julilili42/papers huggingface dataset:
HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy
2021-04-01

Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level. Methods Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing. Results The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference. Conclusion Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org .
United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia
2021-04-01

Abstract Background Functional dyspepsia (FD) is one of the most common conditions in clinical practice. In spite of its prevalence, FD is associated with major uncertainties in terms of its definition, underlying pathophysiology, diagnosis, treatment, and prognosis. Methods A Delphi consensus was initiated with 41 experts from 22 European countries who conducted a literature summary and voting process on 87 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus (defined as &gt;80% agreement) was reached for 36 statements. Results The panel agreed with the definition in terms of its cardinal symptoms (early satiation, postprandial fullness, epigastric pain, and epigastric burning), its subdivision into epigastric pain syndrome and postprandial distress syndrome, and the presence of accessory symptoms (upper abdominal bloating, nausea, belching), and overlapping conditions. Also, well accepted are the female predominance of FD, its impact on quality of life and health costs, and acute gastrointestinal infections, and anxiety as risk factors. In terms of pathophysiological mechanisms, the consensus supports a role for impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention, Helicobacter pylori infection, and altered central processing of signals from the gastroduodenal region. There is consensus that endoscopy is mandatory for establishing a firm diagnosis of FD, but that in primary care, patients without alarm symptoms or risk factors can be managed without endoscopy. There is consensus that H. pylori status should be determined in every patient with dyspeptic symptoms and H. pylori positive patients should receive eradication therapy. Also, proton pump inhibitor therapy is considered an effective therapy for FD, but no other treatment approach reached a consensus. The long‐term prognosis and life expectancy are favorable. Conclusions and Inferences A multinational group of European experts summarized the current state of consensus on the definition, diagnosis and management of FD.
Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis
2021-04-01

BACKGROUND Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon ( POLE ) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE ‐mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment. METHODS A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one‐stage meta‐analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC). RESULTS Three hundred fifty‐nine women with POLE ‐mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47‐7.58; log‐rank P &lt; .01). Except for stage ( P &lt; .01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease‐specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5‐14.2 years). Adjuvant treatment was not associated with outcome. CONCLUSIONS Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de‐escalating treatment for these patients. LAY SUMMARY Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon ( POLE ). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE ‐mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.
Longitudinal analysis of axial length growth in a German cohort of healthy children and adolescents
2021-04-01

Abstract Purpose To generate continuous growth curves for axial length (AL) in German children. We hypothesise that percentile curves of AL can be used as a predictive measure of myopia. Methods In this longitudinal and cross‐sectional LIFE Child Study, children’s non‐cycloplegic refraction data was collected using the Zeiss i.Profiler plus while AL was measured using the Haag‐Streit Lenstar. Reference growth curves were estimated as a continuous non‐parametric function of age. Results Data from 4511 visits of 1965 participants (1021 boys and 944 girls) between 3 and 18 years of age were analysed. For all ages and percentiles, the estimated AL was higher in boys than girls. AL differences between boys and girls were most pronounced in the 98 th percentile at 3 years of age, being 0.93 mm longer eyes in boys. This difference decreased to 0.21 mm at 18 years of age. While the lower percentiles of AL reach their final value around age 13, the 50 th percentile was still increasing by 0.05 mm per year until the end of the observation period. While, in general, children with longer eyes are more likely to develop myopia, this relationship is weaker between the ages of 5 and 8. Conclusion The LIFE Child Study data provides European AL data. In both Germany and China, AL has comparable growth rates when the baseline ALs are compared as percentiles. Thus, percentile curves of AL can be used as a predictive measure for the likelihood of developing as well as the progression of myopia.
Perturbers: SPHERE detection limits to planetary-mass companions in protoplanetary disks
2021-04-01

