Immunity to the Melanoma Inhibitor of Apoptosis Protein (ML-IAP; livin) in Patients with Malignant Melanoma

Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families. Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma, contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein was utilized to screen cellular responses in stage I–IV patients and healthy controls by ELISPOT. A broad array of $CD4^+$ and $CD8^+$ cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLA-A*0201 epitopes were analyzed further for frequency of reactivity. The generation of specific $CD4^+$ and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis support the development of ML-IAP as a disease marker and therapeutic target

Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects

The objective of this meta-analysis is to evaluate the odds of colorectal adenoma (CRA) in colorectal cancer screening participants with different body mass index (BMI) levels, and examine if this association was different according to gender and ethnicity. The EMBASE and MEDLINE were searched to enroll high quality observational studies that examined the association between investigator-measured BMI and colonoscopy-diagnosed CRA. Data were independently extracted by two reviewers. A random-effects meta-analysis was conducted to estimate the summary odds ratio (SOR) for the association between BMI and CRA. The Cochran’s Q statistic and I2 analyses were used to assess the heterogeneity. A total of 17 studies (168,201 subjects) were included. When compared with subjects having BMI < 25, individuals with BMI 25–30 had significantly higher risk of CRA (SOR 1.44, 95% CI 1.30–1.61; I2 = 43.0%). Subjects with BMI ≥ 30 had similarly higher risk of CRA (SOR 1.42, 95% CI 1.24–1.63; I2 = 18.5%). The heterogeneity was mild to moderate among studies. The associations were significantly higher than estimates by previous meta-analyses. There was no publication bias detected (Egger’s regression test, p = 0.584). Subgroup analysis showed that the magnitude of association was significantly higher in female than male subjects (SOR 1.43, 95% CI 1.30–1.58 vs. SOR 1.16, 95% CI 1.07–1.24; different among different ethnic groups (SOR 1.72, 1.44 and 0.88 in White, Asians and Africans, respectively) being insignificant in Africans; and no difference exists among different study designs. In summary, the risk conferred by BMI for CRA was significantly higher than that reported previously. These findings bear implications in CRA risk estimation

Validation of an open source, remote web‐based eye‐tracking method (WebGazer) for research in early childhood

Measuring eye movements remotely via the participant's webcam promises to be an attractive methodological addition to in-person eye-tracking in the lab. However, there is a lack of systematic research comparing remote web-based eye-tracking with in-lab eye-tracking in young children. We report a multi-lab study that compared these two measures in an anticipatory looking task with toddlers using WebGazer.js and jsPsych. Results of our remotely tested sample of 18-27-month-old toddlers (N = 125) revealed that web-based eye-tracking successfully captured goal-based action predictions, although the proportion of the goal-directed anticipatory looking was lower compared to the in-lab sample (N = 70). As expected, attrition rate was substantially higher in the web-based (42%) than the in-lab sample (10%). Excluding trials based on visual inspection of the match of time-locked gaze coordinates and the participant's webcam video overlayed on the stimuli was an important preprocessing step to reduce noise in the data. We discuss the use of this remote web-based method in comparison with other current methodological innovations. Our study demonstrates that remote web-based eye-tracking can be a useful tool for testing toddlers, facilitating recruitment of larger and more diverse samples; a caveat to consider is the larger drop-out rate

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Evaluation of a novel magneto-optical method for the detection of malaria parasites

Improving the efficiency of malaria diagnosis is one of the main goals of current malaria research. We have recently developed a magneto-optical (MO) method which allows high-sensitivity detection of malaria pigment (hemozoin crystals) in blood via the magnetically induced rotational motion of the hemozoin crystals. Here, we evaluate this MO technique for the detection of Plasmodium falciparum in infected erythrocytes using in-vitro parasite cultures covering the entire intraerythrocytic life cycle. Our novel method detected parasite densities as low as approximately 40 parasites per microliter of blood (0.0008% parasitemia) at the ring stage and less than 10 parasites/microL (0.0002% parasitemia) in the case of the later stages. These limits of detection, corresponding to approximately 20 pg/microL of hemozoin produced by the parasites, exceed that of rapid diagnostic tests and compete with the threshold achievable by light microscopic observation of blood smears. The MO diagnosis requires no special training of the operator or specific reagents for parasite detection, except for an inexpensive lysis solution to release intracellular hemozoin. The devices can be designed to a portable format for clinical and in-field tests. Besides testing its diagnostic performance, we also applied the MO technique to investigate the change in hemozoin concentration during parasite maturation. Our preliminary data indicate that this method may offer an efficient tool to determine the amount of hemozoin produced by the different parasite stages in synchronized cultures. Hence, it could eventually be used for testing the susceptibility of parasites to antimalarial drugs

A Unified Approach to Demographic Data Collection for Research with Young Children Across Diverse Cultures

Culture is a key determinant of children’s development both in its own right and as a measure of generalizability of developmental phenomena. Studying the role of culture in development requires information about participants’ demographic backgrounds. However, both reporting and treatment of demographic data are limited and inconsistent in child development research. A barrier to reporting demographic data in a consistent fashion is that no standardized tool currently exists to collect these data. Variation in cultural expectations, family structures, and life circumstances across communities make the creation of a unifying instrument challenging. Here, we present a framework to standardize demographic reporting for early child development (birth to 3 years of age), focusing on six core sociodemographic construct categories: biological information, gestational status, health status, community of descent, caregiving environment, and socioeconomic status. For each category, we discuss potential constructs and measurement items and provide guidance for their use and adaptation to diverse contexts. These items are stored in an open repository of context-adapted questionnaires that provide a consistent approach to obtaining and reporting demographic information so that these data can be archived and shared in a more standardized format

Oceanic Residual Depth Measurements, the Plate Cooling Model and Global Dynamic Topography

Convective circulation of the mantle causes deflections of the Earth's surface that vary as a function of space and time. Accurate measurements of this dynamic topography are complicated by the need to isolate and remove other sources of elevation, arising from flexure and lithospheric isostasy. The complex architecture of continental lithosphere means that measurement of present-day dynamic topography is more straightforward in the oceanic realm. Here, we present an updated methodology for calculating oceanic residual bathymetry, which is a proxy for dynamic topography. Corrections are applied that account for the effects of sedimentary loading and compaction, for anomalous crustal thickness variations, for subsidence of oceanic lithosphere as a function of age, and for non-hydrostatic geoid height variations. Errors are formally propagated to estimate measurement uncertainties. We apply this methodology to a global database of 1,936 seismic surveys located on oceanic crust and generate 2,297 spot measurements of residual topography, including 1,161 with crustal corrections. The resultant anomalies have amplitudes of ±1 km and wavelengths of ∼1,000 km. Spectral analysis of our database using cross-validation demonstrates that spherical harmonics up to and including degree 30 (i.e. wavelengths down to 1,300 km) are required to accurately represent these observations. Truncation of the expansion at a lower maximum degree erroneously increases the amplitude of inferred long-wavelength dynamic topography. There is a strong correlation between our observations and free-air gravity anomalies, magmatism, ridge seismicity, vertical motions of adjacent rifted margins, and global tomographic models. We infer that shorter wavelength components of the observed pattern of dynamic topography may be attributable to the presence of thermal anomalies within the shallow asthenospheric mantle.This research is supported by a BP-Cambridge collaboration