T cells of colorectal cancer patients' stimulated by neoantigenic and cryptic peptides better recognize autologous tumor cells.

BACKGROUND: Patients with cancers that exhibit extraordinarily high somatic mutation numbers are ideal candidates for immunotherapy and enable identifying tumor-specific peptides through stimulation of tumor-reactive T cells (Tc). METHODS: Colorectal cancers (CRC) HROC113 and HROC285 were selected based on high TMB, microsatellite instability and HLA class I expression. Their HLA ligandome was characterized using mass spectrometry, compared with the HLA ligand atlas and HLA class I-binding affinity was predicted. Cryptic peptides were identified using Peptide-PRISM. Patients' Tc were isolated from either peripheral blood (pTc) or tumor material (tumor-infiltrating Tc, TiTc) and expanded. In addition, B-lymphoblastoid cells (B-LCL) were generated and used as antigen-presenting cells. pTc and TiTc were stimulated twice for 7 days using peptide pool-loaded B-LCL. Subsequently, interferon gamma (IFNγ) release was quantified by ELISpot. Finally, cytotoxicity against autologous tumor cells was assessed in a degranulation assay. RESULTS: 100 tumor-specific candidate peptides-97 cryptic peptides and 3 classically mutated neoantigens-were selected. The neoantigens originated from single nucleotide substitutions in the genes IQGAP1, CTNNB1, and TRIT1. Cryptic and neoantigenic peptides inducing IFNγ secretion of Tc were further investigated. Stimulation of pTc and TiTc with neoantigens and selected cryptic peptides resulted in increased release of cytotoxic granules in the presence of autologous tumor cells, substantiating their improved tumor cell recognition. Tetramer staining showed an enhanced number of pTc and TiTc specific for the IQGAP1 neoantigen. Subpopulation analysis prior to peptide stimulation revealed that pTc mainly consisted of memory Tc, whereas TiTc constituted primarily of effector and effector memory Tc. This allows to infer that TiTc reacting to neoantigens and cryptic peptides must be present within the tumor microenvironment. CONCLUSION: These results prove that the analyzed CRC present both mutated neoantigenic and cryptic peptides on their HLA class I molecules. Moreover, stimulation with these peptides significantly strengthened tumor cell recognition by Tc. Since the overall number of neoantigenic peptides identifiable by HLA ligandome analysis hitherto is small, our data emphasize the relevance of increasing the target scope for cancer vaccines by the cryptic peptide category.

Behavioral Outcomes and Neural Network Modeling of a Novel, Putative, Recategorization Sound Therapy.

The mechanisms underlying sound's effect on tinnitus perception are unclear. Tinnitus activity appears to conflict with perceptual expectations of "real" sound, resulting in it being a salient signal. Attention diverted towards tinnitus during the later stages of object processing potentially disrupts high-order auditory streaming, and its uncertain nature results in negative psychological responses. This study investigated the benefits and neurophysiological basis of passive perceptual training and informational counseling to recategorize phantom perception as a more real auditory object. Specifically, it examined underlying psychoacoustic correlates of tinnitus and the neural activities associated with tinnitus auditory streaming and how malleable these are to change with targeted intervention. Eighteen participants (8 females, 10 males, mean age = 61.6 years) completed the study. The study consisted of 2 parts: (1) An acute exposure over 30 min to a sound that matched the person's tinnitus (Tinnitus Avatar) that was cross-faded to a selected nature sound (Cicadas, Fan, Water Sound/Rain, Birds, Water and Bird). (2) A chronic exposure for 3 months to the same "morphed" sound. A brain-inspired spiking neural network (SNN) architecture was used to model and compare differences between electroencephalography (EEG) patterns recorded prior to morphing sound presentation, during, after (3-month), and post-follow-up. Results showed that the tinnitus avatar generated was a good match to an individual's tinnitus as rated on likeness scales and was not rated as unpleasant. The five environmental sounds selected for this study were also rated as being appropriate matches to individuals' tinnitus and largely pleasant to listen to. There was a significant reduction in the Tinnitus Functional Index score and subscales of intrusiveness of the tinnitus signal and ability to concentrate with the tinnitus trial end compared to baseline. There was a significant decrease in how strong the tinnitus signal was rated as well as ratings of how easy it was to ignore the tinnitus signal on severity rating scales. Qualitative analysis found that the environmental sound interacted with the tinnitus in a positive way, but participants did not experience change in severity, however, characteristics of tinnitus, including pitch and uniformity of sound, were reported to change. The results indicate the feasibility of the computational SNN method and preliminary evidence that the sound exposure may change activation of neural tinnitus networks and greater bilateral hemispheric involvement as the sound morphs over time into natural environmental sound; particularly relating to attention and discriminatory judgments (dorsal attention network, precentral gyrus, ventral anterior network). This is the first study that attempts to recategorize tinnitus using passive auditory training to a sound that morphs from resembling the person's tinnitus to a natural sound. These findings will be used to design future-controlled trials to elucidate whether the approach used differs in effect and mechanism from conventional Broadband Noise (BBN) sound therapy.

Prediction of tinnitus masking benefit within a case series using a spiking neural network model.