The detection of a wide range of substructures such as rings, cavities, and spirals has become a common outcome of high spatial resolution imaging of protoplanetary disks, both in the near-infrared scattered light and in the thermal millimetre continuum emission. The most frequent interpretation of their origin is the presence of planetary-mass companions perturbing the gas and dust distribution in the disk (perturbers), but so far the only bona fide detection has been the two giant planets carving the disk around PDS 70. Here, we present a sample of 15 protoplanetary disks showing substructures in SPHERE scattered-light images and a homogeneous derivation of planet detection limits in these systems. To obtain mass limits we rely on different post-formation luminosity models based on distinct formation conditions, which are critical in the first million years of evolution. We also estimate the mass of these perturbers through a Hill radius prescription and a comparison to ALMA data. Assuming that one single planet carves each substructure in scattered light, we find that more massive perturbers are needed to create gaps within cavities than rings, and that we might be close to a detection in the cavities of RX J1604.3-2130A, RX J1615.3-3255, Sz Cha, HD 135344B, and HD 34282. We reach typical mass limits in these cavities of 3–10 M Jup . For planets in the gaps between rings, we find that the detection limits of SPHERE high-contrast imaging are about an order of magnitude away in mass, and that the gaps of PDS 66 and HD 97048 seem to be the most promising structures for planet searches. The proposed presence of massive planets causing spiral features in HD 135344B and HD 36112 are also within SPHERE’s reach assuming hot-start models. These results suggest that the current detection limits are able to detect hot-start planets in cavities, under the assumption that they are formed by a single perturber located at the centre of the cavity. More realistic planet mass constraints would help to clarify whether this is actually the case, which might indicate that perturbers are not the only way of creating substructures.
MR-Guided Radiotherapy for Liver Malignancies
2021-04-01

MR guided radiotherapy represents one of the most promising recent technological innovations in the field. The possibility to better visualize therapy volumes, coupled with the innovative online adaptive radiotherapy and motion management approaches, paves the way to more efficient treatment delivery and may be translated in better clinical outcomes both in terms of response and reduced toxicity. The aim of this review is to present the existing evidence about MRgRT applications for liver malignancies, discussing the potential clinical advantages and the current pitfalls of this new technology.
Annotation and initial evaluation of a large annotated German oncological corpus
2021-04-01

Abstract Objective We present the Berlin-Tübingen-Oncology corpus (BRONCO), a large and freely available corpus of shuffled sentences from German oncological discharge summaries annotated with diagnosis, treatments, medications, and further attributes including negation and speculation. The aim of BRONCO is to foster reproducible and openly available research on Information Extraction from German medical texts. Materials and Methods BRONCO consists of 200 manually deidentified discharge summaries of cancer patients. Annotation followed a structured and quality-controlled process involving 2 groups of medical experts to ensure consistency, comprehensiveness, and high quality of annotations. We present results of several state-of-the-art techniques for different IE tasks as baselines for subsequent research. Results The annotated corpus consists of 11 434 sentences and 89 942 tokens, annotated with 11 124 annotations for medical entities and 3118 annotations of related attributes. We publish 75% of the corpus as a set of shuffled sentences, and keep 25% as held-out data set for unbiased evaluation of future IE tools. On this held-out dataset, our baselines reach depending on the specific entity types F1-scores of 0.72–0.90 for named entity recognition, 0.10–0.68 for entity normalization, 0.55 for negation detection, and 0.33 for speculation detection. Discussion Medical corpus annotation is a complex and time-consuming task. This makes sharing of such resources even more important. Conclusion To our knowledge, BRONCO is the first sizable and freely available German medical corpus. Our baseline results show that more research efforts are necessary to lift the quality of information extraction in German medical texts to the level already possible for English.
DominantACO2mutations are a frequent cause of isolated optic atrophy
2021-04-01

Abstract Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells.
The World at Our Fingertips
2021-04-01

Abstract Where do you end and the external world begin? This might seem to be a straightforward, binary question: your skin is the boundary, with the self on one side and the rest of the world on the other. Peripersonal space shows that the division is not that simple. The boundary is blurrier than you might have thought. Our ability to monitor the space near the body appears to be deeply ingrained. Our evolutionary history has equipped our brains with a special mechanism to track multisensory stimuli that can potentially interact with our physical body in its immediate surroundings and prime appropriate actions. The processing of the immediate space around one’s body thus displays highly specific multisensory and motor features, distinct from those that characterize the processing of regions of space that are further away. The computational specificities here lead one to wonder whether classic theories of perception apply to the special case of peripersonal space. We think that there is a need to reassess the relationship between perception, action, emotion, and self-awareness in the highly special context of the immediate surroundings of our body. For the first time, leading experts on peripersonal space in cognitive psychology, neuropsychology, neuroscience, and ethology gathered in this volume describe the vast number of fascinating discoveries about this special way of representing space. For the first time too, these empirical results and the questions they open are brought into dialogue with philosophy.
Ca 2+ signalling is critical for autoantibody‐induced blistering of human epidermis in pemphigus*
2021-04-01

Ca<sup>2+</sup> -mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by Dsg1 and Dsg3. Interfering with PLC and Ca<sup>2+</sup> signalling may be a promising approach to treat epidermal manifestations of pemphigus.
Increased Brain Age Gap Estimate (BrainAGE) in Young Adults After Premature Birth
2021-04-01

