- The Crk adapter protein is essential for Drosophila embryogenesis, where it regulates multiple actin-dependent morphogenic events. [Journal Article]
- MBMol Biol Cell 2019 Jul 18; :mbcE19050302
- Small SH2/SH3 adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The Cr…
Small SH2/SH3 adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The Crk family has tissue-specific roles in phagocytosis, cell migration and neuronal development, and mediates oncogenic signaling in pathways like that of Abelson kinase. However, redundancy among the two mammalian family members and the position of the Drosophila gene on the fourth chromosome precluded assessment of Crk's full role in embryogenesis. We circumvented these limitations with shRNA and CRISPR technology to assess Crk's function in Drosophila morphogenesis. We found Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates cortical localization of the Arp2/3 complex, its regulator SCAR, and F-actin to actin caps and pseudocleavage furrows. Crk loss leads to loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics. Movie S1 Movie S1 Crk knockdown often leads to wide-spread nuclear loss but embryos can largely repair the epithelium before gastrulation. Time-lapse movies showing actin dynamics in control and crkS-RNAi embryos expressing Moesin::GFP to label F-actin. The Movie begins during the last syncytial nuclear division and extends until the onset of gastrulation. In the crkS-RNAi embryo, large patches of nuclear loss are apparent following the last nuclear division. During cellularization, cells at the margins of these patches can be seen exhibiting protrusive cell behavior and migrating into areas of cell loss to enclose the blastoderm embryo prior to the onset of gastrulation. Images acquired at 10 s intervals and displayed at 10 frames per second. Time between frames varies between genotypes due to different sizes of region scanned. Scan time was 2.82 seconds for the control embryo and 2.30 seconds for the crkS-RNAi embryo. Movie S2 Movie S2 Crk knockdown leads to reduced actin cap expansion and less apparent pseudocleavage furrows during syncytial nuclear cycles. Time-lapse movies showing actin dynamics in control and crkS-RNAi embryos expressing Moesin::GFP to label F-actin during nuclear cycles 10-14. In both control and crkS-RNAi embryos, actin caps form, expand, and merge into pseudocleavage furrows. However, in crkS-RNAi conditions, actin cap expansion is reduced compared to controls, leading to impaired pseudocleavage furrow formation. Images acquired every 10 s and displayed at 10 frames per second. Time between frames varies between genotypes due to different sizes of region scanned. Scan time was 2.30 seconds for the control embryo and 2.93 seconds for crkS-RNAi embryo. Focal plane was occasionally adjusted to maintain a clear view of the furrows. This video is related to figure 6K,L. Movie S3 Movie S3 Crk loss impairs actin cap expansion and myosin remodeling during syncytial nuclear cycles. Time-lapse movies showing myosin dynamics in control and crkS-RNAi embryos during nuclear cycles 10-14, via MRLC::GFP (=Sqh). In control embryos, inter-cap myosin zones are remodeled during actin cap expansion, resulting in an enrichment of myosin in pseudocleavage furrows. In crkS-RNAi embryos, this remodeling is impaired, resulting in broader inter-cap myosin zones and reduced enrichment of myosin in pseudocleavage furrows. Images acquired every 10 s and displayed at 10 frames per second. Time between frames varies between genotypes due to different sizes of region scanned. Scan time was 2.01 seconds for the control embryo and 2.43 seconds for the crkS-RNAi embryo. Focal plane was occasionally adjusted to maintain a clear view of the furrows. This video is related to figure 6Q-T.
- Real-world experience with cabazitaxel in patients with metastatic castration-resistant prostate cancer: a final, pooled analysis of the compassionate use programme and early access programme. [Journal Article]
- OOncotarget 2019 Jun 25; 10(41):4161-4168
- CONCLUSIONS: The safety profile of cabazitaxel in this pooled analysis of two cabazitaxel early access programmes was manageable and consistent with previous Phase III trials (TROPIC, PROSELICA).
- Sonoprinting of nanoparticle-loaded microbubbles: Unraveling the multi-timescale mechanism. [Journal Article]
- BBiomaterials 2019; 217:119250
- Ultrasound-triggered microbubble-assisted drug delivery is a promising tool for localized therapy. Several studies have shown the potential of nanoparticle-loaded microbubbles to effectively enhance …
Ultrasound-triggered microbubble-assisted drug delivery is a promising tool for localized therapy. Several studies have shown the potential of nanoparticle-loaded microbubbles to effectively enhance the delivery of therapeutic agents to target tissue. We recently discovered that nanoparticle-carrying microbubbles can deposit the nanoparticles in patches onto cell membranes, a process which we termed 'sonoprinting'. However, the biophysical mechanisms behind sonoprinting are not entirely clear. In addition, the question remains how the ultrasound parameters, such as acoustic pressure and pulse duration, influence sonoprinting. Aiming for a better understanding of sonoprinting, this report investigates the behavior of nanoparticle-loaded microbubbles under ultrasound exposure, making use of three advanced optical imaging techniques with frame rates ranging from 5 frames per second to 10 million frames per second, to capture the biophysical cell-bubble interactions that occur on a multitude of timescales. We observed that non-spherically oscillating microbubbles release their nanoparticle payload in the first few cycles of ultrasound insonation. At low acoustic pressures, the released nanoparticles are transported away from the cells by microstreaming, which does not favor uptake of the nanoparticles by the cells. However, higher acoustic pressures (>300 kPa) and longer ultrasound pulses (>100 cycles) lead to rapid translation of the microbubbles, due to acoustic radiation forces. As a result, the released nanoparticles are transported along in the wake of the microbubbles, which eventually leads to the deposition of nanoparticles in elongated patches on the cell membrane, i.e. sonoprinting. We conclude that a sufficiently high acoustic pressure and long pulses are needed for sonoprinting of nanoparticles on cells.
