Placental involvement by non-Hodgkin lymphoma in a Crohn disease patient on long-term thiopurine therapy.

We report the first published case of aggressive diffuse large B-cell (non-Hodgkin) lymphoma in a 35-year-old pregnant woman who had Crohn disease and was taking long-term thiopurine therapy: the patient developed placental insufficiency, and there was intrauterine fetal death.

Indomethacin administered early in the postnatal period results in reduced glomerular number in the adult rat.

Indomethacin and ibuprofen are administered to close a patent ductus arteriosus (PDA) during active glomerulogenesis. Light and electron microscopic glomerular changes with no change in glomerular number were seen following indomethacin and ibuprofen treatment during glomerulogenesis at 14 days after birth in a neonatal rat model. This present study aimed to determine whether longstanding renal structural changes are present at 30 days and 6 mo (equivalent to human adulthood). Rat pups were administered indomethacin or ibuprofen antenatally on days 18-20 (0.5 mg·kg(-1)·dose(-1) indomethacin; 10 mg·kg(-1)·dose(-1) ibuprofen) or postnatally intraperitoneally from day 1 to 3 or day 1 to 5 (0.2 mg·kg(-1)·dose(-1) indomethacin; 10 mg·kg(-1)·dose(-1) ibuprofen). Control groups received no treatment or normal saline intraperitoneally. Pups were killed at 30 days of age and 6 mo of age. Tissue blocks from right kidneys were prepared for light and electron microscopic examination, while total glomerular number was determined in left kidneys using unbiased stereology. Eight pups were included in each group from 14 maternal rats. At 30 days and 6 mo, there were persistent electron microscopy abnormalities of the glomerular basement membrane in those receiving postnatal indomethacin and ibuprofen. There were no significant light microscopy findings at 30 days or 6 mo. At 6 mo, there were significantly fewer glomeruli in those receiving postnatal indomethacin but not ibuprofen (P = 0.003). In conclusion, indomethacin administered during glomerulogenesis appears to reduce the number of glomeruli in adulthood. Alternative options for closing a PDA should be considered including ibuprofen as well as emerging therapies such as paracetamol.

Effects of photobiomodulation and caffeine treatment on acute kidney injury in a hypoxic ischemic neonatal rat model.

Hypoxic ischemic encephalopathy (HIE) occurs in 2-5/1000 births, with acute kidney injury (AKI) occurring in 40%. AKI increases morbidity and mortality. Caffeine, an adenosine receptor antagonist, and photobiomodulation (PBM), working on cytochrome c oxidase, are potential treatments for AKI. To examine effects of caffeine and PBM on AKI in rats, Day 7 pups underwent a HIE intervention (Modified Rice-Vannucci model) replicating pathology observed in humans. Caffeine was administered for 3 days and/or PBM for 5 days following HIE. Weights and urine for biomarkers (NGAL, albumin, KIM-1, osteopontin) were collected prior to HIE, daily post intervention and at sacrifice. Both treatments reduced kidney injury seen on electron microscopy, but not when combined. HIE elevated urinary NGAL and albumin on Days 1-3 post-HIE, before returning to control levels. This elevation was significantly reduced by PBM or caffeine. KIM-1 was significantly elevated for 7 days post-HIE and was reduced by both treatments. Osteopontin was not altered by HIE or the treatments. Treatments, individually but not in combination, improved HIE-induced reductions in the enzymatic activity of mitochondrial complexes II-III. PBM and caffeine also improved weight gain. PBM and caffeine reduces AKI diagnosed by urinary biomarkers and confirmed by EM findings.

Probing single-photon ionization on the attosecond time scale.

We study photoionization of argon atoms excited by attosecond pulses using an interferometric measurement technique. We measure the difference in time delays between electrons emitted from the 3s(2) and from the 3p(6) shell, at different excitation energies ranging from 32 to 42 eV. The determination of photoemission time delays requires taking into account the measurement process, involving the interaction with a probing infrared field. This contribution can be estimated using a universal formula and is found to account for a substantial fraction of the measured delay.

Efavirenz as a potential drug for the treatment of triple-negative breast cancers.

PURPOSE: In contrast to hormone receptor driven breast cancer, patients presenting with triple-negative breast cancer (TNBC) often have limited drug treatment options. Efavirenz, a non-nucleoside reverse transcriptase (RT) inhibitor targets abnormally overexpressed long interspersed nuclear element 1 (LINE-1) RT and has been shown to be a promising anticancer agent for treating prostate and pancreatic cancers. However, its effectiveness in treating patients with TNBC has not been comprehensively examined. METHODS: In this study, the effect of Efavirenz on several TNBC cell lines was investigated by examining several cellular characteristics including viability, cell division and death, changes in cell morphology as well as the expression of LINE-1. RESULTS: The results show that in a range of TNBC cell lines, Efavirenz causes cell death, retards cell proliferation and changes cell morphology to an epithelial-like phenotype. In addition, it is the first time that a whole-genome RNA sequence analysis has identified the fatty acid metabolism pathway as a key regulator in this Efavirenz-induced anticancer process. CONCLUSION: In summary, we propose Efavirenz is a potential anti-TNBC drug and that its mode of action can be linked to the fatty acid metabolism pathway.