Masking has been widely used as a tinnitus therapy, with large individual differences in its effectiveness. The basis of this variation is unknown. We examined individual tinnitus and psychological responses to three masking types, energetic masking (bilateral broadband static or rain noise [BBN]), informational masking (BBN with a notch at tinnitus pitch and 3-dimensional cues) and a masker combining both effects (BBN with spatial cues). Eleven participants with chronic tinnitus were followed for 12 months, each person used each masking approach for 3 months with a 1 month washout-baseline. The Tinnitus Functional Index (TFI), Tinnitus Rating Scales, Positive and Negative Affect Scale and Depression Anxiety Stress Scales, were measured every month of treatment. Electroencephalography (EEG) and psychoacoustic assessment was undertaken at baseline and following 3 months of each masking sound. The computational modeling of EEG data was based on the framework of brain-inspired Spiking Neural Network (SNN) architecture called NeuCube, designed for this study for mapping, learning, visualizing and classifying of brain activity patterns. EEG was related to clinically significant change in the TFI using the SNN model. The SNN framework was able to predict sound therapy responders (93% accuracy) from non-responders (100% accuracy) using baseline EEG recordings. The combination of energetic and informational masking was an effective treatment sound in more individuals than the other sounds used. Although the findings are promising, they are preliminary and require confirmation in independent and larger samples.

A Retinotopic Spiking Neural Network System for Accurate Recognition of Moving Objects Using NeuCube and Dynamic Vision Sensors.

This paper introduces a new system for dynamic visual recognition that combines bio-inspired hardware with a brain-like spiking neural network. The system is designed to take data from a dynamic vision sensor (DVS) that simulates the functioning of the human retina by producing an address event output (spike trains) based on the movement of objects. The system then convolutes the spike trains and feeds them into a brain-like spiking neural network, called NeuCube, which is organized in a three-dimensional manner, representing the organization of the primary visual cortex. Spatio-temporal patterns of the data are learned during a deep unsupervised learning stage, using spike-timing-dependent plasticity. In a second stage, supervised learning is performed to train the network for classification tasks. The convolution algorithm and the mapping into the network mimic the function of retinal ganglion cells and the retinotopic organization of the visual cortex. The NeuCube architecture can be used to visualize the deep connectivity inside the network before, during, and after training and thereby allows for a better understanding of the learning processes. The method was tested on the benchmark MNIST-DVS dataset and achieved a classification accuracy of 92.90%. The paper discusses advantages and limitations of the new method and concludes that it is worth exploring further on different datasets, aiming for advances in dynamic computer vision and multimodal systems that integrate visual, aural, tactile, and other kinds of information in a biologically plausible way.

NCLEX fairness and sensitivity review.

The National Council Licensing Examination is an examination that is used for the purpose of licensing registered nurses and practical/vocational nurses. To help ensure that the examination questions (items) are fair and unbiased, all items undergo a fairness and sensitivity review as part of the item development process. This article focuses on the fairness and sensitivity review.

Developing and evaluating innovative items for the NCLEX: Part 2, item characteristics and cognitive processing.

This article is a continuation of the research on the development and evaluation of innovative item formats for the NCLEX examinations that was published in the March/April 2009 edition of Nurse Educator. The authors discuss the innovative item templates and evaluate the statistical characteristics and level of cognitive processing required to answer the examination items.

Alternate item types: continuing the quest for authentic testing.

Many test developers suggest that multiple-choice items can be used to evaluate critical thinking if the items are focused on measuring higher order thinking ability. The literature supports the use of alternate item types to assess additional competencies, such as higher level cognitive processing and critical thinking, as well as ways to allow examinees to demonstrate their competencies differently. This research study surveyed nurses after taking a test composed of alternate item types paired with multiple-choice items. The participants were asked to provide opinions regarding the items and the item formats. Demographic information was asked. In addition, information was collected as the participants responded to the items. The results of this study reveal that the participants thought that, in general, the items were more authentic and allowed them to demonstrate their competence better than multiple-choice items did. Further investigation into the optimal blend of alternate items and multiple-choice items is needed.

Evaluating innovative items for the NCLEX, part I: usability and pilot testing.

National Council of State Boards of Nursing (NCSBN) has recently conducted preliminary research on the feasibility of including various types of innovative test questions (items) on the NCLEX. This article focuses on the participants' reactions to and their strategies for interacting with various types of innovative items. Part 2 in the May/June issue will focus on the innovative item templates and evaluation of the statistical characteristics and the level of cognitive processing required to answer the examination items.

Setting the passing standard for the National Council Licensure Examination for Registered Nurses.

The Board of Directors of the National Council of State Boards of Nursing evaluates the NCLEX-RN examination passing standard every 3 years. In December 2006, the Board decided that the NCLEX-RN passing standard should be increased from -0.2800 to -0.2100 logits. This article provides information regarding standard-setting methodologies, empirical data used by the Board of Directors in determining the passing standard, and implications of the new passing standard for faculty.

Monitoring entry-level practice: keeping the national council licensure examination for registered nurses current.

The National Council Licensure Examination for Registered Nurses assesses whether a candidate has the ability to provide safe and effective nursing care upon entry into practice. It is essential that this assessment be current and relevant to nursing practice. The authors discuss methods that are used to provide evidence to support the 2007 NCLEX-RN Test Plan and to maintain the currency of the examination.

Recommending a minimum English proficiency standard for entry-level nursing.

The purpose of this research was to provide sufficient information to the National Council of State Boards of Nursing (NCSBN) to make a defensible recommended passing standard for English proficiency. This standard was based upon the Test of English as a Foreign Language (TOEFL). A large panel of nurses and nurse regulators (N = 25) was convened to determine how much English proficiency is required to be minimally competent as an entry-level nurse. Two standard setting procedures were combined to produce recommendations for each panelist. In conjunction with collateral information, these recommendations were reviewed by the NCSBN Examination Committee, which decided upon an NCSBN recommended standard, a TOEFL score of 220.

The NCLEX-RN examination: charting the course of nursing practice.

The author describes the changes in the 2004 NCLEX-RN(R) Test Plan and provides information about the alternate item formats that are being developed for the NCLEX examination. Nursing educators will learn details about the new test plan and review sample alternate items. Information from this article can be used for curriculum review and to prepare students to take the NCLEX examination.