Single Ab Research Articles

EXTH-85. ASSESSMENT OF ANTI-CD69 ANTIBODY THERAPY ALONE OR IN COMBINATION WITH ANTI-PD-1 IN MURINE GBM

Abstract BACKGROUND Glioblastoma multiforme (GBM) is an aggressive central nervous system malignancy with a dismal prognosis. There is continued interest in trying multiple immunotherapy modalities for this intractable cancer. Cluster of differentiation 69 (CD69), is an early marker of T and NK cell activation. CD69 play multiple roles in T cell-mediated immunoregulation with immune inhibitory role in antitumor immunity. Previous preclinical work in non-CNS malignancies has demonstrated that targeting CD69 can improve clinical outcome and anti-tumor immunity. We aimed to assess anti-CD69 Ab therapy alone or in combination with anti-PD-1 in murine GBM. METHODS We explored transcriptomic data from 163 GBM patients using the TCGA database. We then tested the therapeutic value of anti-CD69 immunotherapy in a preclinical model of GBM and assessed the ideal timing of treatment with anti-CD69 Ab by evaluating survival and immune tumor-microenvironment by flow cytometry. Two treatment-timings with anti-CD69 Ab were further evaluated either alone, or in combination with anti-PD1 Abs and compared to control and to anti-PD1 only treatment. Survival data was collected. RESULTS CD69 expression was significantly increased in GBM patients tissues as compared with normal brains and increased CD69 expression was associated with worse progression-free survival. Treatment-timing with single dose anti-CD69 Ab at day 1 or three doses at days 4, 8 and 12 post tumor-injection minimally improved the median survival time of animals. In addition, effective CD69 blockage and significantly elevated PD-1 expression on NK cells was found in these timings, making them good candidates to evaluate anti-CD69 Ab therapy alone or in combination with anti-PD-1 Ab. However, when assessing these treatment-timings with anti-CD69 Ab alone or in combination with anti-PD1 no survival benefit was found. CONCLUSION This is the first study assessing anti-CD69 Ab therapy alone or in combination with anti-PD-1 in murine GBM. While some effect was found on the cellular level, this didn’t translate to survival benefit and results are overall negative.

Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8+ T cell activity and biomarker during the evolution of Type 1 Diabetes.

Surviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death-1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesized that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death. Beta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry, and ELISA. EV PD-L1: PD-1 binding was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8 T cells. Plasma EV and soluble PD-L1 were assayed in plasma of individuals with islet autoantibody positivity (Ab+) or recent-onset type 1 diabetes and compared to non-diabetic controls. PD-L1 protein colocalized with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. 24-h IFN-α or IFN-γ treatment induced a two-fold increase in EV PD-L1 cargo without a corresponding increase in number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8 T cells. Plasma EV PD-L1 levels were increased in islet Ab+ individuals, particularly in those with single Ab+, Additionally, in from individuals with either Ab+ or type 1 diabetes, but not in controls, plasma EV PD-L1 positively correlated with circulating C-peptide, suggesting that higher EV-PD-L1 could be protective for residual beta cell function. IFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8 T cell proliferation and cytotoxicity. Circulating EV PD-L1 is higher in islet autoantibody positive patients compared to controls. Circulating EV PD-L1 levels correlate with residual C-peptide at different stages in type 1 diabetes progression. These findings suggest that EV PD-L1 could contribute to heterogeneity in type 1 diabetes progression and residual beta cell function and raise the possibility that EV PD-L1 could be exploited as a means to inhibit immune-mediated beta cell death.

Making physical activity fun and accessible to adults with intellectual disabilities: A pilot study of a gamification intervention.

Only about 9% of individuals with intellectual disabilities reach the government's physical activity (PA) recommendations. Combining gamification and technology seems particularly promising in overcoming personal and environmental barriers to PA participation. Eighteen adults with varying levels of intellectual disabilities completed a pilot study to assess the initial effects of a cycling gamification intervention on levels of PA, fitness, psychosocial outcomes, and challenging behaviours. The study comprised three designs: pre-post single group, AB single-case, and qualitative. Social validity, implementation barriers and facilitators were also explored. Nearly all 18 participants cycled daily. Time and distance cycled daily increase during the intervention while a decrease in stereotyped behaviours was observed. Participants and staff found the intervention enjoyable and socially valid. Results of the multiple-design study suggest that gamification interventions may be a suitable, enjoyable, and promising way to contribute to PA participation of adults with intellectual disabilities.

