Opportunities in cancer imaging: a review of oesophageal, gastric and colorectal malignancies.

The incidence of gastrointestinal (GI) malignancy is increasing worldwide. In particular, there is a concerning rise in incidence of GI cancer in younger adults. Direct endoscopic visualisation of luminal tumour sites requires invasive procedures, which are associated with certain risks, but remain necessary because of limitations in current imaging techniques and the continuing need to obtain tissue for diagnosis and genetic analysis; however, management of GI cancer is increasingly reliant on non-invasive, radiological imaging to diagnose, stage, and treat these malignancies. Oesophageal, gastric, and colorectal malignancies require specialist investigation and treatment due to the complex nature of the anatomy, biology, and subsequent treatment strategies. As cancer imaging techniques develop, many opportunities to improve tumour detection, diagnostic accuracy and treatment monitoring present themselves. This review article aims to report current imaging practice, advances in various radiological modalities in relation to GI luminal tumour sites and describes opportunities for GI radiologists to improve patient outcomes.

A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.

Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.

Skin metastasis, an uncommon course of prostate carcinoma: a report of two cases.

Prostate cancer is one of the most common cancers among men worldwide and in the USA. Most prostate cancer progression either locally invades to seminal vesicles or metastasizes distally to bone. Skin is not a common site of metastasis for the majority of malignancies including prostate cancer. This paper reports two extremely rare cases of prostate carcinoma metastatic to the skin: a 74-year-old man previously treated with radiation for prostate cancer with cutaneous metastases to the shoulder and a 68-year-old man with prostate adenocarcinoma and cutaneous metastases to the groin. Both patients were diagnosed with skin punch biopsy and later confirmed with immunohistochemical staining for PSA and prostate specific acid phosphatase, specific for prostatic carcinoma. Although unusual, development of multiple skin lesions in patients with prostate adenocarcinoma should raise the flags of cutaneous metastases.

Transgenic mice containing a human heavy chain immunoglobulin gene fragment cloned in a yeast artificial chromosome.

We have developed a method for the introduction of yeast artificial chromosomes (YACs) into transgenic mice. An 85 kilobase (kb) fragment of the human heavy chain immunoglobulin gene was cloned as a YAC, and embryonic stem cell lines carrying intact, integrated YACs were derived by co-lipofection of the YAC with an unlinked selectable marker. Chimaeric founder animals were produced by blastocyst injection, and offspring transgenic for the YAC were obtained. Analysis of serum from these offspring for human heavy chain antibody subunits demonstrated expression of the YAC-borne immunoglobulin gene fragment. Co-lipofection may prove to be a highly-successful means of producing transgenic mice containing large gene fragments in YACs.

Mecp2 truncation in male mice promotes affiliative social behavior.

Mouse models of Rett syndrome, with targeted mutations in the Mecp2 gene, show a high degree of phenotypic consistency with the clinical syndrome. In addition to severe and age-specific regression in motor and cognitive abilities, a variety of studies have demonstrated that Mecp2 mutant mice display impaired social behavior. Conversely, other studies indicate complex enhancements of social behavior in Mecp2 mutant mice. Since social behavior is a complicated accumulation of constructs, we performed a series of classic and refined social behavior tasks and revealed a relatively consistent pattern of enhanced pro-social behavior in hypomorphic Mecp2 (308/Y) mutant mice. Analyses of repetitive motor acts, and cognitive stereotypy did not reveal any profound differences due to genotype. Taken together, these results suggest that the mutations associated with Rett syndrome are not necessarily associated with autism-relevant social impairment in mice. However, this gene may be a valuable candidate for revealing basic mechanisms of affiliative behavior.

Decreasing surface albedo signifies a growing importance of clouds for Greenland Ice Sheet meltwater production.

Clouds regulate the Greenland Ice Sheet's surface energy balance through the competing effects of shortwave radiation shading and longwave radiation trapping. However, the relative importance of these effects within Greenland's narrow ablation zone, where nearly all meltwater runoff is produced, remains poorly quantified. Here we use machine learning to merge MODIS, CloudSat, and CALIPSO satellite observations to produce a high-resolution cloud radiative effect product. For the period 2003-2020, we find that a 1% change in cloudiness has little effect (±0.16 W m-2) on summer net radiative fluxes in the ablation zone because the warming and cooling effects of clouds compensate. However, by 2100 (SSP5-8.5 scenario), radiative fluxes in the ablation zone will become more than twice as sensitive (±0.39 W m-2) to changes in cloudiness due to reduced surface albedo. Accurate representation of clouds will therefore become increasingly important for forecasting the Greenland Ice Sheet's contribution to global sea-level rise.

