Search

Breast cancer is the primary cause of cancer-related death in women. Women diagnosed with estrogen receptor (ER)-positive breast cancer have prolonged treatment durations. Owing to the paucity of research and lack of consensus regarding conception planning and pregnancy for patients with ER-positive breast cancer, we aimed to assess pregnancy and survival outcomes in women with ER-positive breast cancer during and after treatment.We conducted a systematic review of the available studies on pregnancy after ER-positive breast cancer. The assessed outcomes included overall survival (OS), disease-free survival (DFS), hormonal therapy duration, and pregnancy outcomes.Ultimately, 2,669 patients from five studies were included in this study. When all breast cancer receptor subtypes were included in the analysis, pregnancy after breast cancer was associated with a time-dependent protective effect on both DFS and OS. This protective effect was not evident when examining ER-positive patients with subsequent pregnancies, and no significant differences in DFS were observed. ER-positive patients who became pregnant received significantly lower rates of hormonal therapy. Hormonal treatment at the time of pregnancy was correlated with increased rates of termination owing to concerns about teratogenic effects.Pregnancy after breast cancer did not significantly affect DFS in ER-positive patients over a follow-up period of 5-10 years from diagnosis, although did significantly affect hormonal treatment duration in the reviewed studies. Further analysis and in-depth studies are required to assess the effects of altered hormonal treatment times, as well as patient management related to pregnancy planning after breast cancer.

Purposefully-designed, science content courses have the potential to help prepare future elementary teachers by helping to develop their understanding of the practices of science. We extend this area of research by investigating how students’ experiences in such a course contributes to their understanding of the coherence of science practices within a science investigation. We investigated U.S. college students’ understanding of coherent science inquiry investigations after completing an inquiry-based astronomy course designed for preservice elementary teachers. We assessed preservice teachers' (N=63) understanding of the coherence between question, data gathering, and evidence-based explanations using a novel format: student-generated astronomy-based children’s storybooks. Most students (59%) wrote storybooks featuring coherent investigations; in other words, their stories featured characters who linked an investigation question to data collection and to an evidence-based explanation. Over the three years of data collection, the percentage of preservice teachers who wrote coherent investigations in their final storybooks increased from 35% to 71% suggesting that additional scaffolding provided by the faculty in years 2 and 3 helped students understand these practices. Our findings suggest that purposefully-designed, science content courses can help preservice teachers learn about coherent science inquiry in astronomy. We also suggest that projects tied to the students’ own future careers, such as creating children’s science storybooks, can be used as assessment tools by faculty to assess preservice teachers’ development of science practices.

In the last few decades, tremendous effort has been dedicated to mimicking the efficient ionic current rectification (ICR) of biological nanopores. Nanoporous membranes and singular nanopores with ICR functionality have been fabricated using advanced, yet costly technologies. We herein demonstrate that a simple, novel, and robust ICR platform can be constructed using 80 nm silica nanoparticles and a piece of 15 nm track-etched polycarbonate membrane. Efficient ICR can be obtained when voltages of different polarities are applied across the membrane, due to the asymmetric electrophoretic migration of silica nanoparticles whose surfaces are modified with different functional groups. The effect of pore size, ionic strength, pH, voltage magnitude, and density of silica nanoparticles on the efficiency of the ICR system has been systematically investigated in this report. Our results clearly show that smaller pore, lower ionic strength, appropriate pH value, higher electrical field strength, lower density of silica nanoparticles can generally enhance the efficiency of the ICR system. The principles of this new ICR system may find many potential applications in controllable drug delivery, energy storage and water purification.

Summary THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression., Highlights • Wild-type THAP1 regulates ESC potential, survival, and proliferation • THAP1 is essential for ESC differentiation, particularly neuroectodermal • Thap1C54Y or ΔExon2 ESCs prolong expression of pluripotent genes upon differentiation • Thap1C54Y or ΔExon2 EBs show increased cell death and abnormal differentiation, Ehrlich and colleagues identified THAP1, mutations of which cause dystonia (DYT6), as an essential regulator of ESC survival, proliferation, and differentiation. As THAP1 mutations result in a neurologic disease, this work examined the effects of a causative mutation, C54Y, and an essentially null allele, ΔExon2, on neuronal differentiation.

The development of small interfering RNA (siRNA) to silence specific genes offers a new means of understanding and treating a range of respiratory diseases, including inflammatory lung disease. The alveolar macrophage (AM) is a key component of the inflammatory process in the lungs, associated with high levels of gene expression in inflammatory lung disease and therefore an attractive target for therapeutic siRNA. Delivery of siRNA to macrophages presents a significant delivery challenge, as fully differentiated alveolar macrophages are difficult to access and transfect. In this study we engineered particles suitable for inhalation that would efficiently transfect macrophages postinhalation. The process for encapsulation of siRNA in poly(lactic-co-glycolic acid) microparticles (MPs) was optimized using a double emulsion technique, and the resulting particles were characterized for size, shape, aerosol characteristics, encapsulation efficiency, and integrity of encapsulated siRNA. The cell uptake of the siRNA-loaded microparticles was determined by flow cytometry, confocal laser scanning microscopy (CLSM), and high-content analysis (HCA) with MPs capable of transfecting up to 55% of cells. Anti-TNFα siRNA-MPs were then prepared to study the functional activity of encapsulated siRNA in LPS-stimulated macrophages as a model of inflammation. The anti-TNFα siRNA-MPs were able to decrease TNFα expression by 45% over 48 h in the differentiated human monocytic cell line THP-1 compared to negligible knockdown using commercial transfection reagents and offered significant, sustained siRNA knockdown of TNFα in primary monocytes for up to 72 h.

