Tumor-specific mutations form novel immunogenic peptides called neoantigens. Neoantigens can be used as a biomarker predicting patient response to cancer immunotherapy. Although a predicted binding ...affinity (IC50) between peptide and major histocompatibility complex class I is currently used for neoantigen prediction, large number of false-positives exist.
We developed Neopepsee, a machine-learning-based neoantigen prediction program for next-generation sequencing data. With raw RNA-seq data and a list of somatic mutations, Neopepsee automatically extracts mutated peptide sequences and gene expression levels. We tested 14 immunogenicity features to construct a machine-learning classifier and compared with the conventional methods based on IC50 regarding sensitivity and specificity. We tested Neopepsee on independent datasets from melanoma, leukemia, and stomach cancer.
Nine of the 14 immunogenicity features that are informative and inter-independent were used to construct the machine-learning classifiers. Neopepsee provides a rich annotation of candidate peptides with 87 immunogenicity-related values, including IC50, expression levels of neopeptides and immune regulatory genes (e.g. PD1, PD-L1), matched epitope sequences, and a three-level (high, medium, and low) call for neoantigen probability. Compared with the conventional methods, the performance was improved in sensitivity and especially two- to threefold in the specificity. Tests with validated datasets and independently proven neoantigens confirmed the improved performance in melanoma and chronic lymphocytic leukemia. Additionally, we found sequence similarity in proteins to known pathogenic epitopes to be a novel feature in classification. Application of Neopepsee to 224 public stomach adenocarcinoma datasets predicted ∼7 neoantigens per patient, the burden of which was correlated with patient prognosis.
Neopepsee can detect neoantigen candidates with less false positives and be used to determine the prognosis of the patient. We expect that retrieval of neoantigen sequences with Neopepsee will help advance research on next-generation cancer immunotherapies, predictive biomarkers, and personalized cancer vaccines.
Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with ...non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440 and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.
The human gut microbiome has been associated with many health factors but variability between studies limits exploration of effects between them. Gut microbiota profiles are available for >2700 ...members of the deeply phenotyped TwinsUK cohort, providing a uniform platform for such comparisons. Here, we present gut microbiota association analyses for 38 common diseases and 51 medications within the cohort. We describe several novel associations, highlight associations common across multiple diseases, and determine which diseases and medications have the greatest association with the gut microbiota. These results provide a reference for future studies of the gut microbiome and its role in human health.
Background
Since the recent establishment of a murine model of eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), both the development of new drugs for treatment or prevention of ...eosinophilic CRSwNP and elucidation of their pathogenesis have been feasible. We investigated the therapeutic effects of resveratrol on CRSwNP and its mechanism of action using a murine model.
Methods
After induction of eosinophilic CRSwNP, the therapeutic effects of resveratrol were tested and compared with those of triamcinolone acetonide. Histopathologic changes were evaluated using hematoxylin and eosin for overall inflammation, Sirius red for eosinophils, and Masson's trichrome stain for collagen. The expression levels of the interleukin (IL)‐4, IL‐5, prostaglandin D synthase, and leukotriene C4 synthase genes were assessed by quantitative real‐time PCR. Cyclooxygense‐2 and 5‐lipoxygense levels were evaluated by immunohistochemical staining and Western blot analysis.
Results
The degree of eosinophilic infiltration and subepithelial fibrosis was significantly decreased by administration of high‐dose resveratrol, the potency of which was similar to that of triamcinolone acetonide. The expression levels of the IL‐4, IL‐5, prostaglandin D synthase, and leukotriene C4 synthase genes were significantly decreased by administration of low‐ or high‐dose resveratrol. The production of 5‐lipoxygenase was strongly inhibited by high‐dose resveratrol.
Conclusions
Resveratrol may be useful for the prevention of eosinophilic CRSwNP. A key mechanism of its action is believed to be its anti‐inflammatory effect, particularly on eosinophils, by inhibiting the lipoxygenase pathway.
The effects of the surface energy of polymer gate dielectrics on pentacene morphology and the electrical properties of pentacene field‐effect transistors (FETs) are reported, using ...surface‐energy‐controllable poly(imide‐siloxane)s as gate‐dielectric layers. The surface energy of gate dielectrics strongly influences the pentacene film morphology and growth mode, producing Stranski–Krastanov growth with large and dendritic grains at high surface energy and three‐dimensional island growth with small grains at low surface energy. In spite of the small grain size (≈ 300 nm) and decreased ordering of pentacene molecules vertical to the gate dielectric with low surface energy, the mobility of FETs with a low‐surface‐energy gate dielectric is larger by a factor of about five, compared to their high‐surface‐energy counterparts. In pentacene growth on the low‐surface‐energy gate dielectric, interconnection between grains is observed and gradual lateral growth of grains causes the vacant space between grains to be filled. Hence, the higher mobility of the FETs with low‐surface‐energy gate dielectrics can be achieved by interconnection and tight packing between pentacene grains. On the other hand, the high‐surface‐energy dielectric forms the first pentacene layer with some voids and then successive, incomplete layers over the first, which can limit the transport of charge carriers and cause lower carrier mobility, in spite of the formation of large grains (≈ 1.3 μm) in a thicker pentacene film.
