Fine-tuning activity-dependent bulk endocytosis via kinases and phosphatases

The regulation of activity-dependent bulk endocytosis, the dominant mode of membrane retrieval in response to intense neuronal activity, is poorly understood. In this JCB issue, Peng et al. (2021. J. Cell. Biol.https://doi.org/10.1083/jcb.202011028) propose a novel molecular mechanism for the coordination of activity-dependent bulk endocytosis that builds on Minibrain kinase and its presynaptic substrate synaptojanin-1.I. Milosevic is supported by funding from the John Black Foundation, John Fell Fund (H5D00100), and Horizon 2020 (MIA-Portugal/857524), while M.A. Cousin is supported by The Wellcome Trust (204954/ Z/16/Z), Simons Foundation (529508), Epilepsy Research UK (P2003), and Cure Huntington’s Disease Initiative (A-11210)

Modeling the Spatial Distribution of Chronic Tumor Hypoxia: Implications for Experimental and Clinical Studies

Tumor oxygenation status is considered one of the important prognostic markers in cancer since it strongly influences the response of cancer cells to various treatments; in particular, to radiation therapy. Thus, a proper and accurate assessment of tumor oxygen distribution before the treatment may highly affect the outcome of the treatment. The heterogeneous nature of tumor hypoxia, mainly influenced by the complex tumor microenvironment, often makes its quantification very difficult. The usual methods used to measure tumor hypoxia are biomarkers and the polarographic needle electrode. Although these techniques may provide an acceptable assessment of hypoxia, they are invasive and may not always give a spatial distribution of hypoxia, which is very useful for treatment planning. An alternative method to quantify the tumor hypoxia is to use theoretical simulations with the knowledge of tumor vasculature. The purpose of this paper is to model tumor hypoxia using a known spatial distribution of tumor vasculature obtained from image data, to analyze the accuracy of polarographic needle electrode measurements in quantifying hypoxia, to quantify the optimum number of measurements required to satisfactorily evaluate the tumor oxygenation status, and to study the effects of hypoxia on radiation response. Our results indicate that the model successfully generated an accurate oxygenation map for tumor cross-sections with known vascular distribution. The method developed here provides a way to estimate tumor hypoxia and provides guidance in planning accurate and effective therapeutic strategies and invasive estimation techniques. Our results agree with the previous findings that the needle electrode technique gives a good estimate of tumor hypoxia if the sampling is done in a uniform way with 5-6 tracks of 20–30 measurements each. Moreover, the analysis indicates that the accurate measurement of oxygen profile can be very useful in determining right radiation doses to the patients

Relativistic ionization-rescattering with tailored laser pulses

The interaction of relativistically strong tailored laser pulses with an atomic system is considered. Due to a special tailoring of the laser pulse, the suppression of the relativistic drift of the ionized electron and a dramatic enhancement of the rescattering probability is shown to be achievable. The high harmonic generation rate in the relativistic regime is calculated and shown to be increased by several orders of magnitude compared to the case of conventional laser pulses. The energies of the revisiting electron at the atomic core can approach the MeV domain, thus rendering hard x-ray harmonics and nuclear reactions with single atoms feasible

Dosimetric comparison of intensity-modulated, conformal, and four-field pelvic radiotherapy boost plans for gynecologic cancer: a retrospective planning study

PURPOSE: To evaluate intensity-modulated radiation therapy (IMRT) as an alternative to conformal radiotherapy (CRT) or 4-field box boost (4FB) in women with gynecologic malignancies who are unsuitable for brachytherapy for technical or medical reasons. METHODS: Dosimetric and toxicity information was analyzed for 12 patients with cervical (8), endometrial (2) or vaginal (2) cancer previously treated with external beam pelvic radiotherapy and a CRT boost. Optimized IMRT boost treatment plans were then developed for each of the 12 patients and compared to CRT and 4FB plans. The plans were compared in terms of dose conformality and critical normal tissue avoidance. RESULTS: The median planning target volume (PTV) was 151 cm(3 )(range 58–512 cm(3)). The median overlap of the contoured rectum with the PTV was 15 (1–56) %, and 11 (4–35) % for the bladder. Two of the 12 patients, both with large PTVs and large overlap of the contoured rectum and PTV, developed grade 3 rectal bleeding. The dose conformity was significantly improved with IMRT over CRT and 4FB (p ≤ 0.001 for both). IMRT also yielded an overall improvement in the rectal and bladder dose-volume distributions relative to CRT and 4FB. The volume of rectum that received the highest doses (>66% of the prescription) was reduced by 22% (p < 0.001) with IMRT relative to 4FB, and the bladder volume was reduced by 19% (p < 0.001). This was at the expense of an increase in the volume of these organs receiving doses in the lowest range (<33%). CONCLUSION: These results indicate that IMRT can improve target coverage and reduce dose to critical structures in gynecologic patients receiving an external beam radiotherapy boost. This dosimetric advantage will be integrated with other patient and treatment-specific factors, particularly internal tumor movement during fractionated radiotherapy, in the context of a future image-guided radiation therapy study