Endoplasmic reticulum (ER) stress has been implicated in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). MicroRNAs are small ribonucleic acids which can modulate protein expression by binding to the 3'UTR of target mRNAs. We recently identified increased miR-29a expression in response to ER stress in neurons, with members of the miR-29 family implicated in cancer and neurodegeneration. We found high expression of miR-29a in the mouse brain and spinal cord by quantitative PCR analysis and increased expression of miR-29a in the spinal cord of SOD1(G93A) transgenic mice, a mouse model of familial ALS. In situ hybridisation experiments revealed increased miR-29a expression in the lumbar spinal cord of SOD1(G93A) transgenic mice from postnatal day 70 onward when compared to wild-type mice. miR-29a knockdown was achieved in the CNS in vivo after a single intracerebroventricular injection of a miR-29a-specific antagomir. While analysis of disease progression and motor function could not identify a significant alteration in ALS disease manifestations, a trend towards increased lifespan was observed in male SOD1(G93A) mice. These findings demonstrate that miR-29a may act as a marker for disease progression in SOD1(G93A) mice, and provide first proof-of-concept for a therapeutic modulation of miR-29a function in ALS.

Disturbance of homeostasis within the endoplasmic reticulum (ER) lumen leads to the accumulation of unfolded and misfolded proteins. This results in the activation of an evolutionary conserved stress response termed ER stress that, if unresolved, induces apoptosis. Previously the Bcl-2 homology domain 3-Only Protein Puma was identified as a mediator of ER stress-induced apoptosis in neurons. In the search of alternative contributors to ER stress-induced apoptosis, a downregulation of the anti-apoptotic Bcl-2 family protein Mcl-1 was noted during ER stress in both mouse cortical neurons and human SH-SY5Y neuroblastoma cells. Downregulation of Mcl-1 was associated with an upregulation of microRNA-29a (miR-29a) expression, and subsequent experiments showed that miR-29a targeted the 3'-untranslated region of the anti-apoptotic Bcl-2 family protein, Mcl-1. Inhibition of miR-29a expression using sequence-specific antagomirs or the overexpression of Mcl-1 decreased cell death following tunicamycin treatment, while gene silencing of Mcl-1 increased cell death. miR-29a did not alter the signalling branches of the ER stress response, rather its expression was controlled by the ER stress-induced transcription factor activating-transcription-factor-4 (ATF4). The current data demonstrate that the ATF4-mediated upregulation of miR-29a enhances the sensitivity of neurons to ER stress-induced apoptosis.

Community acquired pneumonia (CAP) is the leading infectious cause of mortality worldwide with approximately 10% of patients hospitalized requiring intensive care unit (ICU) admission. The ability to predict clinical stability (CS) and treatment failure (TF) enables the clinician to alter antibiotics appropriately, facilitate a timely ICU admission, or arrange a suitable discharge. The detection of CS and TF can be difficult and changes in clinical signs may be subtle or delayed. Thus clinical scores and biomarkers are routinely used to identify severity and monitor clinical progression. The evidence, however, is vast and the definitive role of these systems is at times difficult to elucidate. The aim of this review is to analyse the current literature and to provide a rational and clinically focused view of the predictive utility of various systems used to identify CS and TF in CAP.

We report a very rare case of methaemoglobinaemia associated with glucose 6 phosphate dehydrogenase (G6PD) deficiency, complicating a respiratory illness in a preterm neonate. This neonate had consistently low saturation readings despite being ventilated at moderately high pressures in 100% oxygen. An arterial blood gas confirmed a high methaemoglobin level and a high pO2, inconsistent with the saturations. In addition, the bilirubin increased to exchange levels and was difficult to control with quadruple phototherapy. A double volume exchange transfusion was performed, which reduced both bilirubin and methaemoglobin. The pulse oximetry then started to correlate well with pO2. G6PD deficiency was confirmed.Paediatricians should remember that methaemoglobinaemia is a rare but important cause of persistently low saturations, and exchange transfusion is a reliable treatment for this condition.

UNLABELLED We report a very rare case of methaemoglobinaemia associated with glucose 6 phosphate dehydrogenase (G6PD) deficiency, complicating a respiratory illness in a preterm neonate. This neonate had consistently low saturation readings despite being ventilated at moderately high pressures in 100% oxygen. An arterial blood gas confirmed a high methaemoglobin level and a high pO2, inconsistent with the saturations. In addition, the bilirubin increased to exchange levels and was difficult to control with quadruple phototherapy. A double volume exchange transfusion was performed, which reduced both bilirubin and methaemoglobin. The pulse oximetry then started to correlate well with pO2. G6PD deficiency was confirmed. CONCLUSION Paediatricians should remember that methaemoglobinaemia is a rare but important cause of persistently low saturations, and exchange transfusion is a reliable treatment for this condition.