Scientific Excellence in the Forensic Science Community

This Article was prepared as a companion to the Fordham Law Review Reed Symposium on Forensic Expert Testimony, Daubert, and Rule 702, held on October 27, 2017, at Boston College School of Law. The Symposium took place under the sponsorship of the Judicial Conference Advisory Committee on Evidence Rules. For an overview of the Symposium, see Daniel J. Capra, Foreword: Symposium on Forensic Testimony, Daubert, and Rule 702, 86 Fordham L. Rev. 1459 (2018)

Time for change: a new training programme for morpho-molecular pathologists?

The evolution of cellular pathology as a specialty has always been driven by technological developments and the clinical relevance of incorporating novel investigations into diagnostic practice. In recent years, the molecular characterisation of cancer has become of crucial relevance in patient treatment both for predictive testing and subclassification of certain tumours. Much of this has become possible due to the availability of next-generation sequencing technologies and the whole-genome sequencing of tumours is now being rolled out into clinical practice in England via the 100 000 Genome Project. The effective integration of cellular pathology reporting and genomic characterisation is crucial to ensure the morphological and genomic data are interpreted in the relevant context, though despite this, in many UK centres molecular testing is entirely detached from cellular pathology departments. The CM-Path initiative recognises there is a genomics knowledge and skills gap within cellular pathology that needs to be bridged through an upskilling of the current workforce and a redesign of pathology training. Bridging this gap will allow the development of an integrated 'morphomolecular pathology' specialty, which can maintain the relevance of cellular pathology at the centre of cancer patient management and allow the pathology community to continue to be a major influence in cancer discovery as well as playing a driving role in the delivery of precision medicine approaches. Here, several alternative models of pathology training, designed to address this challenge, are presented and appraised

Feasibility of neutron radiographing reactor fuel assemblies

Verification of fast reactor safety requires experiments wherein fuel bundles, enclosed in massive steel capsules, are subjected to simulated accident conditions in reactors such as TREAT(16) at ANL Idaho. To date, only small bundles (one to seven pins) have been tested in the experimental series. Determination of the fuel configuration within the capsule has depended on the neutron hodoscope during the reactor power burst and on thermal neutron radiographic techniques for more precise determination before and after the test. The purpose of this study is to determine whether there are neutron radiographic techniques that could provide the nondestructive evaluation capability needed for extension of the experimental series to much larger fuel bundles (e.g., 37 pins to 217 pins) as is projected for the NRC-ERDA fast reactor safety studies program SAREF.(17) There are two parts to the total problem: (1) can an adequate signal to noise ratio be obtained and (2) can the information from such complex geometries be adequately decoded by means, for example, of two or three dimensional image reconstruction techniques. This thesis addresses the first question only. It is shown that neutrons of epi-thermal energy could provide useful penetration and contrast sensitivity. Experiments performed, using pin bundles of simulated fuel designed to give the same neutron attenuation characteristics as fuel of the "Fast Flux Test Facility" (FFTF), confirm that the epi-thermal flux intensity available from a typical TRIGA research reactor is sufficient and that sensitivity can be obtained to at least a single pellet sized axial gap in the center of a 217 pin FFTF fuel assembly. The study includes evaluations of (1) neutron source characteristics, (2) neutron imaging methods, (3) fuel bundle simulation, (4) neutron beam generated fission background and (5) the dependence of radiographic sensitivity on angle of orientation for symmetrical bundles

Dopamine D2 receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse

Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D2-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D2-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D2-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D2-receptors to G-proteins was also significantly reduced in knockout mice, supporting the compromised agonist binding. Furthermore, pre-synaptic dopamine release in knockout striatal sections was less responsive than control sections to dopamine D2-receptor ligands. Behaviorally, the locomotor activity of knockout mice was less responsive to the inhibitory effect of quinpirole than wild-type mice. Involvement of specific methionine residue oxidation in the dopamine D2-receptor third intracellular loop is suggested by in vitro studies. We conclude that ablation of methionine sulfoxide reductase can affect dopamine signaling through altering dopamine D2-receptor physiology and may be related to symptoms associated with neurological disorders and diseases

MAPO-18 Catalysts for the Methanol to Olefins Process: Influence of Catalyst Acidity in a High-Pressure Syngas (CO and H2) Environment

The transition from integrated petrochemical complexes toward decentralized chemical plants utilizing distributed feedstocks calls for simpler downstream unit operations. Less separation steps are attractive for future scenarios and provide an opportunity to design the next-generation catalysts, which function efficiently with effluent reactant mixtures. The methanol to olefins (MTO) reaction constitutes the second step in the conversion of CO2, CO, and H2 to light olefins. We present a series of isomorphically substituted zeotype catalysts with the AEI topology (MAPO-18s, M = Si, Mg, Co, or Zn) and demonstrate the superior performance of the M(II)-substituted MAPO-18s in the conversion of MTO when tested at 350 °C and 20 bar with reactive feed mixtures consisting of CH3OH/CO/CO2/H2. Co-feeding high pressure H2 with methanol improved the catalyst activity over time, but simultaneously led to the hydrogenation of olefins (olefin/paraffin ratio < 0.5). Co-feeding H2/CO/CO2/N2 mixtures with methanol revealed an important, hitherto undisclosed effect of CO in hindering the hydrogenation of olefins over the Brønsted acid sites (BAS). This effect was confirmed by dedicated ethene hydrogenation studies in the absence and presence of CO co-feed. Assisted by spectroscopic investigations, we ascribe the favorable performance of M(II)APO-18 under co-feed conditions to the importance of the M(II) heteroatom in altering the polarity of the M–O bond, leading to stronger BAS. Comparing SAPO-18 and MgAPO-18 with BAS concentrations ranging between 0.2 and 0.4 mmol/gcat, the strength of the acidic site and not the density was found to be the main activity descriptor. MgAPO-18 yielded the highest activity and stability upon syngas co-feeding with methanol, demonstrating its potential to be a next-generation MTO catalyst

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease

A primary health-care intervention on pre- and postnatal risk factor behavior to prevent childhood allergy. The Prevention of Allergy among Children in Trondheim (PACT) study

Background: This study aimed to evaluate the impact of a primary prevention intervention program on risk behavior for allergic diseases among children up to 2 years of age. The setting was in ordinary pre- and postnatal primary health care in Trondheim, Norway. Methods: The Prevention of Allergy among Children in Trondheim, Norway (PACT) study invited all pregnant women and parents to children up to 2 years of age in the community to participate in a non-randomized, controlled, multiple life-style intervention study. Interventional topics was increased dietary intake of cod liver oil and oily fish for women during pregnancy and for infants during the first 2 years of life, reduced parental smoking and reduced indoor dampness. A control cohort was established prior to the intervention cohort with “follow up as usual”. Questionnaires were completed in pregnancy, 6 weeks after birth and at 1 and 2 years of age. Trends in exposure and behavior are described. Results: Intake of oily fish and cod liver oil increased statistically significantly among women and infants in the intervention cohort compared to the control cohort. There was a low postnatal smoking prevalence in both cohorts, with a trend towards a decreasing smoking prevalence in the control cohort. There was no change in indoor dampness or in behavior related to non- intervened life-style factors. Conclusions: The dietary intervention seemed to be successful. The observed reduced smoking behavior could not be attributed to the intervention program, and the latter had no effect on indoor dampness

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach