Morphological identification of acute leukemia is a powerful tool used by hematologists to determine the family of such a disease. In some cases, experienced physicians are even able to determine the ...leukemia subtype of the sample. However, the identification process may have error rates up to 40% (when classifying acute leukemia subtypes) depending on the physician's experience and the sample quality. This problem raises the need to create automatic tools that provide hematologists with a second opinion during the classification process. Our research presents a contextual analysis methodology for the detection of acute leukemia subtypes from bone marrow cells images. We propose a cells separation algorithm to break up overlapped regions. In this phase, we achieved an average accuracy of 95% in the evaluation of the segmentation process. In a second phase, we extract descriptive features to the nucleus and cytoplasm obtained in the segmentation phase in order to classify leukemia families and subtypes. We finally created a decision algorithm that provides an automatic diagnosis for a patient. In our experiments, we achieved an overall accuracy of 92% in the supervised classification of acute leukemia families, 84% for the lymphoblastic subtypes, and 92% for the myeloblastic subtypes. Finally, we achieved accuracies of 95% in the diagnosis of leukemia families and 90% in the diagnosis of leukemia subtypes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
T-cell recognition of peptides incorporating nonsynonymous mutations, or neoepitopes, is a cornerstone of tumor immunity and forms the basis of new immunotherapy approaches including personalized ...cancer vaccines. Yet as they are derived from self-peptides, the means through which immunogenic neoepitopes overcome immune self-tolerance are often unclear. Here we show that a point mutation in a non-major histocompatibility complex anchor position induces structural and dynamic changes in an immunologically active ovarian cancer neoepitope. The changes pre-organize the peptide into a conformation optimal for recognition by a neoepitope-specific T-cell receptor, allowing the receptor to bind the neoepitope with high affinity and deliver potent T-cell signals. Our results emphasize the importance of structural and physical changes relative to self in neoepitope immunogenicity. Considered broadly, these findings can help explain some of the difficulties in identifying immunogenic neoepitopes from sequence alone and provide guidance for developing novel, neoepitope-based personalized therapies.
Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding ...of how rejection occurs despite immunosuppression (IS). We performed combined single cell RNA transcriptomic and TCRα/β sequencing on rBx from patients with ACR under differing IS: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within clonally expanded cells (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCRα/β cDNAs from CD8EXP into Jurkat76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful anti-rejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps to improve detection, assessment, and treatment of rejection.
Purpose
To report the incidence and quantity of silicone oil microbubbles and the relationship with the number of intravitreal anti‐vascular endothelial growth factor (VEGF) injections and evaluate ...if microbubbles induce artefacts on optical coherence tomography (OCT) images.
Methods
Observational, descriptive, cross‐sectional study. Patients with wet age‐related macular degeneration were included who had been treated for 1 year minimally with anti‐VEGF injections repackaged in the hospital pharmacy. Detection and quantification of silicone microbubbles by mydriatic biomicroscopic examination were conducted 1 month after the last injection. The numbers of microbubbles were quantified on a scale of 0–3: 0, none; 1 scarce (1–10 microbubbles); 2 moderate (10–30); or 3 numerous (>30). Shadowing on OCT images was classified as 0–3: 0, none; 1 obscuring some retinal layers; 2 obscuring all retinal layers; or 3 obscuring the retinal thickness.
Results
The study included 142 eyes of 98 patients (mean age, 82.4 years + 7.3; range, 65–97) treated with 2377 injections. Microbubbles were detected in 127 (89.4%) eyes, 62 (43.6%) with numerous microbubbles and 36 (25.4%) and 29 (20.4%), respectively, with scarce and moderate numbers. A positive correlation was found between the numbers of injections and intravitreal silicone (rho, 0.7). Optical coherence tomography (OCT) artefacts were detected in 11 eyes; the artefacts obscured all retinal layers in three eyes. No significant relationship could be established between the appearance of floaters and the microbubbles.
Conclusion
The presence and number of silicone microbubbles were correlated with the number of intravitreal injections. Microbubbles can produce OCT artefacts, which can hinder the treatment decision.
T cell receptor cross-reactivity allows a fixed T cell repertoire to respond to a much larger universe of potential antigens. Recent work has emphasized the importance of peptide structural and ...chemical homology, as opposed to sequence similarity, in T cell receptor cross-reactivity. Surprisingly, though, T cell receptors can also cross-react between ligands with little physiochemical commonalities. Studying the clinically relevant receptor DMF5, we demonstrate that cross-recognition of such divergent antigens can occur through mechanisms that involve heretofore unanticipated rearrangements in the peptide and presenting MHC protein, including binding-induced peptide register shifts and extensions from MHC peptide binding grooves. Moreover, cross-reactivity can proceed even when such dramatic rearrangements do not translate into structural or chemical molecular mimicry. Beyond demonstrating new principles of T cell receptor cross-reactivity, our results have implications for efforts to predict and control T cell specificity and cross-reactivity and highlight challenges associated with predicting T cell reactivities.
MHC restriction, which describes the binding of TCRs from CD4
T cells to class II MHC proteins and TCRs from CD8
T cells to class I MHC proteins, is a hallmark of immunology. Seemingly rare TCRs that ...break this paradigm exist, but mechanistic insight into their behavior is lacking. TIL1383I is a prototypical class-mismatched TCR, cloned from a CD4
T cell but recognizing the tyrosinase tumor antigen presented by the class I MHC HLA-A2 in a fully functional manner. Here we find that TIL1383I binds this class I target with a highly atypical geometry. Despite unorthodox binding, TCR signaling, antigen specificity, and the ability to use CD8 are maintained. Structurally, a key feature of TIL1383I is an exceptionally long CDR3β loop that mediates functions that are traditionally performed separately by hypervariable and germline loops in canonical TCR structures. Our findings thus expand the range of known TCR binding geometries compatible with normal function and specificity, provide insight into the determinants of MHC restriction, and may help guide TCR selection and engineering for immunotherapy.