Predicting the timing of wrong decisions with LATER.

Response time, or latency, is increasingly being used to provide information about neural decision processes. LATER (Linear Approach to Threshold with Ergodic Rate) is a quasi-Bayesian model of decision-making, with the additional feature that it introduces a degree of gratuitous randomisation into the decision process. It has had some success in predicting latencies under various conditions, but has not specifically been applied to an equally important aspect of decision-making, namely errors: a complete model of decision-making should not only account for latency distributions of correct decisions but also of wrong ones. We therefore used a decision task that generates large numbers of errors: subjects are told to look at suddenly appearing targets of one colour, but not another. We found that subjects' faster responses are as likely to be correct as wrong, but eventually the latency distributions diverge, with errors becoming infrequent. It seems that colour information, arriving after a delay, results both in cancellation of the developing response to the mere existence of the target and in delayed initiation of the correct response. A simple model, using LATER units in a similar way to one that has previously successfully modelled countermanding, accurately predicts latency distributions and proportions of all responses, whether correct or incorrect, demonstrating that the LATER model can indeed account for errors as well as correct responses.

Repetitive transcranial magnetic stimulation for the treatment of postpartum depression.

BACKGROUND: Postpartum depression (PPD) is a common and gravely disabling health concern. Repetitive transcranial magnetic stimulation (rTMS) is an FDA approved treatment for major depression and may be a valuable tool in the treatment of PPD. The treatment effect of rTMS is rapid, generally well tolerated, without systemic effects, and without medication exposure to a fetus and/or breastfed infant. METHODS: Six women with PPD received 20 sessions of 10 Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) over a 4 week period. Psychiatric rating scales (BDI, EPDS, STATI), cognitive assessments (MMSE, Trails B, List Generation) and breastfeeding practices were surveyed at baseline and post rTMS treatment. BDI and EPDS were obtained weekly, as well as 3 months and 6 months post study conclusion. RESULTS: Average BDI, EPDS, and STAI scores declined over the 4-week duration of rTMS treatment. Of the six patients, four achieved remission as assessed by EPDS and one achieved remission and two responded as assessed by BDI. Mean BDI and EPDS scores at 3 and 6 months follow-up remained below levels at study entry. No evidence of cognitive changes or breastfeeding disruptions. LIMITATIONS: This was an exploratory study with small sample size with no sham control arm. Daily administration of rTMS provides potential for confounding of behavioral activation in the otherwise often isolative postpartum period. CONCLUSIONS: rTMS was safe and well tolerated among participants with evidence of sustained improvements in depression and anxiety scores. This study supports rTMS as a promising non-pharmacologic treatment modality for perinatal depression.

Cloning and characterization of a potassium-dependent sodium/calcium exchanger in Drosophila.

Sodium/calcium(-potassium) exchangers (NCX and NCKX) are critical for the rapid extrusion of calcium, which follows the stimulation of a variety of excitable cells. To further understand the mechanisms of calcium regulation in signaling, we have cloned a Drosophila sodium/calcium-potassium exchanger, Nckx30C. The overall deduced protein topology for NCKX30C is similar to that of mammalian NCKX, having five membrane-spanning domains in the NH(2) terminus separated from six at the COOH-terminal end by a large intracellular loop. We show that NCKX30C functions as a potassium-dependent sodium/calcium exchanger, and is not only expressed in adult neurons as was expected, but is also expressed during ventral nerve cord development in the embryo and in larval imaginal discs. Nckx30C is expressed in a dorsal-ventral pattern in the eye-antennal disc in a pattern that is similar to, but broader than that of wingless, suggesting that large fluxes of calcium may be occurring during imaginal disc development. Nckx30C may not only function in the removal of calcium and maintenance of calcium homeostasis during signaling in the adult, but may also play a critical role in signaling during development.

Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania.

The glutamate receptor 6 (GluR6 or GRIK2, one of the kainate receptors) gene resides in a genetic linkage region (6q21) associated with bipolar disorder (BPD), but its function in affective regulation is unknown. Compared with wild-type (WT) and GluR5 knockout (KO) mice, GluR6 KO mice were more active in multiple tests and super responsive to amphetamine. In a battery of specific tests, GluR6 KO mice also exhibited less anxious or more risk-taking type behavior and less despair-type manifestations, and they also had more aggressive displays. Chronic treatment with lithium, a classic antimanic mood stabilizer, reduced hyperactivity, aggressive displays and some risk-taking type behavior in GluR6 KO mice. Hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. The membrane levels of other glutamatergic receptors were not significantly altered by GluR6 ablation or chronic lithium treatment. Together, these biochemical and behavioral results suggest a unique role for GluR6 in controlling abnormalities related to the behavioral symptoms of mania, such as hyperactivity or psychomotor agitation, aggressiveness, driven or increased goal-directed pursuits, risk taking and supersensitivity to psychostimulants. Whether GluR6 perturbation is involved in the mood elevation or thought disturbance of mania and the cyclicity of BPD are unknown. The molecular mechanism underlying the behavioral effects of lithium in GluR6 KO mice remains to be elucidated.

