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Single neutral pion production via muon antineutrino charged-current interactions in plastic scintillator (CH) is studied using the MINERvA detector exposed to the NuMI low-energy, wideband antineutrino beam at Fermilab. Measurement of this process constrains models of neutral pion production in nuclei, which is important because the neutral-current analog is a background for ν¯e appearance oscillation experiments. The differential cross sections for π0 momentum and production angle, for events with a single observed π0 and no charged pions, are presented and compared to model predictions. These results comprise the first measurement of the π0 kinematics for this process.

Summary: Enhanced stemness in colorectal cancer has been reported and it contributes to aggressive progression, but the underlying mechanisms remain unclear. Here we report a Wnt ligand, Dickkopf-2 (DKK2) is essential for developing colorectal cancer stemness. Genetic depletion of DKK2 in intestinal epithelial or stem cells reduced tumorigenesis and expression of the stem cell marker genes including LGR5 in a model of colitis-associated cancer. Sequential mutations in APC, KRAS, TP53, and SMAD4 genes in colonic organoids revealed a significant increase of DKK2 expression by APC knockout and further increased by additional KRAS and TP53 mutations. Moreover, DKK2 activates proto-oncogene tyrosine-protein kinse Src followed by increased LGR5 expressing cells in colorectal cancer through degradation of HNF4α1 protein. These findings suggest that DKK2 is required for colonic epithelial cells to enhance LGR5 expression during the progression of colorectal cancer.

A replication study of a previous genome-wide association study (GWAS) suggested that a SNP linked to the POLB gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased expression of Pol β, a key enzyme in the base excision repair (BER) pathway. To determine whether decreased Pol β activity results in SLE, we constructed a mouse model of POLB that encodes an enzyme with slow DNA polymerase activity. We show that mice expressing this hypomorphic POLB allele develop an autoimmune pathology that strongly resembles SLE. Of note, the mutant mice have shorter immunoglobulin heavy-chain junctions and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol β activity during the generation of immune diversity leads to lupus-like disease in mice, and suggest that decreased expression of Pol β in humans is an underlying cause of SLE.

Background: Human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-25% of breast cancers. Complete eradication of disease following neoadjuvant therapies and chemotherapy has been referred to as pathological complete response (pCR)., Aims: To determine clinicopathological predictors of pCR to neoadjuvant therapies and to evaluate pCR as a surrogate to enhanced survival., Methods: Consecutive female patients with HER2 positive (HER+) breast cancer managed surgically in a single institution between 2005 and 2015 were included. Descriptive statistics and binary logistic regression were used to determine predictors of pCR. Appraisal of pCR as a predictor of survival was performed using Kaplan-Meier curves and Cox regression analysis., Results: 451 patients were included with a mean age of 56.6 ± 13.4 years (range 23-95). Disease-free (DFS) and overall survival (OS) was 82.3% (371/451) and 82.6% (376/451) respectively with a median follow-up of 108.0 months (range 3-184.0). 118 were treated in the neoadjuvant setting (26.2%): tumour size <50 mm (Odds Ratio (OR): 12.156, P = 0.023) and progesterone receptor negativity (OR: 2.762, P = 0.008) independently predicted breast pCR, while ductal carcinoma (OR: 3.203, P = 0.030) and grade 3 disease (OR: 2.788, P = 0.018) predicted axillary pCR. Both breast and axillary pCR predicted enhanced DFS (Hazard Ratio (HR): 0.470 & HR: 0.449) and OS (HR: 0.383 & HR: 0.307). Axillary pCR independently predicted improved OS (HR: 0.326)., Conclusion: pCR is sensitive biomarker and surrogate to survival outcomes in HER2+ breast cancer. Patients likely to achieve pCR may be predicted from traditional clinicopathological characteristics and molecular parameters., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inelastic phenomena such as softening and unrecoverable inelastic strains induced by loading have been observed experimentally in soft tissues such as arteries. These phenomena need to be accounted for in constitutive models of arterial tissue so that computational models can accurately predict the outcomes of interventional procedures such as balloon angioplasty and stenting that involve non-physiological loading of the tissue. In this study, a novel constitutive model is described that accounts for inelastic effects such as Mullins-type softening and permanent set in a fibre reinforced tissue. The evolution of inelasticity is governed by a set of internal variables. Softening is introduced through a typical continuum damage mechanics approach, while the inelastic residual strains are introduced through an additive split in the stress tensor. Numerical simulations of aorta and carotid arterial tissue subjected to uniaxial testing in the longitudinal, circumferential and axial directions are used to demonstrate the model's ability to reproduce the anisotropic inelastic behaviour of the tissue. Material parameters derived from best-fits to experimental data are provided to describe these inelastic effects for both aortic and carotid tissue., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

