Machine learning is a branch of artificial intelligence that employs a variety of statistical, probabilistic and optimization techniques that allows computers to “learn” from past examples and to detect hard-to-discern patterns from large, noisy or complex data sets. This capability is particularly well-suited to medical applications, especially those that depend on complex proteomic and genomic measurements. As a result, machine learning is frequently used in cancer diagnosis and detection. More recently machine learning has been applied to cancer prognosis and prediction. This latter approach is particularly interesting as it is part of a growing trend towards personalized, predictive medicine. In assembling this review we conducted a broad survey of the different types of machine learning methods being used, the types of data being integrated and the performance of these methods in cancer prediction and prognosis. A number of trends are noted, including a growing dependence on protein biomarkers and mi...

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Applications of Machine Learning in Cancer Prediction and Prognosis

Summary: Hantaviruses are enzootic viruses that maintain persistent infections in their rodent hosts without apparent disease symptoms. The spillover of these viruses to humans can lead to one of two serious illnesses, hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome. In recent years, there has been an improved understanding of the epidemiology, pathogenesis, and natural history of these viruses following an increase in the number of outbreaks in the Americas. In this review, current concepts regarding the ecology of and disease associated with these serious human pathogens are presented. Priorities for future research suggest an integration of the ecology and evolution of these and other host-virus ecosystems through modeling and hypothesis-driven research with the risk of emergence, host switching/spillover, and disease transmission to humans.

A Global Perspective on Hantavirus Ecology, Epidemiology, and Disease

There is substantial variation between individuals in the immune response to vaccination. In this review, we provide an overview of the plethora of studies that have investigated factors that influence humoral and cellular vaccine responses in humans. These include intrinsic host factors (such as age, sex, genetics, and comorbidities), perinatal factors (such as gestational age, birth weight, feeding method, and maternal factors), and extrinsic factors (such as preexisting immunity, microbiota, infections, and antibiotics). Further, environmental factors (such as geographic location, season, family size, and toxins), behavioral factors (such as smoking, alcohol consumption, exercise, and sleep), and nutritional factors (such as body mass index, micronutrients, and enteropathy) also influence how individuals respond to vaccines. Moreover, vaccine factors (such as vaccine type, product, adjuvant, and dose) and administration factors (schedule, site, route, time of vaccination, and coadministered vaccines and other drugs) are also important. An understanding of all these factors and their impacts in the design of vaccine studies and decisions on vaccination schedules offers ways to improve vaccine immunogenicity and efficacy.

Factors That Influence the Immune Response to Vaccination

Allergic individuals exposed to minute quantities of allergen experience an immediate response. Immediate hypersensitivity reflects the permanent sensitization of mucosal mast cells by allergen-specific IgE antibodies bound to their high-affinity receptors (FcepsilonRI). A combination of factors contributes to such long-lasting sensitization of the mast cells. They include the homing of mast cells to mucosal tissues, the local synthesis of IgE, the induction of FcepsilonRI expression on mast cells by IgE, the consequent downregulation of FcgammaR (through an insufficiency of the common gamma-chains), and the exceptionally slow dissociation of IgE from FcepsilonRI. To understand the mechanism of the immediate hypersensitivity phenomenon, we need explanations of why IgE antibodies are synthesized in preference to IgG in mucosal tissues and why the IgE is so tenaciously retained on mast cell-surface receptors. There is now compelling evidence that the microenvironment of mucosal tissues of allergic disease favors class switching to IgE; and the exceptionally high affinity of IgE for FcepsilonRI can now be interpreted in terms of the recently determined crystal structures of IgE-FcepsilonRI and IgG-FcgammaR complexes. The rate of local IgE synthesis can easily compensate for the rate of the antibody dissociation from its receptors on mucosal mast cells. Effective mechanisms ensure that allergic reactions are confined to mucosal tissues, thereby minimizing the risk of systemic anaphylaxis.

The biology of IGE and the basis of allergic disease.

Hantaviruses are enveloped RNA viruses each carried by a specific rodent species. Three hantaviruses, Puumala, Dobrava, and Saaremaa viruses, are known to cause haemorrhagic fever with renal syndrome. In Europe. Puumala causes a generally mild disease, nephropathia epidemica, which presents most commonly with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision, whereas Dobrava infections often also have haemorrhagic complications. There are few available data about the clinical picture of confirmed Saaremaa infections, but epidemiological evidence suggests that it is less pathogenic than Dobrava, and that Saaremaa infections are more similar to nephropathia epidemica caused by Puumala. Along with its rodent host, the bank vole (Clethrionomys glareolus), Puumala is reported throughout most of Europe (excluding the Mediterranean region), whereas Dobrava, carried by the yellow-necked mouse (Apodemus flavicollis), and Saaremaa, carried by the striped field mouse (Apodemus agrarius), are reported mainly in eastern and central Europe. The diagnosis of acute hantavirus infection is based on the detection of virus-specific IgM. Whereas Puumala is distinct, Dobrava and Saaremaa are genetically and antigenically very closely related and were previously thought to be variants of the same virus. Typing of a specific hantavirus infection requires neutralisation antibody assays or reverse transcriptase PCR and sequencing.