Presentation of peptides by class I MHC proteins underlies T cell immune responses to pathogens and cancer. The association between peptide binding affinity and immunogenicity has led to the ...engineering of modified peptides with improved MHC binding, with the hope that these peptides would be useful for eliciting cross-reactive immune responses directed toward their weak binding, unmodified counterparts. Increasing evidence, however, indicates that T cell receptors (TCRs) can perceive such anchor-modified peptides differently than wild-type (WT) peptides, although the scope of discrimination is unclear. We show here that even modifications at primary anchors that have no discernible structural impact can lead to substantially stronger or weaker T cell recognition depending on the TCR. Surprisingly, the effect of peptide anchor modification can be sensed by a TCR at regions distant from the site of modification, indicating a through-protein mechanism in which the anchor residue serves as an allosteric modulator for TCR binding. Our findings emphasize caution in the use and interpretation of results from anchor-modified peptides and have implications for how anchor modifications are accounted for in other circumstances, such as predicting the immunogenicity of tumor neoantigens. Our data also highlight an important need to better understand the highly tunable dynamic nature of class I MHC proteins and the impact this has on various forms of immune recognition.
•T cell receptors distinguish between the wild type and anchor-modified gp100209 melanoma antigens.•The clinical candidate SILv44 recognizes the WT antigen with stronger affinity and potency than the ...anchor-modified antigen.•Higher affinity for the wild type antigen explains the SILv44′s superior tumor control in mouse models of melanoma.•Anchor modified peptides should be used cautiously, as the presumption that they are wild type surrogates may be wrong.
Although there are exceptions and outliers, T cell functional responses generally correlate with the affinity of a TCR for a peptide/MHC complex. In one recently described outlier case, the most promising clinical candidate in a series of TCRs specific for the gp100209 melanoma antigen bound with the weakest solution affinity and produced the least amount of cytokine in vitro. Hypotheses for this outlier behavior included unusual cytokine expression patterns arising from an atypical TCR binding geometry. Studying this instance in more detail, we found here that outlier behavior is attributable not to unusual cytokine patterns or TCR binding, but the use of a position 2 anchor-modified peptide variant in in vitro experiments instead of the wild type antigen that is present in vivo. Although the anchor-modified variant has been widely used in basic and clinical immunology as a surrogate for the wild type peptide, prior work has shown that TCRs can clearly distinguish between the two. We show that when this differential recognition is accounted for, the functional properties of gp100209-specific TCRs track with their affinity towards the peptide/MHC complex. Beyond demonstrating the correlates with T cell function for a clinically relevant TCR, our results provide important considerations for selection of TCRs for immunotherapy and the use of modified peptides in immunology.
This paper presents an intelligent surveillance platform based on the usage of large numbers of inexpensive sensors designed and developed inside the European Eureka Celtic project HuSIMS. With the ...aim of maximizing the number of deployable units while keeping monetary and resource/bandwidth costs at a minimum, the surveillance platform is based on the usage of inexpensive visual sensors which apply efficient motion detection and tracking algorithms to transform the video signal in a set of motion parameters. In order to automate the analysis of the myriad of data streams generated by the visual sensors, the platform's control center includes an alarm detection engine which comprises three components applying three different Artificial Intelligence strategies in parallel. These strategies are generic, domain-independent approaches which are able to operate in several domains (traffic surveillance, vandalism prevention, perimeter security, etc.). The architecture is completed with a versatile communication network which facilitates data collection from the visual sensors and alarm and video stream distribution towards the emergency teams. The resulting surveillance system is extremely suitable for its deployment in metropolitan areas, smart cities, and large facilities, mainly because cheap visual sensors and autonomous alarm detection facilitate dense sensor network deployments for wide and detailed coverage.
The cognitive distraction caused by Virtual Reality (VR) seems to cause a decrease both in pain and its perception as in the time spent thinking about possible pain, among anxiety about hysteroscopy ...procedure. The main objective of this investigation was to evaluate the efficacy of virtual reality for pain relief during outpatient hysteroscopy.
: A total of 83 patients underwent outpatient diagnostic hysteroscopy in a single-centre, open-label, randomized control trial. Overall, 180 women with medical indication for an outpatient diagnostic hysteroscopy were randomized. Ten were excluded due to the impossibility of entering the endometrial cavity caused by a cervical canal that was not permeable, and 15 did not tolerate the pain at the beginning and during the procedure, excluding themselves from the final model. Finally, 154 were analysed per protocol to use VR (
= 82, study group) or standard treatment (
= 72, control group) assessing the differences between both groups by reduction in pain using Visual Analogue Scale score (VAS: 0-10 cm) and clinical data (arterial pressure, heart rate, and oxygen saturation) at the end of hysteroscopy, at 15 and 30 min after hysteroscopy.
: Women with VR outpatient diagnostic hysteroscopy experienced less pain at final (VAS score 2.451 vs. 3.972, standard mean difference (SMD) -1.521, 95% CI -2.601 to -0.440;
= 0.006), at 15 min (VAS 1.769 vs. 3.300, SMD -1.531, 95% CI -2.557 to -0.504;
= 0.004), and at 30 min (VAS 1.621 vs. 2.719, SMD -1.099, 95% CI -2.166 to -0.031;
= 0.044) after the ending of the hysteroscopy, compared with no VR.
: The use of VR during outpatient diagnostic hysteroscopy proved effective in the reduction of pain in this randomized control trial. It shows wide potential role in ambulatory gynaecologic procedures to avoid repeating tests, perform surgeries without anaesthesia, and the use of medication and its side effects.
PDF