Phase measurement of resonant two-photon ionization in helium.

We study resonant two-color two-photon ionization of helium via the 1s3p (1)P(1) state. The first color is the 15th harmonic of a tunable Ti:sapphire laser, while the second color is the fundamental laser radiation. Our method uses phase-locked high-order harmonics to determine the phase of the two-photon process by interferometry. The measurement of the two-photon ionization phase variation as a function of detuning from the resonance and intensity of the dressing field allows us to determine the intensity dependence of the transition energy.

Author Correction: LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical role of flow cytometry in redefining bone marrow involvement in diffuse large B-cell lymphoma (DLBCL) - a new perspective.

AIMS: The clinical role of flow cytometry in staging bone marrow in diffuse large B-cell lymphoma (DLBCL), especially its impact on outcome, remains uncertain. The aim was to determine the contribution of flow cytometry to conventional staging, and to study the impact of this revised staging on survival. METHODS AND RESULTS: One hundred and thirteen cases of DLBCL diagnosed at The Canberra Hospital from 1996 to 2005 were identified. Blinded analysis of bone marrow (BM) morphology and flow cytometric data showed involvement on morphology (M) in 25 (22.1%) cases, on flow cytometry (F) in 21 (18.6%) cases and overall (M + F) in 32 cases (28.3%); discordance was noted in 16 cases (16.1%). Cases with and without marrow involvement on conventional staging alone (M) had no significant difference in survival (P = NS). However, when BM involvement was defined as positivity on morphology and/or flow cytometry (M + F), the median survival of patients with involvement was significantly worse than patients without involvement (P = 0.026). CONCLUSIONS: Flow cytometry-positive cases should be included with those positive on morphology in a summative model to define BM involvement in DLBCL, as it may have a potential impact on predicting outcome.

Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis.

BACKGROUND: A recent study has shown that the measurement of specific IgE antibodies to B-cell epitope peptides of wheat omega-5 gliadin (Pep A) and high molecular weight glutenin subunit (Pep B) are useful to diagnose wheat-dependent exercise-induced anaphylaxis (WDEIA). AIMS OF THE STUDY: We sought to compare the sensitivity and specificity of the in vitro tests for measuring the specific IgE antibodies to recombinant omega-5 gliadin (romega-5 gliadin) with those for wheat, gluten, Pep A, and Pep B in identification of patients with WDEIA. METHODS: Fifty patients with WDEIA, 25 healthy subjects and 25 patients with atopic dermatitis with specific IgE antibodies to wheat but without experience of allergic reactions after ingestion of wheat products were enrolled in this study. The concentrations of specific IgE antibodies were measured using ImmunoCAP. The empirical receiver operating characteristics curves (ROC) for each test were prepared and the areas under the ROC curve (AUC) were compared. RESULTS: In patients with WDEIA, the sensitivities of the allergen-specific IgE tests for wheat, gluten, Pep A, Pep B and romega-5 gliadin were 48%, 56%, 76%, 22%, and 80%, respectively. The seven of 10 WDEIA patients with no specific IgE antibodies to romega-5 gliadin had specific IgE antibodies to Pep B. The highest AUC (0.850) was observed in the test for romega-5 gliadin. CONCLUSIONS: Measuring the concentration of specific IgE antibodies to romega-5 gliadin is more useful than to wheat, gluten, or Pep A in the identification of patients with WDEIA.

IgE antibodies to omega-5 gliadin associate with immediate symptoms on oral wheat challenge in Japanese children.

