Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p \u3c 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy

Gravitational-Wave Stochastic Background Detection with Resonant-Mass Detectors

In this paper we discuss how the standard optimal Wiener filter theory can be applied, within a linear approximation, to the detection of an isotropic stochastic gravitational-wave background with two or more detectors. We apply then the method to the AURIGA-NAUTILUS pair of ultra low temperature bar detectors, near to operate in coincidence in Italy, obtaining an estimate for the sensitivity to the background spectral density of $\simeq 10^{-49}\ Hz^{-1}$, that converts to an energy density per unit logarithmic frequency of$\simeq 8\times10^{-5}\times\rho_c$with$\rho_c\simeq1.9 \times 10^{-26}\ kg/m^3$the closure density of the Universe. We also show that by adding the VIRGO interferometric detector under construction in Italy to the array, and by properly re- orienting the detectors, one can reach a sensitivity of$\simeq 6 \times10^{-5}\times\rho_c$. We then calculate that the pair formed by VIRGO and one large mass spherical detector properly located in one of the nearby available sites in Italy can reah a sensitivity of$\simeq 2\times10^{-5}\times \rho_c$while a pair of such spherical detectors at the same sites of AURIGA and NAUTILUS can achieve sensitivities of$\simeq 2 \times10^{-6}\rho_c$.Comment: 32 pages, postscript file, also available at http://axln01.lnl.infn.it/reports/stoch.htm

The Effect of iCook 4-H, a Childhood Obesity Prevention Program, on Blood Pressure and Quality of Life in Youth and Adults: A Randomized Control Trial

Objective: Obesity increases the risk of developing hypertension and from population-based samples with estimations that of 2-4% of the U.S. pediatric population has hypertension, which may affect quality of life. This study examined the effects of an obesity prevention program on blood pressure and quality of life in youth and adult participants. Methods: A multi-state research team recruited treatment dyads (youth and their adult meal preparer) to participate in a 12-week randomized control trial and follow-up through 24 months. The treatment group received a cooking and physical activity intervention, followed by booster sessions and mailed newsletters over the remaining two-year period. The control group received no intervention. Resting blood pressure and health related quality of life (HRQOL) surveys were administered at 0,4,12 and 24 months. Results: 228 dyads were recruited (n=77 control and n=151 for treatment). Youth and adult systolic blood pressure (SBP) increased over the 24 months (p=0.003 and p=0.03, respectively) with no differences between groups. From baseline to 24 months both control and treatment youths’ physical and psychological HRQOL increased (p=0.01 and p=0.002, respectively). At 0 and 4 months, youth and adult SBP was positively correlated (r=0.24, p=0.003 and r=0.33, p\u3c0.001, respectively). In the treatment group, there was an inverse association between adult SBP and youth psychological HRQOL at 4 months (r=-0.20, p=0.04), and a similar trend in adult SBP and youth physical HRQOL at 4 months in the treatment group (r=-0.19, p=0.05). Conclusion: A youth-adult dyad obesity prevention program consisting of culinary, mealtime and physical activity education, elicited improvements in HRQOL in youth participants

Incorporating predicted functions of nonsynonymous variants into gene-based analysis of exome sequencing data: a comparative study

Next-generation sequencing has opened up new avenues for the genetic study of complex traits. However, because of the small number of observations for any given rare allele and high sequencing error, it is a challenge to identify functional rare variants associated with the phenotype of interest. Recent research shows that grouping variants by gene and incorporating computationally predicted functions of variants may provide higher statistical power. On the other hand, many algorithms are available for predicting the damaging effects of nonsynonymous variants. Here, we use the simulated mini-exome data of Genetic Analysis Workshop 17 to study and compare the effects of incorporating the functional predictions of single-nucleotide polymorphisms using two popular algorithms, SIFT and PolyPhen-2, into a gene-based association test. We also propose a simple mixture model that can effectively combine test results based on different functional prediction algorithms

The tissue micro-array data exchange specification: a web based experience browsing imported data