Estimation of Water Consumption of Haloxylon ammodendron Sand-Fixing Forest in Minqin Oasis-Desert Ecotone of China Based on Leaf Index, China

In order to accurately estimate the water consumption of a Minqin desert Haloxylon ammodendron sand fixation forest, we used thermal equilibrium stem flow measurement to monitor the stem flow dynamics of Minqin desert H. ammodendron (5, 10, 15, and 20 years old, respectively, denoted as H5, H10, H15, and H20). In this study, we chose the growth index of assimilated branches (expressed as Ab in the following text) as the scalar quantity for expansion, and then estimated the water consumption of the H. ammodendron sand fixation forest by fitting the correlation between the water consumption of single H. ammodendron plants and the surface area and dry weight of single Ab. The results showed that the growth of assimilated H. ammodendron branches and the plant’s monthly water consumption were synchronized, and that the growth of Ab and water consumption were significantly higher during the fast-growth period of H. ammodendron (July) compared to during the leaf-expanding (May) and leaf-falling periods (October). After correlation analysis, it was determined that there was a linear function between the surface area and dry weight of Ab and water consumption in H. ammodendron. The simulated water consumption values (kg) of H. ammodendron sand fixation forests were greatly affected by stand density and branching configuration, and the simulated values of H. ammodendron assimilated branch growth (cm) were slightly smaller than the measured values for forests of different ages, while the simulated values of assimilated branch surface area (cm2) had a much smaller relative error (8.92%) on average. Therefore, it is feasible to use the surface area and dry weight of Ab to calculate the water consumption of H. ammodendron sand fixation forests. This can enable the reliable estimation of the water consumption of H. ammodendron forests and provide a reference for desert vegetation sand fixation afforestation and its ecological water management.

Solution Self-Assembly of Amphiphilic Tadpole-like Giant Molecules Constructed by Monotethering Diblock Copolymer Chain onto a Nanoparticle.

The self-assembly behavior of a tadpole-like giant molecule (TGM) constructed from a hydrophobic nanoparticle (NP) monotethered by a single amphiphilic AB diblock copolymer chain was investigated by combining self-consistent field theory and density functional theory in solution. The effects of the hydrophobicities of the B blocks and NPs (i.e., solvent properties) on the self-assembly behavior of the TGMs were investigated in the cases of weak and strong intramolecular interactions (i.e., incompatibilities) between the components of giant molecules, respectively. Besides conventional ordered aggregates (such as spheres, rings, and vesicles) with hydrophobic B-cores covered by NP shells, several aggregates with novel hierarchical structures, including vesicles with NP-inserted hydrophobic walls, bead-string-like micelles, and long cylindrical micelles with NP bumps, were obtained by tuning the solvent properties under different intramolecular interactions. Noteworthy that the simulation results show that the arrangement of the NP bumps on the long cylindrical micelles may have a certain degree of helicity, which means that these micelles may have some unique electromagnetic features such as circular dichroism. Phase diagrams as a function of the hydrophobicities of the B blocks and NPs were constructed to show the formation conditions of these novel structures. These findings can not only offer new insights into understanding of the self-assembly behavior of the TGM in solution but also provide useful guidance for simple and efficient regulation of the morphology, as well as the NP distribution and arrangement of the ordered aggregates in experiments.