It has been hypothesised that the stress distribution within the arterial wall may provide an indicator of atherosclerotic plaque rupture. This study presents an automated method for the generation of finite element models of the carotid bifurcation from in vivo computerised tomographic angiography. Models generated using this method have been used to investigate plaque vulnerability, assessing the influence of geometric factors and the stress distribution within the wall. Structured hexahedral meshes of the carotid bifurcation were created using a custom built automated system. Systolic pressure and appropriate boundary conditions were applied to each of the models. Six symptomatic patients were considered, generating models from each of their left and right carotid bifurcations (12 in total). Results from their symptomatic bifurcation were compared with their contralateral asymptomatic side. K(delta), a measure of the difference in curvature of the inner and outer plaque surfaces, was found to be significantly higher in symptomatic arteries than in asymptomatic arteries (p<0.05). The location of maximum K(delta) (the plaque shoulders) was also found to be a region of high von Mises stress yet no significant difference was found in maximum von Mises stress between the symptomatic and asymptomatic groups. Results suggest that K(delta) is an important factor in the development of a symptomatic plaque and with further investigation could be a useful indicator of plaque rupture., (2010 Elsevier Ltd. All rights reserved.)

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with poorly characterized genetics. We performed high resolution comparative genomic hybridization on 25 MCC specimens using a high-density oligonucleotide microarray. Tumors frequently carried extra copies of chromosomes 1, 3q, 5p, and 6 and lost chromosomes 3p, 4, 5q, 7, 10, and 13. MCC tumors with less genomic aberration were associated with improved survival (P=0.04). Tumors from 13 of 22 MCC patients had detectable Merkel cell polyomavirus DNA, and these tumors had fewer genomic deletions. Three regions of genomic alteration were of particular interest: a deletion of 5q12-21 occurred in 26% of tumors, a deletion of 13q14-21 was recurrent in 26% of tumors and contains the well-characterized tumor suppressor RB1, and a previously unreported focal amplification at 1p34 was present in 39% of tumors and centers on L-Myc (MYCL1). L-Myc is related to the c-Myc proto-oncogene, has transforming activity, and is amplified in the closely related small cell lung cancer. Normal skin showed no L-Myc expression, whereas 4/4 MCC specimens tested expressed L-Myc RNA in relative proportion to the DNA copy number gain. These findings suggest several genes that may contribute to MCC pathogenesis, most notably L-Myc.

The need to apply modern technologies to analyze DNA from diverse clinical samples often stumbles on suboptimal sample quality. We developed a simple approach to assess DNA fragmentation in minute clinical samples of widely different origin and the likelihood of success of degradation-tolerant whole genome amplification (restriction and circularization-aided rolling circle amplification, RCA-RCA) and subsequent polymerase chain reaction (PCR). A multiplex PCR amplification of four glyceraldehyde-3-phosphate dehydrogenase amplicons of varying sizes was performed using genomic DNA from clinical samples, followed by size discrimination on agarose gel or fluorescent denaturing high-performance liquid chromatography (dHPLC). RCA-RCA followed by real-time PCR was also performed, for correlation. Even minimal quantities of longer PCR fragments ( approximately 300 to 400 bp), visible via high-sensitivity fluorescent dHPLC or agarose gel, were essential for the success of RCA-RCA and subsequent PCR-based assays. dHPLC gave a more accurate correlation between DNA fragmentation and sample quality than agarose gel electrophoresis. Multiplex-PCR-dHPLC predicted correctly the likelihood of assay success in formalin-fixed, paraffin-embedded samples fixed under controlled conditions and of different ages, in laser capture microdissection samples, in tissue print micropeels, and plasma-circulating DNA. Estimates of the percent information retained relative to snap-frozen DNA are derived for real-time PCR analysis. The assay is rapid and convenient and can be used widely to characterize DNA from any clinical sample of unknown quality.