Recent evidence suggests increased metabolic and physiologic aging rates in premature-born adults. While the lasting consequences of premature birth on human brain development are known, its impact on brain aging remains unclear. We addressed the question of whether premature birth impacts brain age gap estimates (BrainAGE) using an accurate and robust machine-learning framework based on structural MRI in a large cohort of young premature-born adults ( n = 101) and full-term (FT) controls ( n = 111). Study participants are part of a geographically defined population study of premature-born individuals, which have been followed longitudinally from birth until young adulthood. We investigated the association between BrainAGE scores and perinatal variables as well as with outcomes of physical (total intracranial volume, TIV) and cognitive development (full-scale IQ, FS-IQ). We found increased BrainAGE in premature-born adults [median (interquartile range) = 1.4 (−1.3–4.7 years)] compared to full-term controls ( p = 0.002, Cohen’s d = 0.443), which was associated with low Gestational age (GA), low birth weight (BW), and increased neonatal treatment intensity but not with TIV or FS-IQ. In conclusion, results demonstrate elevated BrainAGE in premature-born adults, suggesting an increased risk for accelerated brain aging in human prematurity.
Pathogens That Cause Acute Febrile Illness Among Children and Adolescents in Burkina Faso, Madagascar, and Sudan
2021-04-01

Abstract Background The etiology and optimal clinical management of acute febrile illness (AFI) is poorly understood. Methods Blood samples taken from study participants with acute fever (≥37.5°C) or a history of fever and recruited into the previous Typhoid Fever Surveillance in Africa (TSAP) study were evaluated using a polymerase chain reaction (PCR)-based TaqMan-Array Card designed to detect a panel of bacterial, viral, and parasitic pathogens. Clinical metadata were also assessed. Results A total of 615 blood samples available for analysis originated from Burkina Faso (n = 53), Madagascar (n = 364), and Sudan (n = 198) and were taken from participants ranging in age from 0–19 years. Through the TaqMan-Array Card, at least 1 pathogen was detected in 62% (33 of 53), 24% (86 of 364), and 60% (118 of 198) of specimens from Burkina Faso, Madagascar, and Sudan, respectively. The leading identified pathogen overall was Plasmodium spp., accounting for 47% (25 of 53), 2.2% (8 of 364), and 45% (90 of 198) of AFI at the respective sites. In Madagascar, dengue virus was the most prevalent pathogen (10.2%). Overall, 69% (357 of 516) of patients with clinical diagnoses of malaria, respiratory infection, or gastrointestinal infection were prescribed a World Health Organization guideline-recommended empiric antibiotic, whereas only 45% (106 of 237) of patients with pathogens detected were treated with an antibiotic exerting likely activity. Conclusions A PCR approach for identifying multiple bacterial, viral, and parasitic pathogens in whole blood unveiled a diversity of previously undetected pathogens in AFI cases and carries implications for the appropriate management of this common syndrome.
Second-generation colon capsule endoscopy for detection of colorectal polyps: Systematic review and meta-analysis of clinical trials
2021-04-01

Abstract Background and study aims Adherence to colorectal cancer (CRC) screening is still unsatisfactory in many countries, thereby limiting prevention of CRC. Colon capsule endoscopy (CCE), a minimally invasive procedure, could be an alternative to fecal immunochemical tests or optical colonoscopy for CRC screening, and might increase adherence in CRC screening. This systematic review and meta-analysis evaluates the diagnostic accuracy of CCE compared to optical colonoscopy (OC) as the gold standard, adequacy of bowel preparation regimes and the patient perspective on diagnostic measures. Methods We conducted a systematic literature search in PubMed, EMBASE and the Cochrane Register for Clinical Trials. Pooled estimates for sensitivity, specificity and the diagnostic odds ratio with their respective 95 % confidence intervals (CI) were calculated for studies providing sufficient data. Results Of 840 initially identified studies, 13 were included in the systematic review and up to 9 in the meta-analysis. The pooled sensitivities and specificities for polyps ≥ 6 mm were 87 % (95 % CI: 83 %–90 %) and 87 % (95 % CI: 76 %–93 %) in 8 studies, respectively. For polyps ≥ 10 mm, the pooled estimates for sensitivities and specificities were 87 % (95 % CI: 83 %–90 %) and 95 % (95 % CI: 92 %–97 %) in 9 studies, respectively. A patients’ perspective was assessed in 31 % (n = 4) of studies, and no preference of CCE over OC was reported. Bowel preparation was adequate in 61 % to 92 % of CCE exams. Conclusions CCE provides high diagnostic accuracy in an adequately cleaned large bowel. Conclusive findings on patient perspectives require further studies to increase acceptance/adherence of CCE for CRC screening.