Higher order Morita approximation and its validity for random copolymer adsorption onto homogeneous and periodic heterogeneous surfaces

Adsorption of a single AB random copolymer (RC) chain onto homogeneous and inhomogeneous ab surfaces with a regular periodic pattern is studied theoretically. For the averaging over disorder in the RC sequence, the constrained annealed approximation, known as the Morita approximation is employed. A general scheme for constructing the Morita approximation of an arbitrary order m is proposed; it is based on representation of the RC monomer sequence as a Markov chain of overlapping –1)-ads. The problem is solved within the framework of the generating functions approach for the two-dimensional partially directed walk model of the polymer on a square lattice. Temperature dependences of various adsorption characteristics are obtained. The accuracy of the Morita approximation is assessed by comparison with the numerical results for RC with quenched sequences obtained by the transfer matrix approach. It is shown that for RC adsorption on a homogeneous surface for AB-copolymers with adsorbing A and neutral B blocks, it is sufficient to use the Morita approximation of second or third order. If the non-adsorbing B block is repelled from the surface, then a higher order of the approximation (5th–6th) is required. An important indicator of validity of the Morita approximation is the entropy: if the order of the approximation is not high enough, the entropy becomes negative in the low-temperature regime which means that the Morita approximation is wrong in this order. In the case when the surface is periodically inhomogeneous, the Morita approximation works worse and very high orders are required, which can be beyond the computational capabilities. Moreover, the Morita approximations become degenerate: approximations of two or more consecutive orders give the same result.

1440-P: Single Islet Antigen 2 Antibody–Positive (IA2A Ab+) Children Exhibit Significant Metabolic Abnormalities and 5-Year Type 1 Diabetes (T1D) Risk

Current T1D staging defines multiple Ab+ as the start of T1D (Stage 1 or 2 depending on presence of dysglycemia). However, single Ab+ individuals are considered low-risk and are typically not considered for inclusion in prevention trials. We hypothesized that single IA2A+ children exhibit metabolic compromise with appreciable Stage 3 (clinical diabetes) risk. To test this, we evaluated 2163 confirmed single Ab+ children (IA2A, glutamic acid decarboxylase [GADA], or insulin [IAA]) with available OGTT data in the TrialNet natural history study. With and without age and BMI adjustment (Table), IA2A+ children had higher area under the curve (AUC) glucose, lower AUC C-peptide, and higher diabetes risk indices (Diabetes Prevention Trial Type 1 Risk Score [DPTRS] and Index60). Cox regression demonstrated that IA2A+ children were most likely to have progressed to Stage 3 (50.9% vs. 12.0% or 9.6% over 5 years). Of single Ab+ children who did not progress to Stage 3, GADA+ most frequently progressed to multiple Ab+ (34.0% over 5 years). In conclusion, amongst single Ab+ children, IA2A+ children have greater metabolic dysfunction and rates of progression to Stage 3. These findings suggest that single IA2A+ children exhibit substantial T1D risk, should also be considered as having Stage 1 T1D, and be considered for eligibility in prevention studies. Disclosure E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. D.D.Cuthbertson: None. E.Bosi: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. M.J.Redondo: None. B.M.Nathan: None. H.M.Ismail: Consultant; Rise Therapeutics. L.M.Jacobsen: None. J.Sosenko: None.

1441-P: Index60 Stratification Enhances Current Staging for Type 1 Diabetes by Identifying At-Risk Single Islet Autoantibody Positive (Ab+) Individuals

The current staging system for T1D development is used for participant selection in prevention trials. This system is based on multiple Ab+ and the presence or absence of dysglycemia, but does not address C-peptide measures or single Ab+ individuals. Since a limited number of Ab+ individuals are available for trials, we used TrialNet Pathway to Prevention (TNPTP) study data to assess whether a composite glucose and C-peptide measure, Index60, could identify single Ab+ individuals (designated as Stage 0) with comparable risk to those in Stages 1 or 2 for progression to Stage 3. Table 1A compares normoglycemic Stage 0 individuals with Index60 values above the median (>-0.045) of the full TNPTP cohort (n=6107) vs. those at Stage 1 with Index60 below the median (< -0.045). Table 1B compares those at Stage 0 with dysglycemia and higher Index60 vs. those at Stage 2 with lower Index60. In both comparisons, Index60 stratification identified Stage 0 individuals with metabolic features characteristic of T1D (e.g., lower C-peptide with higher glucose) and comparable 5-year risk to Stage 1 or Stage 2 individuals. Thus, by considering individuals with 1 Ab and C-peptide measures, the current staging system could be improved for risk discernment and to identify appropriate eligibility for prevention trials. Disclosure E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. D.D.Cuthbertson: None. E.Bosi: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. M.J.Redondo: None. B.M.Nathan: None. H.M.Ismail: Consultant; Rise Therapeutics. L.M.Jacobsen: None. J.Sosenko: None.

