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"Lang, F."
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Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma
MIR-491
is commonly co-deleted with its adjacent
CDKN2A
on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of
MIR-491
is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of
MIR-491
(miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets
EGFR
,
CDK6
and
Bcl-xL
, whereas miR-491-3p targets
IGFBP2
and
CDK6
. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary
Ink4a-Arf
-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore,
MIR-491
is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.
Journal Article
مقدمة في النظرية السياسية الدولية
يتناول الكتاب الثروة والعنف والطبيعة والإيمان وفي كل منحى من هذه المناحي يستند الكتاب إلى شخصيات محورية في النظرية السياسية كي يستكشف النظام العالمي الحالي ويفسره ويقيمه حيث تتناول فصول هذا الكتاب قضايا خلافية مثل التدخل الإنساني وحقوق المثليات والمثليين ومزدوجي الميل الجنسي ومغايري الهوية الجنسانية والتغير المناخي كما يحث الكتاب الطلاب على الدخول في حوار حول النظرية السياسية الدولية وهو حوار من شأنه أن يساعد على توجيههم داخل نظام دولي متزايد التعقيد والتعددية.
Book
Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target
A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify
S100A4
as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting
S100a4
in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.
Glioblastoma (GBM) is an immune cold tumour that is refractory to immunotherapy. Here, the authors identify molecular phenotypes of immune-suppressive and -promoting myeloid cells in GBM through single cell RNA sequencing and propose S100A4 as a regulator of immune suppressive T and myeloid cells in GBM.
Journal Article
علم الأساطير الحديث
موضوع علم الأساطير يدرس عالم الآثار حياة الإنسان في بقاياه المادية، يتتبع التقدم والإنحلاء العرضي من الصوان المتقطع عمدا في مضارب الحصى القديمة، إلى السلاح الحجري المصقول، ومن ثم إلى عصور البرونز والحديد، يسترشد بالبقابا المادية \"الناجية\" الأسلحة القديمة والأدوات، والحلي وطالب المؤسسات لديه طريقة مماثلة، حيث يجد آثاره من الماضي غير المتحضر في الأعراف الزراعية، وفي الأساليب القديمة لتوزيع الأرض ... إلخ.
BOOK
Fast estimation of the look-elsewhere effect using Gaussian random fields
We discuss the use of Gaussian random fields to estimate the look-elsewhere effect correction. We show that Gaussian random fields can be used to model the null-hypothesis significance maps from a large set of statistical problems commonly encountered in physics, such as template matching and likelihood ratio tests. Some specific examples are searches for dark matter using pixel arrays, searches for astronomical transients, and searches for fast-radio bursts. Gaussian random fields can be sampled efficiently in the frequency domain, and the excursion probability can be fitted with these samples to extend any estimation of the look-elsewhere effect to lower
p
values. In addition, in cases where the Gaussian random field is stationary and the parameter space is Euclidean, the look-elsewhere effect correction can be computed analytically. We demonstrate these methods using two example template matching problems. Finally, we apply these methods to estimate the trial factor of a
4
3
accelerometer array for the detection of dark matter tracks in the Windchime project. When a global significance of
3
σ
is required, the estimated trial factor for such an accelerometer array is
10
14
for a one-second search, and
10
22
for a 1-year search.
Journal Article
Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial
After brain metastasis resection, whole brain radiotherapy decreases local recurrence, but might cause cognitive decline. We did this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved time to local recurrence compared with that for surgical resection alone.
In this randomised, controlled, phase 3 trial, we recruited patients at a single tertiary cancer centre in the USA. Eligible patients were older than 3 years, had a Karnofsky Performance Score of 70 or higher, were able to have an MRI scan, and had a complete resection of one to three brain metastases (with a maximum diameter of the resection cavity ≤4 cm). Patients were randomly assigned (1:1) with a block size of four to either SRS of the resection cavity (within 30 days of surgery) or observation. Patients were stratified by histology of the primary tumour, metastatic tumour size, and number of metastases. The primary endpoint was time to local recurrence in the resection cavity, assessed by blinded central review of brain MRI scans by the study neuroradiologist in the modified intention-to-treat population that analysed patients by randomised allocation but excluded patients found ineligible after randomisation. Participants and other members of the treatment team (excluding the neuroradiologist) were not masked to treatment allocation. The trial is registered with ClinicalTrials.gov, number NCT00950001, and is closed to new participants.
