MicroRNA-1 Attenuates the Growth and Metastasis of Small Cell Lung Cancer through CXCR4/FOXM1/RRM2 Axis

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS: A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS: Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis

Experimental confirmation of efficient island divertor operation and successful neoclassical transport optimization in Wendelstein 7-X

We present recent highlights from the most recent operation phases of Wendelstein 7-X, the most advanced stellarator in the world. Stable detachment with good particle exhaust, low impurity content, and energy confinement times exceeding 100 ms, have been maintained for tens of seconds. Pellet fueling allows for plasma phases with reduced ion-temperature-gradient turbulence, and during such phases, the overall confinement is so good (energy confinement times often exceeding 200 ms) that the attained density and temperature profiles would not have been possible in less optimized devices, since they would have had neoclassical transport losses exceeding the heating applied in W7-X. This provides proof that the reduction of neoclassical transport through magnetic field optimization is successful. W7-X plasmas generally show good impurity screening and high plasma purity, but there is evidence of longer impurity confinement times during turbulence-suppressed phases.EC/H2020/633053/EU/Implementation of activities described in the Roadmap to Fusion during Horizon 2020 through a Joint programme of the members of the EUROfusion consortium/ EUROfusio

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Estimates for small eigenvalues of the Laplacian and conformal Laplacian on closed manifolds

A central and well-established theme in geometry is eigenvalue estimates for geometric operators on manifolds. In this thesis we obtain new estimates for small eigenvalues of the Laplacian and conformal Laplacian respectively, in two distinct geometric contexts. In the first part of this thesis we consider eigenvalues of the Laplacian on closed hyperbolic surfaces. It is known that for such surfaces degenerating by the collapse of a single simple closed geodesic, the first eigenvalue to highest order depends only on the length of that geodesic and the topology of the limiting surface. We consider the behaviour of the eigenvalues in the more general case of surfaces degenerating by the collapse of multiple simple closed geodesics. We exploit the fact that the geometry of a closed hyperbolic surface of fixed genus depends on a finite number of parameters (up to pullback by diffeomorphisms), the Fenchel-Nielsen coordinates. We prove new local energy estimates for the eigenfunctions of small eigenvalues and use these to obtain estimates for the derivatives of the eigenvalues with respect to the Fenchel-Nielsen coordinates. These are then used to prove that in the case of multiple collapsing geodesics, the small eigenvalues of the Laplacian again to first order depend only on the lengths of the collapsing disconnecting geodesics nd the topology. In the second part of the thesis, we consider the behaviour of the first eigenvalue of the conformal Laplacian for particular families of metrics on closed manifolds of dimension at least three. It is known that the volume-normalised first positive eigenvalue of the conformal Laplacian is not bounded on any conformal class of metrics, contrasting with the behaviour of the Laplacian eigenvalues. We initiate an exploration of this difference in behaviour by proving sharp estimates for the first eigenvalue of the conformal Laplacian for particular families of conformal metrics, which we call asymptotically conical. We also obtain sharp estimates for the behaviour of the volume- and diameter-normalised eigenvalues for these metrics, giving new examples of conformal families of metrics for which the volume-normalised eigenvalues are unbounded

Outcomes of double-breasted spongioplasty as additional tissue coverage in tubularized incised plate urethroplasty

Background: Modern hypospadiology is constantly developing new ideas to improve functional outcomes. Tubularized incised plate urethroplasty (TIPU) with neourethral covering by vascularized tissue (dartos flap, corpus spongiosum) is presently the most common procedure performed. Aim of this study was to evaluate the effectiveness of double-breasted spongioplasty (DBS) as additional tissue coverage in TIPU by comparing it with TIPU without spongioplasty. Methods: We conducted a prospective comparative study from September 2022 to October 2023 on 120 midshaft and distal hypospadias cases aged 1 to 12 years. Group A (n = 60) underwent TIPU without spongioplasty; Group B (n = 60) underwent TIPU with DBS. Pre-operative patient parameters were categorized according to Glans-Meatus-Shaft (GMS) Score. Follow-up was 4 months to one year. Complications like urethrocutaneous fistula (UCF) and meatal stenosis (MS) were recorded. Functional outcomes were assessed using Hypospadias objective scoring evaluation (HOSE). Results: Average age was 5.68 ± 2.26 in group A and 6.40 ± 2.10 in group B. Group A had mean GMS 5.32 ± 1.09; Group B had 5.45 ± 1.12 (p = 0.49). In group A, 4 (6.66 %) had MS, 5 (8.33 %) had UCF; in group B, 5 (8.33 %) had MS, 2 (3.33 %) had UCF (p > 0.05). Dorsal plication for ventral curvature was avoided in 7 patients after DBS. Surgeon evaluated mean HOSE was 14.73 ± 1.87 in Group A and 15.40 ± 1.26 in B (p = 0.02); in group A, 83.33 % while in group B 95 % cases had acceptable HOSE (≥14) (p = 0.04). Conclusion: Double-breasted spongioplasty in TIPU has better functional outcomes when compared with TIPU without spongioplasty and may correct ventral curvature of mild to moderate severity. Level of evidence: LEVEL II

Influence of composting conditions on gaseous emission and compost quality during composting of cow manure and wheat straw

Purpose The composting of manure is the common practice for the feedlots of cattle, but emission of gasses during composting was poorly understood. So, there is need to enhance nutrient contents in composting material, reduce odor and other impurities by various amendment in composting material. This study was planned to find best composting condition for quality compost production. Method Experiment was performed under completely randomized design (CRD) with three factors. First factor (treatment) comprised of three levels e.g.: T1: CM + WS (25% + 75%), T2: CM+WS (50%+50%) and T3: CM +WS (75% +25%). Second factor was composting conditions consisted of two levels e.g., aerobic and anaerobic conditions. Third factor was duration of composting (days). Results Composting conditions significantly influenced emission of greenhouse gasses and compost quality. Maximum gas volume (658 ml) and methane production (58.89%) were produced under anaerobic decomposition of cow manure and wheat straw 3:1, respectively. Maximum carbon dioxide (18.56%) was produced under the aerobic decomposition of cow manure and wheat straw mixed in 1:3 ratio. Nutrient analysis of compost revealed that high-quality compost with maximum total organic carbon (20.1%), total nitrogen (2.47%), phosphorus (0.76%) and potassium (1.49%) was observed from compost produced from anaerobic decomposition of cow manure and wheat straw mixture  @ 3:1.Conclusion This work highlights that the anaerobic composting of cow manure and wheat straw has potential to produce the biogas as well as best quality compost