1298-P: Independent Associations of GAD65, IA2, and ZnT8 Autoantibody (Ab) Positivity with C-Peptide (CPep) in a Diverse Cohort of Youth with Diabetes (DM)

The current DM classification does not fully enable precision medicine in DM due to heterogeneity between and within DM types, especially in racially diverse populations. Insulin deficiency (ID) is one of the most clinically actionable DM outcomes and, while its association with islet autoimmunity is known, the influence of Ab type and number after DM onset is uncertain. Thus, we assessed the effect of Ab characteristics on ID (measured as Cpep loss) in youth with established DM. We studied 151 youth with DM (median [IQR] age 15.0 [4.2] yrs, DM duration 5.4 [3.4] yrs), 61% female, 53% Hispanic and 17% non-Hispanic African American. We measured postprandial serum Cpep, glucose and Ab (GAD65, IA2 and ZnT8) and collected clinical/demographic data. Cpep loss was pre-specified as postprandial CPep <0.6 ng/ml. We found 0, 1, 2, or 3 +Ab in 34%, 22%, 31% and 13% of participants, respectively (Figure, left panel). A Breslow-Day statistic suggested homogeneity of the risk ratios across the 3 Ab types for CPep loss (p = 0.42), which were all larger than 1 (Figure, right panel). Cpep loss was significantly associated with ≥1 (vs 0) Ab+ (p < 0.0001) but not with single (vs multiple) Ab+ (p = 0.60). In sum, each of GAD65, IA2 and ZnT8 Ab are significantly associated with ID among diverse youth with DM. This suggests that models predicting ID post-onset should include each of GAD65, IA2 and ZnT8 Ab. Disclosure M.J.Redondo: None. R.A.Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. D.Dabelea: None. W.Hagopian: Research Support; Janssen Research & Development, LLC, Provention Bio, Inc., Randox R & D. Discover study group: n/a. K.K.Harrall: None. D.H.Glueck: None. M.Tosur: Advisory Panel; Provention Bio, Inc. S.Uysal: None. A.Muir: None. K.Vehik: None. T.M.Brusko: Consultant; Repertoire Immune Medicines, Quell Therapeutics, Research Support; Immunocore, Ltd., Adaptive Biotechnologies. M.A.Atkinson: None. Funding National Institutes of Health (R01DK124395)

A Multi-Dictionary Approach to Abstractness/Concreteness-Based Authorship Attribution


 
 
 We present some early results from a research project aimed at exploring the usefulness of abstractness/concreteness as stylistic features for authorship attribution. We conjecture that authors use abstract/concrete words and phrases in suf- ficiently unique ways, so that machine learning classifiers can learn to distinguish the individual authors’ writing styles. Our approach is based on using the abstractness rat- ings of words and phrases from texts with established au- thorship to generate training vectors for different machine learning classifiers. The combined word/phrase ratings are extracted from two separate abstractness dictionaries – an approach that yields stronger results than using single ab- stractness dictionaries. The paper describes the details of our methodology and compares the results to those obtained using traditional authorship attribution stylistic features. The limitations of our current methodology and directions for further research are outlined at the end of the paper.
 
 

Closing the knowledge gap on the composition of the asbestos bodies

Asbestos bodies (AB) form in the lungs as a result of a biomineralization process initiated by the alveolar macrophages in the attempt to remove asbestos. During this process, organic and inorganic material deposit on the foreign fibers forming a Fe-rich coating. The AB start to form in months, thus quickly becoming the actual interface between asbestos and the lung tissue. Therefore, revealing their composition, and, in particular, the chemical form of Fe, which is the major component of the AB, is essential to assess their possible role in the pathogenesis of asbestos-related diseases. In this work we report the result of the first x-ray diffraction measurements performed on single AB embedded in the lung tissue samples of former asbestos plant workers. The combination with x-ray absorption spectroscopy data allowed to unambiguously reveal that Fe is present in the AB in the form of two Fe-oxy(hydroxides): ferrihydrite and goethite. The presence of goethite, which can be explained in terms of the transformation of ferrihydrite (a metastable phase) due to the acidic conditions induced by the alveolar macrophages in their attempt to phagocytose the fibers, has toxicological implications that are discussed in the paper.