Hantavirus infections in Europe.

The possible immunologic relationship between the pattern of Th1/Th2 cytokine production and tuberculin reactivity was assessed in patients with active Mycobacterium tuberculosis infection. The production of the intracellular cytokines IFN-gamma and IL-4 was measured in CD4+ and CD8+ T cells obtained from peripheral blood and bronchoalveolar lavage fluid (BALF) of 20 tuberculin skin-positive patients and compared with the findings recorded in nine tuberculin skin-negative patients with active pulmonary tuberculosis. Upon stimulation with phorbol 12-myristate acetate/ionomycin for 6 hours, tuberculin-negative patients had a significantly higher proportion of IFN-gamma producing CD4+ T lymphocytes in BALF than in peripheral blood, while both CD4+ and CD8+ T lymphocyte subsets in BALF of tuberculin-positive patients secreted more IFN-gamma than their peripheral blood counterparts. Tuberculin-negative patients had a significantly higher proportion of IFN-gamma producing CD4+ T-lymphocytes in peripheral blood than tuberculin-positive patients. There was no significant difference in the production of IFN-gamma by BALF CD4+ T-lymphocytes, or by either peripheral blood or BALF CD8+ T-lymphocytes. In two tuberculin-negative patients, peripheral blood CD4+ T-lymphocytes produced IL-4. Study results suggested a higher immune activity in the blood of tuberculin-negative patients, with an increased lymphocyte activity in BALF versus peripheral blood in both patient groups.

Cytokine Profile of T lymphocytes from Peripheral Blood and Bronchoalveolar Lavage Fluid in Patients with Active Pulmonary Tuberculosis

Intracellular assessment of cytokines at the single cell level by flow cytometry has recently become available. Several critical parameters such as the cell type used, mode of activation, intensity and timing of cytokine generation should be adjusted for each cytokine tested. We evaluated T cell and monocyte cytokine production after short term culture with polyclonal activators in the presence of protein secretion inhibitors. Three-colour immunofluorescence analysis was used to examine cytoplasmic cytokines, IL-4 and IFN-, in CD4 or CD8 T cells, obtained from healthy individuals and patients with allergic asthma. The kinetics of the expression of proinflammatory cytokines, TNF- and IL-6, in LPS-activated monocytes was analysed following the back gating approach to include monocytes only according to theri size, granularity, and expression of CD14 and CD45. Results and conclusions: proper activation with PMA and ionomycin, determined by expression of CD69, is a prerogative for the detection of intracullular cytokines in T cells. Transient internalisation of CD4 molecule caused by PMA, could be partially circumvented by using the highly sensitive fluorochromes such as phycoerythrin. The addition of secretion inhibitor, monensin of brefeldin A, increased the percentage of cytokine positive cels. Coexpression analysis of IL-4 and IFN- production showed the CD4 subset to produce more IFN- and IL-4, while CD8 subset produced predominantly IFN- . Allergic individuals had a lower percentage of IFN- producing cells than healthy controls and therefore demonstrated higher IL-4/IFN- ratio. The analysis of TNF- and IL-6 in LPS-stimulated monocytes enabled us to demonstrate the kinetics of proinflammatory cytokine production at the single cell level by flow cytometry.

Detection of intracellular cytokines in human lymphocytes and monocytes at the single cell level by flow cytometry

Summary
Background Cysteinyl leukotrienes are potent pro-inflammatory mediators that contribute to the pathophysiologic features observed in allergic asthma. Inhibitors of leukotriene receptors represent novel therapy in asthma treatment. In addition to the protection from early asthmatic responses, these drugs have recently been shown to protect from late airway responses too.

Methods We studied the effect of treatment with an oral antagonist of cysteinyl leukotriene receptors on the increased expression of the low-affinity IgE receptor, CD23, on B cells, and of its ligands, CD11b and CD11c, on CD4+ T cells and monocytes in peripheral blood of patients with allergic asthma. In this uncontrolled open-label study, 14 children with allergic asthma received montelukast, a cysteinyl leukotrine receptor antagonist, for a period of 6 weeks after demonstrating forced expiratory volume in 1 s (FEV1) of less than 80% of the predicted value. Samples of peripheral heparinized blood and sera were obtained before and after therapy completion. Three-colour immunofluorescence analysis was performed, and expression of CD11b and CD11c on CD4+ T lymphocytes and monocytes as well as the expression of CD21 and CD23 on B cells were determined (n=12). Peripheral blood eosinophil count, changes in FEV1 and peak expiratory flow rate (PEFR), asthma exacerbations, and as-needed use of β-agonist were also monitored.