- Effect of body mass index on pregnancy outcomes in a freeze-all policy: an analysis of 22,043 first autologous frozen-thawed embryo transfer cycles in China. [Journal Article]
- BMBMC Med 2019 Jun 26; 17(1):114
- CONCLUSIONS: Among women undergoing first FET with high-quality embryo transfer, low BMI has limited impact on pregnancy and live birth rates. On the contrary, obesity was associated with worse IVF outcomes. Our findings further highlighted that endometrial receptivity played an important role in the poor reproductive outcomes of women with abnormal weight status.
- Complete response with early introduction of cabazitaxel in a patient with multiple lung metastases of castration-resistant prostate cancer following the early detection of metastases using liquid biopsy: a case report. [Journal Article]
- BCBMC Cancer 2019 Jun 11; 19(1):562
- CONCLUSIONS: We presented a rare case of a patient with mCRPC who was successfully treated with early CBZ chemotherapy. The early detection of metastasis using liquid biopsy enabled the introduction of early CBZ chemotherapy for docetaxel-resistant mCRPC.
- Intrauterine insemination: simultaneous with or 36 h after HCG? A randomized clinical trial. [Journal Article]
- RBReprod Biomed Online 2019 Apr 01
- CONCLUSIONS: This multicentre randomized controlled trial did not demonstrate that IUI carried out at the point of HCG triggering increases pregnancy rates compared with IUI carried out around the time of ovulation.
- Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma. [Journal Article]
- NEJMN Engl J Med 2019 May 31
- CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).
- Value-Driven Care in Developmental-Behavioral Pediatrics, Part 1: The Value Proposition of Developmental-Behavioral Pediatrics. [Journal Article]
- JDJ Dev Behav Pediatr 2019 May 16
- The drive to improve quality and reduce cost of health care is leading to a value-driven transformation of the US health care landscape. This is the first of a 2-part series on value-driven care and …
The drive to improve quality and reduce cost of health care is leading to a value-driven transformation of the US health care landscape. This is the first of a 2-part series on value-driven care and its implications for developmental-behavioral pediatrics (DBP). Tools derived from business/manufacturing models have been applied with some success to health care to better understand and enhance value. Value can be defined most simply as health outcomes achieved per dollar spent, but there are challenges in accounting for the full cost of a cycle or episode of care. When taking into account the "five Ds"-Development, Dependency, Differential Epidemiology, Demographics, and Dollars-the potential value of pediatric care is brought into sharper focus. The field of DBP in particular has the potential to add value through prevention, integration, efficiency, standardization, and innovation. The value proposition of DBP is illustrated by focusing on particular conditions or cycles of care commonly encountered in DBP practice: (1) children 0 to 3 years of age identified as having global developmental delay, (2) recent diagnosis of complex attention-deficit hyperactivity disorder (ADHD) (ADHD plus comorbid conditions), and (3) children with autism spectrum disorder and disruptive behavior. The second part of the series focuses on quality of care, emphasizing the important challenges that lie ahead for the field of DBP in measuring outcomes of care. With a discussion of national trends and a local example of a DBP program's response to these trends, the series is intended to provoke discussion and action in the field, contribute to the demonstration of value of a DBP approach to care, and help to chart a course toward growth and sustainability of DBP in an era of value-based care.
- Prolonged pituitary down-regulation with full-dose of gonadotropin-releasing hormone agonist in different menstrual cycles: a retrospective cohort study. [Journal Article]
- PPeerJ 2019; 7:e6837
- CONCLUSIONS: Prolonged pituitary down-regulation achieved by utilizing a full-dose of GnRH-a administrated in either phase of the menstrual cycle can have a positive effect on ongoing pregnancy rate and live-birth rate per fresh embryo transfer cycle. Ovarian cyst formation rate was higher in the follicular phase group, but this did not have any adverse impact on clinical results.
New Search Next
- A Bottom-Up Approach to Encouraging Sustained User Adoption of a Secure Text Messaging Application. [Journal Article]
- ACAppl Clin Inform 2019; 10(2):326-330
- CONCLUSIONS: We believe that a bottom-up approach is important to introducing mobile applications to the inpatient setting and can contribute to sustained user adoption.