BACKGROUND: Gliadins have been implicated in immunoglobulin E (IgE)-mediated allergy to ingested wheat and omega-5-gliadin is known to represent a major allergen in wheat-dependent exercise-induced anaphylaxis. Less known is whether omega-5-gliadin is a clinically relevant allergen in children with immediate allergy to ingested wheat. This study investigates whether specific IgE antibodies to omega-5-gliadin (sIgE-omega-5-gliadin-ab) could be used as a marker for oral wheat challenge outcome in wheat-sensitized children. A secondary objective was to study whether the level of sIgE-omega-5-gliadin was related to symptom severity in children with a positive challenge test. METHODS: Serum samples from 88 children sensitized to wheat, of whom 35 underwent wheat challenge, were collected consecutively. sIgE-omega-5-gliadin-ab was related to a physician's diagnosis of wheat allergy and challenge symptoms. RESULTS: The mean concentration of sIgE-omega-5-gliadin-ab was 7.25 kU(A)/l in patients with wheat allergy and 1.08 kU(A)/l in patients with no wheat allergy (P < 0.01). sIgE-omega-5-gliadin-ab was only detected in 12 of the non-wheat allergic children and 11 of them had a specific IgE to wheat below 1.30 kU(A)/l. Children reacting with severe symptoms upon challenge (n = 8) had increased levels of sIgE-omega-5-gliadin-ab compared to children with moderate, mild or no symptoms (P < 0.001). CONCLUSIONS: The presence of sIgE-omega-5-gliadin-ab is related to the reaction level to wheat challenge outcome in wheat-sensitized children. The sIgE-omega-5-gliadin-ab was found to be associated with a strong convincing history of wheat allergy also in those cases when oral food challenge was avoided. The sIgE-omega-5-gliadin-ab level may serve as a marker for clinical reactivity in wheat-sensitized individuals.

Histopathological examination of the placenta: key issues for pathologists and obstetricians.

The placenta is often not submitted for histopathological examination and obstetricians may be sceptical of the value of the examination. This article looks at the reasons for histopathological assessment of the placenta, examines what clinical information should be provided to pathologists and reviews what information can be gained from this 'diary of the pregnancy', especially for explaining adverse outcomes and potentially guiding the management of future pregnancies.

Anisotropic photoemission time delays close to a Fano resonance.

Electron correlation and multielectron effects are fundamental interactions that govern many physical and chemical processes in atomic, molecular and solid state systems. The process of autoionization, induced by resonant excitation of electrons into discrete states present in the spectral continuum of atomic and molecular targets, is mediated by electron correlation. Here we investigate the attosecond photoemission dynamics in argon in the 20-40 eV spectral range, in the vicinity of the 3s-1np autoionizing resonances. We present measurements of the differential photoionization cross section and extract energy and angle-dependent atomic time delays with an attosecond interferometric method. With the support of a theoretical model, we are able to attribute a large part of the measured time delay anisotropy to the presence of autoionizing resonances, which not only distort the phase of the emitted photoelectron wave packet but also introduce an angular dependence.

LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer.

Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.

Photoionization in the time and frequency domain.

Ultrafast processes in matter, such as the electron emission after light absorption, can now be studied using ultrashort light pulses of attosecond duration (10-18 seconds) in the extreme ultraviolet spectral range. The lack of spectral resolution due to the use of short light pulses has raised issues in the interpretation of the experimental results and the comparison with theoretical calculations. We determine photoionization time delays in neon atoms over a 40-electron volt energy range with an interferometric technique combining high temporal and spectral resolution. We spectrally disentangle direct ionization from ionization with shake-up, in which a second electron is left in an excited state, and obtain excellent agreement with theoretical calculations, thereby solving a puzzle raised by 7-year-old measurements.

Spectral phase measurement of a Fano resonance using tunable attosecond pulses.

Electron dynamics induced by resonant absorption of light is of fundamental importance in nature and has been the subject of countless studies in many scientific areas. Above the ionization threshold of atomic or molecular systems, the presence of discrete states leads to autoionization, which is an interference between two quantum paths: direct ionization and excitation of the discrete state coupled to the continuum. Traditionally studied with synchrotron radiation, the probability for autoionization exhibits a universal Fano intensity profile as a function of excitation energy. However, without additional phase information, the full temporal dynamics cannot be recovered. Here we use tunable attosecond pulses combined with weak infrared radiation in an interferometric setup to measure not only the intensity but also the phase variation of the photoionization amplitude across an autoionization resonance in argon. The phase variation can be used as a fingerprint of the interactions between the discrete state and the ionization continua, indicating a new route towards monitoring electron correlations in time.

Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer.

Epithelial cancers comprise 80-90% of human cancers. During the process of cancer progression, cells lose their epithelial characteristics and acquire stem-like mesenchymal features that are resistant to chemotherapy. This process, termed the epithelial-mesenchymal transition (EMT), plays a critical role in the development of metastases. Because of the unique migratory and invasive properties of cells undergoing the EMT, therapeutic control of the EMT offers great hope and new opportunities for treating cancer. In recent years, a plethora of genes and noncoding RNAs, including miRNAs, have been linked to the EMT and the acquisition of stem cell-like properties. Despite these advances, questions remain unanswered about the molecular processes underlying such a cellular transition. In this article, we discuss how expression of the normally repressed LINE-1 (or L1) retrotransposons activates the process of EMT and the development of metastases. L1 is rarely expressed in differentiated stem cells or adult somatic tissues. However, its expression is widespread in almost all epithelial cancers and in stem cells in their undifferentiated state, suggesting a link between L1 activity and the proliferative and metastatic behaviour of cancer cells. We present an overview of L1 activity in cancer cells including how genes involved in proliferation, invasive and metastasis are modulated by L1 expression. The role of L1 in the differential expression of the let-7 family of miRNAs (that regulate genes involved in the EMT and metastasis) is also discussed. We also summarize recent novel insights into the role of the L1-encoded reverse transcriptase enzyme in epithelial cell plasticity that suggest it might be a potential therapeutic target that could reverse the EMT and the metastasis-associated stem cell-like properties of cancer cells.