BACKGROUND: The AIDS and Cancer Specimen Resource (ACSR) is an HIV/AIDS tissue bank consortium sponsored by the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis (DCTD). The ACSR offers to approved researchers HIV infected biologic samples and uninfected control tissues including tissue cores in micro-arrays (TMA) accompanied by de-identified clinical data. Researchers interested in the type and quality of TMA tissue cores and the associated clinical data need an efficient method for viewing available TMA materials. Because each of the tissue samples within a TMA has separate data including a core tissue digital image and clinical data, an organized, standard approach to producing, navigating and publishing such data is necessary. The Association for Pathology Informatics (API) extensible mark-up language (XML) TMA data exchange specification (TMA DES) proposed in April 2003 provides a common format for TMA data. Exporting TMA data into the proposed format offers an opportunity to implement the API TMA DES. Using our public BrowseTMA tool, we created a web site that organizes and cross references TMA lists, digital "virtual slide" images, TMA DES export data, linked legends and clinical details for researchers. Microsoft Excel(® )and Microsoft Word(® )are used to convert tabular clinical data and produce an XML file in the TMA DES format. The BrowseTMA tool contains Extensible Stylesheet Language Transformation (XSLT) scripts that convert XML data into Hyper-Text Mark-up Language (HTML) web pages with hyperlinks automatically added to allow rapid navigation. RESULTS: Block lists, virtual slide images, legends, clinical details and exports have been placed on the ACSR web site for 14 blocks with 1623 cores of 2.0, 1.0 and 0.6 mm sizes. Our virtual microscope can be used to view and annotate these TMA images. Researchers can readily navigate from TMA block lists to TMA legends and to clinical details for a selected tissue core. Exports for 11 blocks with 3812 cores from three other institutions were processed with the BrowseTMA tool. Fifty common data elements (CDE) from the TMA DES were used and 42 more created for site-specific data. Researchers can download TMA clinical data in the TMA DES format. CONCLUSION: Virtual TMAs with clinical data can be viewed on the Internet by interested researchers using the BrowseTMA tool. We have organized our approach to producing, sorting, navigating and publishing TMA information to facilitate such review. We have converted Excel TMA data into TMA DES XML, and imported it and TMA DES XML from another institution into BrowseTMA to produce web pages that allow us to browse through the merged data. We proposed enhancements to the TMA DES as a result of this experience. We implemented improvements to the API TMA DES as a result of using exported data from several institutions. A document type definition was written for the API TMA DES (that optionally includes proposed enhancements). Independent validators can be used to check exports against the DTD (with or without the proposed enhancements). Linking tissue core images to readily navigable clinical data greatly improves the value of the TMA

An unsymmetric 8-node hexahedral element with high distortion tolerance

Among all 3D 8-node hexahedral solid elements in current finite element library, the ‘best’ one can produce good results for bending problems using coarse regular meshes. However, once the mesh is distorted, the accuracy will drop dramatically. And how to solve this problem is still a challenge that remains outstanding. This paper develops an 8-node, 24-DOF (three conventional DOFs per node) hexahedral element based on the virtual work principle, in which two different sets of displacement fields are employed simultaneously to formulate an unsymmetric element stiffness matrix. The first set simply utilizes the formulations of the traditional 8-node trilinear isoparametric element, while the second set mainly employs the analytical trial functions in terms of 3D oblique coordinates (R, S, T). The resulting element, denoted by US-ATFH8, contains no adjustable factor and can be used for both isotropic and anisotropic cases. Numerical examples show it can strictly pass both the first-order (constant stress/strain) patch test and the second-order patch test for pure bending, remove the volume locking, and provide the invariance for coordinate rotation. Especially, it is insensitive to various severe mesh distortions

Fasting and postprandial plasma ghrelin levels are decreased in patients with liver failure previous to liver transplantation

[Abstract] Anorexia is a problem of paramount importance in patients with advanced liver failure. Ghrelin has important actions on feeding and weight homeostasis. Concentrations of ghrelin are controversial in liver cirrhosis. Our aim was to study fasting ghrelin and their response to an oral glucose tolerance test (OGTT) in liver failure patients and normal subjects. Methods We included 16 patients with severe liver failure prior to liver transplantation. As a control group we included 10 age- and BMI-matched healthy subjects. After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, and ghrelin were obtained at baseline and at times 30, 60, 90, and 120 min, respectively. Results Fasting ghrelin (median and range) were statistically significantly lower for patients compared to the controls, 527 (377–971) pg/ml vs. 643 (523–2163) pg/ml, P = 0.045, for patients and controls, respectively. The area under the curve for total ghrelin post-OGTT were lower in end-stage liver failure patients than in the control group, 58815 (44730–87420) pg/ml min vs. 76560 (56160–206385) pg/ml min, for patients and controls, respectively, P = 0.027. Conclusions Ghrelin levels are significantly decreased both fasting and post-OGTT in patients with liver failure candidates for transplantation. Decreased ghrelin levels could contribute to anorexia in patients with cirrhosis.Instituto de Salud Carlos III; PI051024Instituto de Salud Carlos III; PI070413Xunta de Galicia; PS07/12Xunta de Galicia; PGIDT05PXIC91605PNXunta de Galicia; INCITE08ENA916110E

