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.

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 (AU)

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.

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.

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.

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.

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.

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.

Efficient high-order harmonic generation boosted by below-threshold harmonics.

High-order harmonic generation (HHG) in gases has been established as an important technique for the generation of coherent extreme ultraviolet (XUV) pulses at ultrashort time scales. Its main drawback, however, is the low conversion efficiency, setting limits for many applications, such as ultrafast coherent imaging, nonlinear processes in the XUV range, or seeded free electron lasers. Here we introduce a novel scheme based on using below-threshold harmonics, generated in a "seeding cell", to boost the HHG process in a "generation cell", placed further downstream in the focused laser beam. By modifying the fundamental driving field, these low-order harmonics alter the ionization step of the nonlinear HHG process. Our dual-cell scheme enhances the conversion efficiency of HHG, opening the path for the realization of robust intense attosecond XUV sources.

Tennis racquets in the jaw: eosinophilic granuloma.

A healthy 4-year-old boy presented with a 4 month history of episodic pain and swelling of his left jaw which appeared to respond to antibiotics. An ultrasound, orthopantomogram (OPG), CT scan and MRI revealed a 3 cm well circumscribed lesion in the left mandible near, but not related to, his posterior molar teeth. The radiological differential diagnosis included a mandibular abscess or neoplasm such as Ewing's sarcoma, or Langerhans cell histiocytosis (LCH). A fine needle aspirate (FNA) was performed. The cytology, in conjunction with the immunohistochemistry (S100 protein and CD1a expression by the histiocyte-like cells) and electron microscopy (demonstrating Birbeck bodies) showed features characteristic of LCH. The boy was treated with an intra-lesional injection of methyl prednisolone with radiological and clinical evidence of regression of the lesion. Localised LCH is also known as eosinophilic granuloma (EG). Its pathogenesis is unknown, although recent studies suggest it is a disease that results from mononuclear phagocyte dysregulation that may be infective, autoimmune or neoplastic in origin. EG is rare, usually affecting children 5-15 years. The jaws are affected in 10-20% of cases with mandible involvement more common in adults. No consensus exists for the optimal therapy which includes curettage, intra-lesional prednisolone and chemotherapy.

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.

Clinical characteristics and outcomes of bilateral breast cancer in an Australian cohort.

PURPOSE: Uncertainty remains about the impact of bilateral breast cancer. Characteristics and outcomes of unilateral and bilateral breast cancer were compared within an Australian multi-institutional cohort. METHODS: Demographic, tumour and treatment characteristics were compared among unilateral (n = 2336) and bilateral cases (52 synchronous, 35 metachronous) using descriptive analyses. Disease-specific outcomes were investigated using Cox regression modelling to adjust for prognostic and treatment factors. RESULTS: Factors associated with increased risk of bilateral breast cancer included lobular histology (p = 0.046), family history (p = 0.025) and metropolitan residence (p = 0.006). Mastectomy was more common for bilateral cases (p = 0.001) while radiotherapy was less common (p = 0.015). Index metachronous cases were less likely to receive hormonal therapy (p = 0.001). Five-year survivals for metachronous, synchronous and unilateral cases were 79%, 88% and 94%, respectively. Poorer outcomes remained after adjusting for prognostic factors [HR = 2.26, 1.21-4.21]. CONCLUSION: Our results confirm international findings indicating worse outcomes from bilateral compared with unilateral breast cancer.

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.

Fatty acids alter glycerolipid metabolism and induce lipid droplet formation, syncytialisation and cytokine production in human trophoblasts with minimal glucose effect or interaction.

The diabetic pregnancy is characterized by maternal hyperglycaemia and dyslipidaemia, such that placental trophoblast cells are exposed to both. The objective was to determine the effects of hyperglycaemia, elevated non-esterified fatty acids (NEFA) and their interactions on trophoblast cell metabolism and function. Trophoblasts were isolated from normal term human placentas and established in culture for 16 h prior to experiments. Glucose utilisation, fatty acid oxidation and fatty acid esterification were determined using radiolabelled metabolic tracer methodology at various glucose and NEFA concentrations. Trophoblast lipid droplet formation including adipophilin mRNA expression, viability, apoptosis, syncytialisation, secretion of hormones and pro-inflammatory cytokines were also assessed. Glucose utilisation via glycolysis was near maximal at the low physiological glucose concentration of 4mM; whereas NEFA esterification into triacylglycerol and diacylglycerol increased linearly with increasing NEFA concentrations without evidence of plateau. Culture of trophoblasts in 0.25 mM NEFA for 24h upregulated fatty acid esterification processes, inhibited fatty acid oxidation, inhibited glycerol release (a marker of lipolysis) and promoted adipophilin and lipid droplet formation, all consistent with upregulation of fatty acid storage and buffering capacity. NEFA also promoted trophoblast syncytialisation and TNFalpha, IL-1beta, IL-6 and IL-10 production without effects on cell viability, apoptosis or hormone secretion. Hyperglycaemia caused intracellular glycogen accumulation and reduced lipid droplet formation, but had no other effects on trophoblast metabolism or function. NEFA have effects on trophoblast metabolism and function, mostly independent of glucose, that may have protective as well as pathophysiological roles in pregnancies complicated by diabetes and/or obesity.

Spectral signature of short attosecond pulse trains.

We report experimental measurements of high-order harmonic spectra generated in Ar using a carrier-envelope-offset (CEO) stabilized 12 fs, 800 nm laser field and a fraction (less than 10%) of its second harmonic. Additional spectral peaks are observed between the harmonic peaks, which are due to interferences between multiple pulses in the train. The position of these peaks varies with the CEO and their number is directly related to the number of pulses in the train. An analytical model, as well as numerical simulations, support our interpretation.