Results Montelukast improved FEV1 and PEFR, and decreased peripheral eosinophil counts in all study patients. There was no significant change in the expression of CD21 and CD23 on B cells. The expression of CD11c on CD4+ T cells and of both CD11b and CD11c on monocytes remained similar to the pretreatment expression. However, the percentage of CD11b+CD4+ T lymphocytes significantly decreased after treatment with montelukast. This was accompanied by a significant decrease in the levels of total IgE.

Conclusion The capacity of 6-week montelukast therapy to reduce the percentage of CD11b CD4+ T cells might be a mechanism leading to the immune response modulation on this T cell subset interaction with CD23-expressing B cells and subsequent down-regulation of IgE synthesis.

Effect of cysteinyl leukotriene receptor antagonist on CD11b and CD23 expression in asthmatic children.

The immune and neuroendocrine systems are intricately connected and communicating with all other tissues and organs of the body. Communication between systems is indispensable for integrity maintenance of an organism exposed to all kinds of internal and environmental signals. These signals transfer information between individual cells of every system in order to counteract any deviation from established optimal pattern of stability (homeostasis). Fluctuating environmental conditions can overcome homeostatic range, thus threatening the integrity. This threat (stressor) elicits physiological and behavioral responses through changes of boundaries of control to re-establish stability (allostasis). A state of disturbed integrity (stress) elicits a stress response through the release soluble mediators, thus modifying the immune cell behavior and function. Even threats to our sense of mental integrity may have physical consequences including changes in immune system. In this way psychological stress will not initiate immune reaction but only incite immune cells to additional physiological functions and modulate their reactivity to any concomitant or subsequent antigenic challenges. Thus, protection against pathogenic agents that immune system provides is a consequence of its capacity to maintain homeostasis rather than its goal. Stress may be associated with psychiatric and physical comorbidity with strong influence on immune response. The literature data, including our own, on the effects of stress on various aspects of immunity are reviewed. Although the findings are difficult to reconcile, a common pattern of immune alterations can be defined. The characteristics of stressors are important in determining the kind of change that would occur. Short-term stressors enhanced natural immunity and at the same time, specific cellular immunity was suppressed while humoral immunity was preserved. Chronic stress was found to be associated with global suppression of the immune system, particularly specific immune functions (both cellular and humoral). Finally, age and disease status were found to affect an individual's vulnerability to stress-related decreases in immune function.

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The immune system under stress

The aims of this research were to determine the number of chromosomal aberrations in peripheral blood lymphocytes and to determine the number of circulating lymphocytes with CD103, integrin expressed on intraepithelial lymphocytes, in patients with newly diagnosed Crohn’s disease, celiac disease and healthy controls. In the 30 months study period we included 44 patients ; 19 patients with newly diagnosed celiac disease ; 13 patients with newly diagnosed Crohn’s disease before any treatment was initiated and 12 healthy controls. Chromosome aberrations were analyzed in peripheral blood lymphocytes by a single cytogeneticist. For each subject 100 metaphases were analyzed for chromosome-type and chromatid-type aberrations. Multicolor flow cytometric immunophenotyping was used to enumerate CD103 expressing total T cells (CD3+), helper T cells (CD3+CD4+) and cytotoxic T cells (CD3+CD8+). We found significantly higher number of chromosomal aberrations/100 metaphases in celiac disease and Crohn’s disease group comparing to controls (p=0.01). Similarly, patients in celiac disease group and Crohn’s disease group had significantly higher number of aberrant cells comparing to controls (p<0.001). There was no statistically significant difference between groups in regards to percentage of CD103+ and CD8+103+ cells between groups (p=0.16, p=0.41 ; respectively) and no correlation between total number of chromosomal aberrations and percentage of CD103+ and CD8+103+ cells (p=0.06, p=0.06 ; respectively). Patients with active celiac disease and newly diagnosed Crohn’s disease, before treatment initiation, have significantly increased number of chromosomal aberrations in peripheral blood lymphocytes. No dissemination of intraepithelial cells in the blood and correlation to the chromosomal aberration was found.

Chromosomal aberrations in peripheral blood lymphocytes in patients with newly diagnosed celiac and Crohn's disease.

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