Lineage-Specific Restraint of Pituitary Gonadotroph Cell Adenoma Growth

Although pituitary adenomas are usually benign, unique trophic mechanisms restraining cell proliferation are unclear. As GH-secreting adenomas are associated with p53/p21-dependent senescence, we tested mechanisms constraining non-functioning pituitary adenoma growth. Thirty six gonadotroph-derived non-functioning pituitary adenomas all exhibited DNA damage, but undetectable p21 expression. However, these adenomas all expressed p16, and >90% abundantly expressed cytoplasmic clusterin associated with induction of the Cdk inhibitor p15 in 70% of gonadotroph and in 26% of somatotroph lineage adenomas (p = 0.006). Murine LβT2 and αT3 gonadotroph pituitary cells, and αGSU.PTTG transgenic mice with targeted gonadotroph cell adenomas also abundantly expressed clusterin and exhibited features of oncogene-induced senescence as evidenced by C/EBPβ and C/EBPδ induction. In turn, C/EBPs activated the clusterin promoter ∼5 fold, and elevated clusterin subsequently elicited p15 and p16 expression, acting to arrest murine gonadotroph cell proliferation. In contrast, specific clusterin suppression by RNAis enhanced gonadotroph proliferation. FOXL2, a tissue-specific gonadotroph lineage factor, also induced the clusterin promoter ∼3 fold in αT3 pituitary cells. As nine of 12 pituitary carcinomas were devoid of clusterin expression, this protein may limit proliferation of benign adenomatous pituitary cells. These results point to lineage-specific pathways restricting uncontrolled murine and human pituitary gonadotroph adenoma cell growth

Fitness Consequences of Advanced Ancestral Age over Three Generations in Humans

A rapid rise in age at parenthood in contemporary societies has increased interest in reports of higher prevalence of de novo mutations and health problems in individuals with older fathers, but the fitness consequences of such age effects over several generations remain untested. Here, we use extensive pedigree data on seven pre-industrial Finnish populations to show how the ages of ancestors for up to three generations are associated with fitness traits. Individuals whose fathers, grandfathers and great-grandfathers fathered their lineage on average under age 30 were ~13% more likely to survive to adulthood than those whose ancestors fathered their lineage at over 40 years. In addition, females had a lower probability of marriage if their male ancestors were older. These findings are consistent with an increase of the number of accumulated de novo mutations with male age, suggesting that deleterious mutations acquired from recent ancestors may be a substantial burden to fitness in humans. However, possible non-mutational explanations for the observed associations are also discussed

Quantifying sources of variability in infancy research using the infant-directed-speech preference

Psychological scientists have become increasingly concerned with issues related to methodology and replicability, and infancy researchers in particular face specific challenges related to replicability: For example, high-powered studies are difficult to conduct, testing conditions vary across labs, and different labs have access to different infant populations. Addressing these concerns, we report on a large-scale, multisite study aimed at (a) assessing the overall replicability of a single theoretically important phenomenon and (b) examining methodological, cultural, and developmental moderators. We focus on infants’ preference for infant-directed speech (IDS) over adult-directed speech (ADS). Stimuli of mothers speaking to their infants and to an adult in North American English were created using seminaturalistic laboratory-based audio recordings. Infants’ relative preference for IDS and ADS was assessed across 67 laboratories in North America, Europe, Australia, and Asia using the three common methods for measuring infants’ discrimination (head-turn preference, central fixation, and eye tracking). The overall meta-analytic effect size (Cohen’s d) was 0.35, 95% confidence interval = [0.29, 0.42], which was reliably above zero but smaller than the meta-analytic mean computed from previous literature (0.67). The IDS preference was significantly stronger in older children, in those children for whom the stimuli matched their native language and dialect, and in data from labs using the head-turn preference procedure. Together, these findings replicate the IDS preference but suggest that its magnitude is modulated by development, native-language experience, and testing procedure. (This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 798658.