Carriers of balanced translocations usually carry alterations in gene sequences, which lead to dysfunction during early and late embryogenesis. Related spatial rearrangement causes either cumulative delay in cell cycles and/or anomalies in transcription and translation. This has also an important impact at the time of genomic activation, the longest cell cycle of preimplantation development. Carrier patients may be affected either with primary infertility or by repeated miscarriages [Hum. Reprod. 12 (1997) 2019.]. Assuming that a fraction of the germ cells is karyotypically normal, these patients would greatly benefit from efficient procedures for generation and use of breakpoint-specific DNA hybridisation probes in preconception and preimplantation genetic diagnosis (PGD) after polar body or blastomere biopsy of the embryos. The objective of this research was to design an approach of patient-specific probes for preimplantation diagnosis of chromosome translocations and which could be used eventually to select chromosomally normal embryos from balanced or unbalanced interphase cells prior to their transfer to the mother's womb. This approach was used for a couple, where the female partner was a carrier of a balanced translocation 46,XX,t(4;12)(p16.1;q24.31). First, BAC/PAC clones were chosen from specific chromosome bands from the genome sequence that hybridise adjacent to the chromosomal breakpoints or span them. Then, the probes and hybridisation conditions were optimised using unrelated normal amniocytes, lymphoblastoid cells and lymphocytes from the carrier to increase hybridisation signal intensity and decrease background. Finally, the probes were tested on target cells before they were used for mimicking preconception or preimplantation genetic diagnosis. Three slides were analysed blindly from a normal karyotype, an unbalanced and a balanced translocation. A total of 78 cells were analysed of which in the slide A 19/22 (86%) were found to be unbalanced, in slide B 25/31 (81%) were normal and in slide C 21/25 (84%) were balanced. Thus, it was demonstrated that cells with known structural abnormalities could be detected, based on hybridisation of breakpoint spanning bacterial artificial chromosome (BAC) DNA probes in interphase cells.

A fleshy, polypoidal and partially lobulated lesion that protruded between the eyelids from the medial caruncular region and that infiltrated the contiguous anterior orbital tissues developed over 1 month in a 9-month-old infant. The microscopic features of the tumor included a plump spindle cell population, more polygonal cells, early xanthoma cell transformation, infiltrating lymphocytes and eosinophils, and multinucleated giant cells, the last not exhibiting classic Touton characteristics. The histopathologic differential diagnosis ranged among fibrous histiocytoma, juvenile xanthogranuloma, and eosinophilic granuloma (histiocytosis-X). Results of electron microscopy disclosed abundant rough-surfaced endoplasmic reticulum, a paucity of lysosomes, and no Langerhans' (Birbeck) granules. Immunohistochemistry corroborated the fibrohistiocytic nature of the tumor, because histochemical stains for the enzymes alpha-1-antichymotrypsin and lysozyme, and monoclonal or polyclonal antibodies against common leukocytic antigen and S-100 protein, were negative--whereas they would have been expected to be positive in various combinations in the different histiocytic proliferations. Vimentin was identified in the tumor cells; this is an intermediate cytoplasmic filament almost always present in mesenchymal proliferations. The distinctions between fibrous histiocytomas of stromal cell origin and true histiocytic proliferations of bone marrow cell provenance are explored.

The level of immunoreactive ANP (iANP) as determined by radioimmunoassay, exhibits a fairly even distribution throughout the canine atria. However, the maximal concentration was found in the appendages of both the left and right atrium, and the level was significantly higher on the left side in all analyzed localizations. Reverse-phase HPLC of atrial extracts, coupled with RIA, revealed the presence of three iANP fractions. The dominant fraction (65% of iANP) has an estimated molecular weight 16,300, showing that it corresponds to the hormone precursor. By contrast, in the plasma extract, 92% of iANP coelutes with synthetic human ANP99-126, thus confirming the structural identity of dog and human ANP.