Between Aug 13, 2009, and Feb 16, 2016, 132 patients were randomly assigned to the observation group (n=68) or SRS group (n=64), with 128 patients available for analysis; four patients were ineligible (three from the SRS group and one from the observation group). Median follow-up was 11·1 months (IQR 4·8–20·4). 12-month freedom from local recurrence was 43% (95% CI 31–59) in the observation group and 72% (60–87) in the SRS group (hazard ratio 0·46 [95% CI 0·24–0·88]; p=0·015). There were no adverse events or treatment-related deaths in either group.
SRS of the surgical cavity in patients who have had complete resection of one, two, or three brain metastases significantly lowers local recurrence compared with that noted for observation alone. Thus, the use of SRS after brain metastasis resection could be an alternative to whole-brain radiotherapy.
National Institutes of Health.
Journal Article
Recommended conventions for reporting results from direct dark matter searches
The field of dark matter detection is a highly visible and highly competitive one. In this paper, we propose recommendations for presenting dark matter direct detection results particularly suited for weak-scale dark matter searches, although we believe the spirit of the recommendations can apply more broadly to searches for other dark matter candidates, such as very light dark matter or axions. To translate experimental data into a final published result, direct detection collaborations must make a series of choices in their analysis, ranging from how to model astrophysical parameters to how to make statistical inferences based on observed data. While many collaborations follow a standard set of recommendations in some areas, for example the expected flux of dark matter particles (to a large degree based on a paper from Lewin and Smith in 1995), in other areas, particularly in statistical inference, they have taken different approaches, often from result to result by the same collaboration. We set out a number of recommendations on how to apply the now commonly used Profile Likelihood Ratio method to direct detection data. In addition, updated recommendations for the Standard Halo Model astrophysical parameters and relevant neutrino fluxes are provided. The authors of this note include members of the DAMIC, DarkSide, DARWIN, DEAP, LZ, NEWS-G, PandaX, PICO, SBC, SENSEI, SuperCDMS, and XENON collaborations, and these collaborations provided input to the recommendations laid out here. Wide-spread adoption of these recommendations will make it easier to compare and combine future dark matter results.
Journal Article
Robotic-assisted cholecystectomy is superior to laparoscopic cholecystectomy in the initial training for surgical novices in an ex vivo porcine model: a randomized crossover study
BackgroundRobotic-assisted surgery (RAS) potentially reduces workload and shortens the surgical learning curve compared to conventional laparoscopy (CL). The present study aimed to compare robotic-assisted cholecystectomy (RAC) to laparoscopic cholecystectomy (LC) in the initial learning phase for novices.MethodsIn a randomized crossover study, medical students (n = 40) in their clinical years performed both LC and RAC on a cadaveric porcine model. After standardized instructions and basic skill training, group 1 started with RAC and then performed LC, while group 2 started with LC and then performed RAC. The primary endpoint was surgical performance measured with Objective Structured Assessment of Technical Skills (OSATS) score, secondary endpoints included operating time, complications (liver damage, gallbladder perforations, vessel damage), force applied to tissue, and subjective workload assessment.ResultsSurgical performance was better for RAC than for LC for total OSATS (RAC = 77.4 ± 7.9 vs. LC = 73.8 ± 9.4; p = 0.025, global OSATS (RAC = 27.2 ± 1.0 vs. LC = 26.5 ± 1.6; p = 0.012, and task specific OSATS score (RAC = 50.5 ± 7.5 vs. LC = 47.1 ± 8.5; p = 0.037). There were less complications with RAC than with LC (10 (25.6%) vs. 26 (65.0%), p = 0.006) but no difference in operating times (RAC = 77.0 ± 15.3 vs. LC = 75.5 ± 15.3 min; p = 0.517). Force applied to tissue was similar. Students found RAC less physical demanding and less frustrating than LC.ConclusionsNovices performed their first cholecystectomies with better performance and less complications with RAS than with CL, while operating time showed no differences. Students perceived less subjective workload for RAS than for CL. Unlike our expectations, the lack of haptic feedback on the robotic system did not lead to higher force application during RAC than LC and did not increase tissue damage. These results show potential advantages for RAS over CL for surgical novices while performing their first RAC and LC using an ex vivo cadaveric porcine model.Registration numberresearchregistry6029Graphic abstract
Journal Article