Health-Related Quality of Life after Adolescent Fractures of the Femoral Shaft Stabilized by a Lateral Entry Femoral Nail.

(1) Background: In adolescents, fractures of the femoral shaft that are not suitable for elastic-stable-intramedullary-nailing (ESIN), are challenging. We aimed to evaluate the health-related quality of life (HRQoL) and complications in adolescents treated with intramedullary rodding using the adolescent lateral trochanteric entry femoral nail (ALFN), and to assess if HRQoL was associated with additional injuries. (2) Methods: We followed-up on 15 adolescents with a diaphyseal femoral fracture who were treated with an ALFN from 2004 to 2017. Patients were asked to fill in a questionnaire that includes the iHOT, Peds-QL, and the Pedi-IKDC. (3) Results: The ALFN was used as a primary method of fixation in 13 patients, and as a fixation for failed ESIN in two cases. All 15 fractures healed radiographically. One distal locking screw broke. After a mean follow-up of 2.8 years, the mean iHOT-12 was 14.0 (SD 15.4), PedsQL-function was 85.7 (SD 19.3), PedsQL-social-score was 86.2 (SD 12.5), and the mean Pedi-IKDC was 77.2 (SD 11.3). In patients where the femoral fracture was an isolated injury, the HRQoL-scores were consistently higher compared with patients who sustained additional injures. (4) Conclusions: Treating diaphyseal fractures in adolescents with an ALFN resulted in good radiographic outcomes in all our cases. HRQoL, as measured by the iHOT, PedsQL, and Pedi-IKDC, was good to excellent; but it was consistently inferior in patients with additional injuries. These results suggest that the ALFN is a good alternative when patients are not suitable for ESIN, and that the HRQoL of adolescents who were treated with an ALFN is mainly influenced by the presence of additional injures, and less by the fracture of the femur itself

The Synaptic Vesicle Cycle Revisited:New Insights into the Modes and Mechanisms

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Neuroscience 39(42), (2019): 8209-8216, doi:10.1523/JNEUROSCI.1158-19.2019.Neurotransmission is sustained by endocytosis and refilling of synaptic vesicles (SVs) locally within the presynapse. Until recently, a consensus formed that after exocytosis, SVs are recovered by either fusion pore closure (kiss-and-run) or clathrin-mediated endocytosis directly from the plasma membrane. However, recent data have revealed that SV formation is more complex than previously envisaged. For example, two additional recycling pathways have been discovered, ultrafast endocytosis and activity-dependent bulk endocytosis, in which SVs are regenerated from the internalized membrane and synaptic endosomes. Furthermore, these diverse modes of endocytosis appear to influence both the molecular composition and subsequent physiological role of individual SVs. In addition, previously unknown complexity in SV refilling and reclustering has been revealed. This review presents a modern view of the SV life cycle and discusses how neuronal subtype, physiological temperature, and individual activity patterns can recruit different endocytic modes to generate new SVs and sculpt subsequent presynaptic performance.This work was supported by: Schram-Stiftung T287/25457 and Deutsche Forschungsgemeinschaft (Emmy Noether Young Investigator Award MI-1702/1 to I.M.); the Wellcome Trust (204954/Z/16/Z to M.A.C.); the National Science Foundation (1727260 to S.W.), the National Institutes of Health (NINDS DP2 NS111133 and R01 NS105810 to S.W.); the McKnight Foundation (S.W.); the Sloan Foundation (S.W.); and the National Institutes of Health (NINDS/NIA R01 NS078165 to J.R.M. and NIMH R01 MH066198 to Dr. Ege Kavalali, which supports N.L.C.). We thank Dragomir Milovanovic for helpful comments on this manuscript.2020-04-1