc3 mutant show down regulation of a number of stress responsive genes. All findings indicate that ROC3 positively regulates ABA-induced stomatal closure and the drought response by regulating ROS homeostasis and the expression of various stress-activated genes.
Intrinsic Capacity Assessment by a Mobile Geriatric Team During the Covid-19 Pandemic

In the autumn of 2020, the second wave of the COVID-19 pandemic hit Europe. In this context, because of the insufficient number of beds in geriatric COVID units, non-geriatric wards were confronted with a significant number of admissions of geriatric patients. In this perspective article, we describe the role of a mobile geriatric team in the framework of the COVID-19 pandemic and specifically how it assisted other specialists in the management of hospitalized geriatric patients by implementing a new approach: the systematic assessment and optimization of Intrinsic Capacity functions. For each patient, assessed by this consultative team, an individualized care plan, including an anticipated end-of-life decision-making process, was established. Intensity of care was most often not stated by considering chronological age but rather the comorbidity burden, the frailty status, and the patient's wishes. Further studies are needed to determine if this mobile geriatric team approach was beneficial in terms of mortality, length of stay, or functional, psychological, and cognitive outcomes in COVID-19 geriatric patients.
Phagocytosis and Efferocytosis by Resident Macrophages in the Mouse Pancreas

The tissue microenvironment in the mouse pancreas has been shown to promote very different polarizations of resident macrophages with islet-resident macrophages displaying an inflammatory “M1” profile and macrophages in the exocrine tissue mostly displaying an alternatively activated “M2” profile. The impact of this polarization on tissue homeostasis and diabetes development is unclear. In this study, the ability of pancreas-resident macrophages to phagocyte bacterial and endogenous debris was investigated. Mouse endocrine and exocrine tissues were separated, and tissue-resident macrophages were isolated by magnetic immunolabeling. Isolated macrophages were subjected to flow cytometry for polarization markers and qPCR for phagocytosis-related genes. Functional in vitro investigations included phagocytosis and efferocytosis assays using pH-sensitive fluorescent bacterial particles and dead fluorescent neutrophils, respectively. Intravital confocal imaging of in situ phagocytosis and efferocytosis in the pancreas was used to confirm findings in vivo. Gene expression analysis revealed no significant overall difference in expression of most phagocytosis-related genes in islet-resident vs. exocrine-resident macrophages included in the analysis. In this study, pancreas-resident macrophages were shown to differ in their ability to phagocyte bacterial and endogenous debris depending on their microenvironment. This difference in abilities may be one of the factors polarizing islet-resident macrophages to an inflammatory state since phagocytosis has been found to imprint macrophage heterogeneity. It remains unclear if this difference has any implications in the development of islet dysfunction or autoimmunity.
Validation of a Triplex Quantitative Polymerase Chain Reaction Assay for Detection and Quantification of Traditional Protein Sources, Pisum sativum L. and Glycine max (L.) Merr., in Protein Powder Mixtures

Several botanicals have been traditionally used as protein sources, including the leguminous Pisum sativum L. and Glycine max (L.) Merr. While a rich history exists of cultivating these plants for their whole, protein-rich grain, modern use as powdered supplements present a new challenge in material authentication. The absence of clear morphological identifiers of an intact plant and the existence of long, complex supply chains behoove industry to create quick, reliable analytical tools to identify the botanical source of a protein product (many of which contain multiple sources). The utility of molecular tools for plant-based protein powder authentication is gaining traction, but few validated tools exist. Multiplex quantitative polymerase chain reaction (qPCR) can provide an economical means by which sources can be identified and relative proportions quantified. We followed established guidelines for the design, optimization, and validation of qPCR assay, and developed a triplex qPCR assay that can amplify and quantify pea and soy DNA targets, normalized by a calibrator. The assay was evaluated for analytical specificity, analytical sensitivity, efficiency, precision, dynamic range, repeatability, and reproducibility. We tested the quantitative ability of the assay using pea and soy DNA mixtures, finding exceptional quantitative linearity for both targets – 0.9983 (p < 0.0001) for soy and 0.9915 (p < 0.0001) for pea. Ratios based on mass of protein powder were also tested, resulting in non-linear patterns in data that suggested the requirement of further sample preparation optimization or algorithmic correction. Variation in fragment size within different lots of commercial protein powder samples was also analyzed, revealing low SD among lots. Ultimately, this study demonstrated the utility of qPCR in the context of protein powder mixtures and highlighted key considerations to take into account for commercial implementation.
New Insights Into Lignification via Network and Multi-Omics Analyses of Arogenate Dehydratase Knock-Out Mutants in Arabidopsis thaliana

Multiple Arabidopsis arogenate dehydratase (ADT) knock-out (KO) mutants, with phenotypes having variable lignin levels (up to circa 70% reduction), were studied to investigate how differential reductions in ADTs perturb its overall plant systems biology. Integrated “omics” analyses (metabolome, transcriptome, and proteome) of wild type (WT), single and multiple ADT KO lines were conducted. Transcriptome and proteome data were collapsed into gene ortholog (GO) data, with this allowing for enzymatic reaction and metabolome cross-comparisons to uncover dominant or likely metabolic biosynthesis reactions affected. Network analysis of enzymes–highly correlated to stem lignin levels–deduced the involvement of novel putative lignin related proteins or processes. These included those associated with ribosomes, the spliceosome, mRNA transport, aminoacyl tRNA biosynthesis, and phosphorylation. While prior work helped explain lignin biosynthesis regulation at the transcriptional level, our data here provide support for a new hypothesis that there are additional post-transcriptional and translational level processes that need to be considered. These findings are anticipated to lead to development of more accurate depictions of lignin/phenylpropanoid biosynthesis models in situ, with new protein targets identified for further biochemical analysis and/or plant bioengineering. Additionally, using KEGG defined functional categorization of proteomics and transcriptomics analyses, we detected significant changes to glucosinolate, α-linolenic acid, nitrogen, carotenoid, aromatic amino acid, phenylpropanoid, and photosynthesis-related metabolic pathways in ADT KO mutants. Metabolomics results also revealed that putative carotenoid and galactolipid levels were generally increased in amount, whereas many glucosinolates and phenylpropanoids (including flavonoids and lignans) were decreased in the KO mutants.