Assessment of core-shell nanoparticles surface structure heterogeneity by SAXS contrast variation and ab initio modeling

For the biomedical applications of nanoparticles, the study of their structure is a major step towards understanding the mechanisms of their interaction with biological environment. Detailed structural analysis of particles’ surface is vital for rational design of drug delivery systems. In particular, for core-shell or surface-modified nanoparticles surface structure can be described in terms of shell coating uniformity and shell thickness uniformity around the nanoparticle core. Taken together, these terms can be used to indicate degree of heterogeneity of nanoparticle surface structure. However, characterization of nanoparticle surface structure under physiological conditions is challenging due to limitations of experimental techniques. In this paper, we apply SAXS contrast variation combined with ab initio bead modeling for this purpose. Approach is based on the fact that nanoparticles under study are produced by self-assembly of phospholipid-conjugated molecules that possess moieties with significantly different electron densities enabling SAXS technique to be used to distinguish nanoparticle shell and study its structure. Ab initio single phase and ab initio multiphase modeling based on SAXS curve of nanoparticles in phosphate buffer solution allowed to reconstruct nanoparticle shell coating and assess its uniformity, while serial nanoparticle reconstructions from solutions with gradually increased solvent electron densities revealed relative shell coating thickness around nanoparticle core. Nanoparticle shell structure representation was verified by molecular dynamics simulation and derived full-atom nanoparticle shell structure showed good agreement with SAXS-derived representation. Obtained data indicate that studied nanoparticles exhibit highly heterogeneous surface structure.

Efficacy and safety of ab interno trabeculectomy revision with 5-fluorouracil in advanced glaucoma due to subconjunctival fibrosis

ObjectifDécrire les résultats obtenus chez les patients qui ont subi une révision de trabéculectomie ab interno dans un seul œil, accompagnée de 5-fluorouracil. NatureÉtude de cohorte rétrospective. ParticipantsEnsemble des patients qui avaient subi une révision de trabéculectomie ab interno dans un seul établissement de soins tertiaires pendant les 5 années de l’étude. Tous les patients inclus présentaient une neuropathie optique glaucomateuse avancée, sans égard à l’âge et au sous-type de glaucome. MéthodesAu nombre des paramètres d’évaluation, mentionnons la réussite de l'intervention chirurgicale, le nombre de collyres visant à abaisser la pression intraoculaire (PIO), la meilleure acuité visuelle corrigée, la déviation moyenne du champ visuel ainsi que les complications postopératoires. La réussite à 12 mois reposait sur 2 critères : critère A (PIO < 15 mm Hg et baisse de > 20 % de la PIO) et critère B (PIO < 12 mm Hg et baisse de > 20 % de la PIO). Pour chacun des critères de réussite, on a réparti les patients en 2 groupes selon que la baisse de la PIO a été obtenue sans collyre (réussite complète) ou avec l'ajout de collyres (réussite partielle). RésultatsLa présente étude regroupe 46 yeux de 46 patients. De ce nombre, 34 patients ont été suivis pendant au moins 12 mois après l'intervention aux fins d’évaluation de la réussite. Parmi ces 34 patients, le taux de réussite selon le critère A a été de 68 % (réussite complète : 53 %; réussite partielle : 15 %) et le taux de réussite selon le critère B, de 47 % (réussite complète : 38 %; réussite partielle : 9 %). Une hypotonie précoce a été observée dans 68 % des yeux, sans qu'elle soit associée à des résultats négatifs au chapitre de l'acuité visuelle ou des champs visuels. ConclusionsDans l'ensemble, 47 % des patients présentaient une PIO < 12 mm Hg et une baisse de > 20 % de la PIO (avec ou sans recours aux collyres) lors du suivi à 12 mois. On peut s'attendre à l'apparition d'une hypotonie précoce postopératoire transitoire après une révision de trabéculectomie ab interno.