Poly(imide‐siloxane)s with controllable surface energy are used as gate dielectrics to investigate the effects on pentacene morphology and field‐effect‐ transistor characteristics. Three‐dimensional growth of pentacene and interconnection between pentacene grains is observed on a low‐surface‐energy dielectric (see Figure, width = 2.5 μm), leading to a high‐mobility pentacene field‐effect transistor.
Inflammatory responses and osteoclast differentiation play pivotal roles in the pathogenesis of osteolytic bone diseases such as periodontitis. Although overexpression or inhibition of ...peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) offers a possible therapeutic strategy for chronic inflammatory diseases, the role of PIN1 in periodontal disease is unclear. The aim of the present study was to evaluate PIN1 expression in periodontitis patients as well as the effects of PIN1 inhibition by juglone or PIN1 small-interfering RNA (siRNA) and of PIN1 overexpression using a recombinant adenovirus encoding PIN1 (Ad-PIN1) on the inflammatory response and osteoclastic differentiation in lipopolysaccharide (LPS)- and nicotine-stimulated human periodontal ligament cells (PDLCs). PIN1 was up-regulated in chronically inflamed PDLCs from periodontitis patients and in LPS- and nicotine-exposed PDLCs. Inhibition of PIN1 by juglone or knockdown of PIN1 gene expression by siRNA markedly attenuated LPS- and nicotine-stimulated prostaglandin E2 (PGE2) and nitric oxide (NO) production, as well as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, whereas PIN1 overexpression by Ad-PIN1 increased it. LPS- and nicotine-induced nuclear factor (NF)-κB activation was blocked by juglone and PIN1 siRNA but increased by Ad-PIN1. Conditioned medium prepared from LPS- and nicotine-treated PDLCs increased the number of tartrate-resistant acid phosphatase–stained osteoclasts and osteoclast-specific gene expression. These responses were blocked by PIN1 inhibition and silencing but stimulated by Ad-PIN1. Furthermore, juglone and PIN1 siRNA inhibited LPS- and nicotine-induced osteoclastogenic cytokine expression in PDLCs. This study is the first to demonstrate that PIN1 inhibition exhibits anti-inflammatory effects and blocks osteoclastic differentiation in LPS- and nicotine-treated PDLCs. PIN1 inhibition may be a therapeutic strategy for inflammatory osteolysis in periodontal disease.
Elucidating temporal windows of signaling activity required for synaptic and behavioral plasticity is crucial for understanding molecular mechanisms underlying these phenomena. Here, we developed ...photoactivatable autocamtide inhibitory peptide 2 (paAIP2), a genetically encoded, light-inducible inhibitor of CaMKII activity. The photoactivation of paAIP2 in neurons for 1–2 min during the induction of LTP and structural LTP (sLTP) of dendritic spines inhibited these forms of plasticity in hippocampal slices of rodents. However, photoactivation ∼1 min after the induction did not affect them, suggesting that the initial 1 min of CaMKII activation is sufficient for inducing LTP and sLTP. Furthermore, the photoactivation of paAIP2 expressed in amygdalar neurons of mice during an inhibitory avoidance task revealed that CaMKII activity during, but not after, training is required for the memory formation. Thus, we demonstrated that paAIP2 is useful to elucidate the temporal window of CaMKII activation required for synaptic plasticity and learning.
•PaAIP2 is a genetically encoded, light-inducible inhibitor of CaMKII•PaAIP2 inhibits CaMKII with high specificity and with second-to-minute temporal resolution•PaAIP2 measures the temporal window of CaMKII required for synaptic plasticity•PaAIP2 measures the kinetics of CaMKII activity during learning and memory
Murakoshi, Shin et al. developed a light-inducible inhibitor of CaMKII and demonstrated that a brief illumination of blue light to neurons expressing this inhibitor blocks synaptic plasticity and learning.
To evaluate a trial of immunotherapy as an aid to diagnosis in suspected autoimmune epilepsy.
We reviewed the charts of 110 patients seen at our autoimmune neurology clinic with seizures as a chief ...complaint. Twenty-nine patients met the following inclusion criteria: (1) autoimmune epilepsy suspected based on the presence of ≥ 1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and (2) initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IV immune globulin (IVIg), or both. Patients were defined as responders if there was a 50% or greater reduction in seizure frequency.
Eighteen patients (62%) responded, of whom 10 (34%) became seizure-free; 52% improved with the first agent. Of those receiving a second agent after not responding to the first, 43% improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 vs 22 months; p = 0.048). Responders included 14/16 (87.5%) patients with antibodies to plasma membrane antigens, 2/6 (33%) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33%) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85%).
These retrospective findings justify consideration of a trial of immunotherapy in patients with suspected autoimmune epilepsy.
This study provides Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIg, or both improve seizure control.
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