Recruitment of a hedgehog regulatory circuit in butterfly eyespot evolution.

The origin of new morphological characters is a long-standing problem in evolutionary biology. Novelties arise through changes in development, but the nature of these changes is largely unknown. In butterflies, eyespots have evolved as new pattern elements that develop from special organizers called foci. Formation of these foci is associated with novel expression patterns of the Hedgehog signaling protein, its receptor Patched, the transcription factor Cubitus interruptus, and the engrailed target gene that break the conserved compartmental restrictions on this regulatory circuit in insect wings. Redeployment of preexisting regulatory circuits may be a general mechanism underlying the evolution of novelties.

The characteristics of four ratcheting states in cellular flames.

A premixed flat flame on a circular porous plug burner can form patterns of one or two concentric rings of cells in which brighter, hotter regions are separated by darker, cooler cusps and folds. Dynamic states are found at parameter values that are interleaved between those of the ordered states. Rotating states, modulated rotating states, hopping states, and intermittently ordered states have all been observed with motions of approximately 100 degrees/s. These states have been described using the ideas of dynamical systems. Their characteristics have been analyzed using modal decomposition techniques. Ratcheting states are qualitatively and quantitatively different from these other dynamic states. In ratcheting states one or both of the concentric rings rotate very slowly, approximately 0.8 degrees/s, each speeding up and slowing down in a manner unique to that state. Measurements of the angular displacement and computed values of the angular velocity are presented for four ratcheting states. The experimental results are discussed in the context of the physical characteristics of the flame front and in terms of bifurcations of systems with symmetry. Many of the principal features of ratcheting motion are not yet understood.

Lumbar-pelvic range and coordination during lifting tasks.

Spine motion has been described to have two regions, a neutral zone where lumbar rotation can occur with little resistance and an elastic zone where structures such as ligaments, facet joints and intervertebral disks resist rotation. In vivo, the passive musculature can contribute to further limiting the functional neutral range of lumbar motion. Movement out of this functional neutral range could potentially put greater loads on these structures. In this study, the range of lumbar curvature rotation was examined in twelve healthy, untrained volunteers at four torso inclination angles. The lumbar curvature during straight-leg lifting tasks was then defined as a percentage of this range of possible lumbar curvatures. Subjects were found to remain neutrally oriented during the flexion phase of a lifting task. During the extension phase of the lifting task, however, subjects were found to assume a more kyphotic posture, approaching the edge of the functional range of motion. This was found to be most pronounced for heavy lifting tasks. By allowing the lumbar curvature to go into a highly kyphotic posture, subjects may be taking advantage of stretch-shortening behavior in extensor musculature and associated tendons to reduce the energy required to raise the torso. Such a kyphotic posture during extension, however, may put excessive loading on the elastic structures of the spine and torso musculature increasing the risk of injury.

Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells.

We have investigated the DNA polymerase alpha promoter sequence requirements for the expression of a heterologous gene in actively cycling cells and following serum addition to serum-deprived cells. An 11.4-kb genomic clone that spans the 5' end of this gene and includes 1.62 kb of sequence upstream from the translation start site was isolated. The transcription start site was mapped at 46 +/- 1 nucleotides upstream from the translation start site. The upstream sequence is GC rich and lacks a TATA sequence but has a CCAAT sequence on the opposite strand. Analysis of a set of deletion constructs in transient transfection assays demonstrated that efficient expression of the reporter in cycling cells requires 248 bp of sequence upstream from the cap site. Clustered within these 248 nucleotides are sequences similar to consensus sequences for Sp1-, Ap1-, Ap2-, and E2F-binding sites. The CCAAT sequence and the potential E2F- and Ap1-binding sites are shown to be protected from DNase I digestion by partially purified nuclear proteins. The DNA polymerase alpha promoter can confer upon the reporter an appropriate, late response to serum addition. No single sequence element could be shown to confer serum inducibility. Rather, multiple sequence elements appear to mediate the full serum response.

Saccadometry: the possible application of latency distribution measurement for monitoring concussion.