Acceptance and Commitment Therapy for inpatients with psychosis –an acceptability and feasibility single case AB designed study

BackgroundThere is a lack of research on psychological treatments for psychosis in the inpatient setting. Acceptance and Commitment Therapy for psychosis (ACTp) is a diagnose specific adaptation of the transdiagnostic ACT treatment model which has shown promising results in patients with psychosis. AimThe aim was to explore treatment effects of ACTp on inpatients with psychosis on symptoms, level of functioning, level of activity, psychological flexibility, –health-related quality of life, valued living, and to explore the acceptability and feasibility of ACTp. MethodTwelve inpatients with psychosis were treated with 3–10 daily sessions of ACTp in a non-concurrent single case AB design with additional pre-post and mid-measures. The mean age at clinic A was 48.88 (SD = 11.59) and 48.75 (SD = 16.07) at clinic B. We calculated non - overlap of all pairs (NAP) in daily measures, and reliable change index (RCI), and clinical significance in pre-post measures. ResultsHalf of the participants improved significantly on health-related quality of life and depression in daily measures and on depression and anxiety in pre-post measures. ACTp was quite acceptable and recruitment and the deliverance of therapy in the inpatient setting was feasible. ConclusionIn the present study, participants found the ACTp treatment to be comprehensive and helpful. Recruitment and treatment of inpatients were feasible, however, since most participants were discharged before ACTp protocol was completed, fewer sessions or having sessions more frequently needs further investigation. Daily measurement showed a significant improvement in health-related quality of life and depression for a majority of the participants.

1254-P: Genetic Prediction of C-Peptide Trajectory before Type 1 Diabetes Diagnosis in TrialNet

Modeling the course of C-peptide decline in autoantibody (Ab) positive individuals is important for type 1 diabetes (T1D) prediction and implementation of T1D prevention trials. Single nucleotide polymorphisms in TCF7L2, JAZF1, SLC30A8, INS, PTPRK, G6CP2, CLEC16, PTPN22 and HLA genes are associated with persistent C-peptide at or after T1D diagnosis. We sought to determine whether 12 SNPs in these genes and the T1D genetic risk score-2 (GRS2) can predict C-peptide trajectory before diagnosis of T1D. We studied Ab positive at-risk participants in the TrialNet Pathway to Prevention Study who had ImmunoChip data (N=1217, age at initial screen (mean±SD) 16.1±12.7 years, 51.5% female, 81.0% non-Hispanic white) . Over a mean follow up of 3.4±2. years, 255 (21.0%) developed multiple Ab and 336 (27.6%) developed clinical T1D. We analyzed the influence of these 12 SNPs and the T1D GRS2 on C-peptide AUC during progression from single to multiple Abs, from single Ab to clinical T1D, and from multiple Abs to clinical T1D. Analyses were adjusted for baseline C-peptide AUC, age, glucose AUC, BMI Z-score and HbA1c; the presence of high-risk HLA haplotypes (DR3 and DR4-DQ8) ; and the first 3 principal components. The type 2 diabetes (T2D) -associated TCF7L2 rs7901695 and rs4506565 SNPs were significantly associated with higher C-peptide AUC during progression from multiple Abs to T1D (p&amp;lt;0.04) and neared significance for the single-to-multiple Ab transition (p=0.05) . Additionally, lower T1D GRS2 was significantly associated with higher C-peptide AUC during progression from multiple Abs to T1D (p=0.01) . We observed trend associations of lower C-peptide AUC with JAZF1 SNP rs864745 in both single Ab-to-T1D and multiple Ab-to-T1D progression (both p=0.06) , and with SNPs in SLC30A8 and INS in multiple Abs to T1D (p=0.and 0.08, respectively) . In conclusion, T2D-associated SNPs in the TCF7L2 gene and lower T1D GRS2 predict higher C-peptide particularly in progression from multiple Abs to clinical T1D. Disclosure T.M.Triolo: None. M.J.Redondo: Advisory Panel; Provention Bio, Inc. H.M.Parikh: None. M.Tosur: Advisory Panel; Provention Bio, Inc. P.Gottlieb: Advisory Panel; Janssen Research &amp; Development, LLC, ViaCyte, Inc., Other Relationship; IM Therapeutics, Research Support; Caladrius Biosciences, Inc., Immune Tolerance Network, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk, Precigen, Inc., Tolerion, Inc. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. S.Onengut-gumuscu: None. J.Krischer: None. S.S.Rich: None. A.Steck: None. Funding NIH K12 DK094712NIH RDK121843NIH RDK124395

Applicability of the Thawed Gaussian Wavepacket Dynamics to the Calculation of Vibronic Spectra of Molecules with Double-Well Potential Energy Surfaces.