A safety and feasibility study of the use of 670 nm red light in premature neonates.

OBJECTIVE: Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina affecting extremely preterm or low birth weight infants The aim of this study was to assess the feasibility and safety of 670 nm red light use in a neonatal intensive care unit. STUDY DESIGN: Neonates <30 weeks gestation and <1150 g were enrolled within 48 h of birth. Data collected included cause of preterm delivery, Apgar scores and birthweight. 670 nm red light was administered for 15 min per day from a distance of 25 cm, delivering 9 J cm(-)(2), from the time of inclusion in the study until 34 weeks postmenstrual age. Infants were assessed daily for the presence of any skin burns or other adverse signs. RESULT: Twenty-eight neonates were enrolled, seven 24 to 26 weeks and twenty-one 27 to 29 weeks gestation. The most common cause for preterm delivery was preterm labor (14/28) with five of these having evidence of chorioamnionitis. There were no skin burns or other documented adverse events. Entry into the study was readily achieved and treatment was well accepted by parents and nursing staff. CONCLUSION: 670 nm red light appears to be a safe and feasible treatment for further research in respect to ROP.

Histologic-radiologic correlation of mammographically detected microcalcification in stereotactic core biopsies.

Core biopsy is an alternative technique to surgical excision for assessment of nonpalpable mammographically detected suspicious lesions. The pattern of radiologic calcification is often considered to have diagnostic importance. The aim of this study was to correlate radiologic and histologic features of calcification, with respect to appearance, distribution, and size, to determine the significance, if any, of different radiologic patterns of calcification. Core biopsy samples from 124 women who had 129 mammographically suspicious areas of calcification were examined. Core biopsy samples (five cores per procedure) were obtained stereotactically using a 14-gauge needle in an automated Biopty (Bard Australia, Chatswood, NSW, Australia) gun. In 30 lesions no histologic calcification was found. In the others, there was a poor correlation between radiology and histology with respect to the appearance and distribution of calcification. In a subgroup of 53 women, radiographs of biopsy cores were available to allow correlation with the size of histologic calcification. Calcification of <100 microm assessed histologically was not visible on core biopsy specimen radiographs and may not represent the calcification seen mammographically. Thus, radiography of core biopsy samples and histologic measurement of the size of calcification in core biopsy specimens is useful to reduce false-negative diagnoses in which a biopsy has been performed to evaluate mammographically suspicious calcifications.

Immunohistochemistry of omega class glutathione S-transferase in human tissues.

Omega class glutathione transferase (GSTO) has been recently described in a number of mammalian species. We used immunohistochemistry to determine the cellular and tissue distribution of GSTO1-1 in humans. Expression of GSTO1-1 was abundant in a wide range of normal tissues, particularly liver, macrophages, glial cells, and endocrine cells. We also found nuclear staining in several types of cells, including glial cells, myoepithelial cells of the breast, neuroendocrine cells of colon, fetal myocytes, hepatocytes, biliary epithelium, ductal epithelium of the pancreas, Hoffbauer cells of the placenta, and follicular and C-cells of the thyroid. These observations and the known activity of GSTO1-1 suggest biological functions that are not shared with other GSTs.

VACTERL with hydrocephalus: family with X-linked VACTERL-H.

We describe in a five generation family four affected males with hydrocephalus (4 offspring/4 examined) due to aqueductal stenosis (3/3), symmetrical radial ray abnormalities (4/4), renal anomalies (2/3), anal atresia (3/4), hypoplastic penis/abnormal testes (2/3), and cardiac abnormalities (1/3). X-linked inheritance seems certain in this family. These abnormalities are characteristic of the rare X-linked VACTERL-H syndrome. In addition, one maternal female cousin had a severe tracheo-esophageal fistula. This may represent partial manifestation in a female carrier. Chromosomes were apparently normal (46XY) with no spontaneous or excess induced breakages in one of the affected offspring and his mother. In the absence of a genetic marker, diagnostic ultrasonography is the investigation of choice for early in utero detection of this syndrome. A confident ultrasonographic diagnosis was possible by 20 weeks in the 2 cases examined.