Premature return to play after concussion may have debilitating or even fatal consequences. Computerised neuropsychological test batteries are widely used to monitor recovery, but none meet all specified criteria. One possible alternative is to measure saccadic reaction time or latency. Latency reflects the operation of cerebral decision mechanisms, and is strongly influenced by many agents that impair cortical function. A portable, micro-miniature device (saccadometer) was used to record the eye movements of amateur boxers before and after competitive bouts. Individual latency distributions were significantly affected after blows to the head, though the effects seemed to be reversible, with recovery over a few days. This quantitative, objective and easy to use technique should perhaps be deployed more widely to evaluate its potential in monitoring the effects of sports-related head injuries.

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

Advanced magnetic resonance imaging and neuropsychological assessment for detecting brain injury in a prospective cohort of university amateur boxers.

BACKGROUND/AIM: The safety of amateur and professional boxing is a contentious issue. We hypothesised that advanced magnetic resonance imaging and neuropsychological testing could provide evidence of acute and early brain injury in amateur boxers. METHODS: We recruited 30 participants from a university amateur boxing club in a prospective cohort study. Magnetic resonance imaging (MRI) and neuropsychological testing was performed at three time points: prior to starting training; within 48 h following a first major competition to detect acute brain injury; and one year follow-up. A single MRI acquisition was made from control participants. Imaging analysis included cortical thickness measurements with Advanced Normalization Tools (ANTS) and FreeSurfer, voxel based morphometry (VBM), and Tract Based Spatial Statistics (TBSS). A computerized battery of neuropsychological tests was performed assessing attention, learning, memory and impulsivity. RESULTS: During the study period, one boxer developed seizures controlled with medication while another developed a chronic subdural hematoma requiring neurosurgical drainage. A total of 10 boxers contributed data at to the longitudinal assessment protocol. Reasons for withdrawal were: logistics (10), stopping boxing (7), withdrawal of consent (2), and development of a chronic subdural hematoma (1). No significant changes were detected using VBM, TBSS, cortical thickness measured with FreeSurfer or ANTS, either cross-sectionally at baseline, or longitudinally. Neuropsychological assessment of boxers found attention/concentration improved over time while planning and problem solving ability latency decreased after a bout but recovered after one year. CONCLUSION: While this neuroimaging and neuropsychological assessment protocol could not detect any evidence of brain injury, one boxer developed seizures and another developed a chronic sub-dural haematoma.

Three secretory phospholipase A(2) genes that map to human chromosome 1P35-36 are not mutated in individuals with attenuated adenomatous polyposis coli.

Mutation of Pla2g2a, a secretory phospholipase A(2) gene, dramatically increases the number of intestinal polyps that develop in the multiple intestinal neoplasia (Min) mouse, a murine model for adenomatous polyposis coli in humans. We tested the hypothesis that mutation of the human homologue(s) of this gene might be responsible for the more severe phenotype (hundreds of polyps) seen in a subset of individuals with attenuated adenomatous polyposis coli (AAPC). DNA sequence analysis demonstrated that alterations of PLA2G2A, as well as related genes PLA2G2C and PLA2G5, were evenly distributed between three classes of AAPC subjects: those with small, intermediate, and large numbers of adenomatous colonic polyps. Among 67 additional unrelated AAPC subjects, a stop mutation in PLA2G2C did not correlate with an increased burden of adenomatous polyps. Therefore, mutation of the human homologue(s) of murine Pla2g2a does not appear to be responsible for phenotypic variation among subjects with AAPC.

A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract.

One hundred eight patients with recurrent or metastatic transitional cell carcinoma of the urothelial tract were randomized to receive cisplatin (C) 80 mg/m2 on day 1 every 4 weeks, or methotrexate (M) 50 mg/m2 on days 1 and 15 plus C 80 mg/m2 on day 2 every 4 weeks (C + M). Fifty-three eligible patients were randomized to C + M and 55 to C. In the C + M arm, 45% of patients responded (complete response [CR], 9%) and 31% (CR, 9%) in the C arm (P = .18). In the C arm, 20 patients failing or relapsing after C received M. Two patients responded, and four with progressive disease (PD) and one with a previous partial response (PR) showed no change. The median survival was 8.7 months (C + M arm) and 7.2 months (C arm), P = .7. Relapse-free survival was not significantly different, but C + M was associated with a significantly increased time to disease progression (median, 5.0 months, v 2.8 months for C arm). The response of untreated patients (37%) was not different from those with prior treatment (39%). On the C + M arm, 92% of patients and 96% of patients on the C arm received 85% or more of the scheduled C dose. Significantly more grade 3 or 4 hematological toxicity (27% v 2%; P = .01) and mucositis (20% v 0%; P = .0005) occurred in patients on the C + M arm. Although the initial response rates seen on the combination arm look superior, and the time to disease progression is increased, these effects have not translated into a clinically important increase in the duration of survival and were associated with increased toxicity.