Simulating vibrationally resolved electronic spectra of anharmonic systems, especially those involving double-well potential energy surfaces, often requires expensive quantum dynamics methods. Here, we explore the applicability and limitations of the recently proposed single-Hessian thawed Gaussian approximation for the simulation of spectra of systems with double-well potentials, including 1,2,4,5-tetrafluorobenzene, ammonia, phosphine, and arsine. This semiclassical wavepacket approach is shown to be more robust and to provide more accurate spectra than the conventional harmonic approximation. Specifically, we identify two cases in which the Gaussian wavepacket method is especially useful due to the breakdown of the harmonic approximation: (i) when the nuclear wavepacket is initially at the top of the potential barrier but delocalized over both wells, e.g., along a low-frequency mode, and (ii) when the wavepacket has enough energy to classically go over the low potential energy barrier connecting the two wells. The method is efficient and requires only a single classical ab initio molecular dynamics trajectory, in addition to the data required to compute the harmonic spectra. We also present an improved algorithm for computing the wavepacket autocorrelation function, which guarantees that the evaluated correlation function is continuous for arbitrary size of the time step.

Potential use of antibodies to provide an earlier indication of lymphatic filariasis resurgence in post–mass drug ad ministration surveillance in American Samoa

BackgroundUnder the Global Programme to Eliminate Lymphatic Filariasis (LF), American Samoa conducted 7 rounds of mass drug administration (MDA) between 2000 and 2006. The territory passed transmission assessment surveys (TASs) in 2011 (TAS-1) and 2015 (TAS-2). In 2016, the territory failed TAS-3, indicating resurgence. This study aims to determine if antibodies (Abs) may have provided a timelier indication of LF resurgence in American Samoa. MethodsWe examined school-level antigen (Ag) and Ab status (presence/absence of Ag- and Ab-positive children) and prevalence of single and combined Ab responses to Wb123, Bm14, and Bm33 Ags at each TAS. Pearson chi-square test and logistic regression were used to examine associations between school-level Ab prevalence in TAS-1 and TAS-2 and school-level Ag status in TAS-3. ResultsSchools with higher prevalence of Wb123 Ab in TAS-2 had higher odds of being Ag-positive in TAS-3 (odds ratio [OR] 24.5, 95% confidence interval [CI] 1.2–512.7). Schools that were Ab-positive for WB123 plus Bm14, Bm33, or both Bm14 and Bm33 in TAS-2 had higher odds of being Ag-positive in TAS-3 (OR 16.0–24.5). ConclusionAbs could provide earlier signals of resurgence and enable a timelier response. The promising role of Abs in surveillance after MDA and decision making should be further investigated in other settings.

Quantitative analysis of weak current rectification in molecular tunnel junctions subject to mechanical deformation reveals two different rectification mechanisms for oligophenylene thiols versus alkane thiols.

Metal-molecule-metal junctions based on alkane thiol (CnT) and oligophenylene thiol (OPTn) self-assembled monolayers (SAMs) and Au electrodes are expected to exhibit similar electrical asymmetry, as both junctions have one chemisorbed Au-S contact and one physisorbed, van der Waals contact. Asymmetry is quantified by the current rectification ratio RR apparent in the current-voltage (I-V) characteristics. Here we show that RR < 1 for CnT and RR > 1 for OPTn junctions, in contrast to expectation, and further, that RR behaves very differently for CnT and OPTn junctions under mechanical extension using the conducting probe atomic force microscopy (CP-AFM) testbed. The analysis presented in this paper, which leverages results from the previously validated single level model and ab initio quantum chemical calculations, allows us to explain the puzzling experimental findings for CnT and OPTn in terms of different current rectification mechanisms. Specifically, in CnT-based junctions the Stark effect creates the HOMO level shifting necessary for rectification, while for OPTn junctions the level shift arises from position-dependent coupling of the HOMO wavefunction with the junction electrostatic potential profile. On the basis of these mechanisms, our quantum chemical calculations allow quantitative description of the impact of mechanical deformation on the measured current rectification. Additionally, our analysis, matched to experiment, facilitates direct estimation of the impact of intramolecular electrostatic screening on the junction potential profile. Overall, our examination of current rectification in benchmark molecular tunnel junctions illuminates key physical mechanisms at play in single step tunneling through molecules, and demonstrates the quantitative agreement that can be obtained between experiment and theory in these systems.

Proinsulin:C-peptide ratio trajectories over time in relatives at increased risk of progression to type 1 diabetes

ObjectiveBiomarkers are needed to characterize heterogeneity within populations at risk for type 1 diabetes. The ratio of proinsulin to C-peptide (PI:C ratio), has been proposed as a biomarker of beta cell dysfunction and is associated with progression to type 1 diabetes. However, relationships between PI:C ratios and autoantibody type and number have not been examined. We sought to characterize PI:C ratios in multiple islet autoantibody positive, single autoantibody positive and autoantibody negative relatives of individuals with type 1 diabetes. MethodsWe measured PI:C ratios and autoantibodies with both electrochemiluminescence (ECL) assays (ECL-IAA, ECL-GADA and ECL-IA2A) and radiobinding (RBA) assays (mIAA, GADA, IA2A and ZnT8A) in 98 relatives of individuals with type 1 diabetes followed in the TrialNet Pathway to Prevention Study at the Barbara Davis Center for a mean of 7.4 ​± ​4.1 years. Of these subjects, eight progressed to T1D, 31 were multiple autoantibody (Ab) positive, 37 were single Ab positive and 22 were Ab negative (by RBA). ResultsIn cross-sectional analyses, there were no significant differences in PI:C ratios between type 1 diabetes and/or multiple Ab positive subjects (4.16 ​± ​4.06) compared to single Ab positive subjects (4.08 ​± ​4.34) and negative Ab subjects (3.72 ​± ​3.78) (p ​= ​0.92) overall or after adjusting for age, sex and BMI. Higher PI:C ratios were associated with mIAA titers (p ​= ​0.03) and showed an association with ECL-IA2A titers (p ​= ​0.09), but not with ECL-IAA, GADA, ECL-GADA, IA2A nor ZnT8A titers. In mixed-effects longitudinal models, the trajectories of PI:C ratio over time were significantly different between the Ab negative and multiple Ab positive/type 1 diabetes groups, after adjusting for sex, age, and BMI (p ​= ​0.04). ConclusionsPI:C ratio trajectories increase over time in subjects who have multiple Ab or develop type 1 diabetes and may be a helpful biomarker to further characterize and stratify risk of progression to type 1 diabetes over time.

Current status of cancer immunotherapy for gynecologic malignancies.

Recent cancer immunotherapy development with immune checkpoint inhibitors has shown durable clinical responses in a wide variety of tumor types. These drugs targeting programmed cell death 1, its ligand programmed death ligand 1 and cytotoxic T cell lymphocyte-associated antigen 4 have revolutionized the field of cancer treatment. It is of significant interest in optimizing the immunotherapy for cancer patients beyond the conventional treatments such as surgery, chemotherapy and radiation. Many clinical trials evaluating the safety and efficacy of various combined regimens with immune checkpoint inhibitors have been reported and are in progress. Among gynecologic malignancy, endometrial cancers have distinct subtypes with microsatellite instability-high status and polymerase ɛ mutation. These types have been shown to immunogenic tumors and appropriated candidate for immune checkpoint inhibitors. Also, recurrent cervical cancer showed a promising objective response with single anti-PD1 Ab treatment. Despite their definite outcome and considerable potential of immunotherapy, not all patients received a survival benefit and further understanding of human tumor immunology is essential to improve this type of therapy. In this review, we have summarized the updated results of clinical trials of cancer immunotherapy for gynecologic malignancies and discussed the future perspectives.