1,872 research outputs found

    Breast Cancer Cell Type and Biomechanical Properties of Decellularized Mouse Organs Drives Tumor Cell Colonization

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    Tissue engineering has emerged as an indispensable tool for the reconstruction of organ-specific environments. Organ-derived extracellular matrices (ECM) and, especially, decellularized tissues (DCL) are recognized as the most successful biomaterials in regenerative medicine, as DCL preserves the most essential organ-specific ECM properties such as composition alongside biomechanics characterized by stiffness and porosity. Expansion of the DCL technology to cancer biology research, drug development, and nanomedicine is pending refinement of the existing DCL protocols whose reproducibility remains sub-optimal varying from organ to organ. We introduce a facile decellularization protocol universally applicable to murine organs, including liver, lungs, spleen, kidneys, and ovaries, with demonstrated robustness, reproducibility, high purification from cell debris, and architecture preservation, as confirmed by the histological and SEM analysis. The biomechanical properties of as-produced DCL organs expressed in terms of the local and total stiffness were measured using our facile methodology and were found well preserved in comparison with the intact organs. To demonstrate the utility of the developed DCL model to cancer research, we engineered three-dimensional tissue constructs by recellularization representative decellularized organs and collagenous hydrogel with human breast cancer cells of pronounced mesenchymal (MDA-MB-231) or epithelial (SKBR-3) phenotypes. The biomechanical properties of the DCL organs were found pivotal to determining the cancer cell fate and progression. Our histological and scanning electron microscopy (SEM) study revealed that the larger the ECM mean pore size and the smaller the total stiffness (as in lung and ovary), the more proliferative and invasive the mesenchymal cells became. At the same time, the low local stiffness ECMs (ranged 2.8–3.6 kPa) did support the epithelial-like SKBR-3 cells’ viability (as in lung and spleen), while stiff ECMs did not. The total and local stiffness of the collagenous hydrogel was measured too low to sustain the proliferative potential of both cell lines. The observed cell proliferation patterns were easily interpretable in terms of the ECM biomechanical properties, such as binding sites, embedment facilities, and migration space. As such, our three-dimensional tissue engineering model is scalable and adaptable for pharmacological testing and cancer biology research of metastatic and primary tumors, including early metastatic colonization in native organ-specific ECM

    Collins and Sivers transverse-spin asymmetries in inclusive muoproduction of ρ0\rho^0 mesons

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    The production of vector mesons in deep inelastic scattering is an interesting yet scarsely explored channel to study the transverse spin structure of the nucleon and the related phenomena. The COMPASS collaboration has performed the first measurement of the Collins and Sivers asymmetries for inclusively produced ρ0\rho^0 mesons. The analysis is based on the data set collected in deep inelastic scattering in 20102010 using a 160GeV/c160\,\,\rm{GeV}/c μ+\mu^+ beam impinging on a transversely polarized NH3\rm{NH}_3 target. The ρ0\rho^{0} mesons are selected from oppositely charged hadron pairs, and the asymmetries are extracted as a function of the Bjorken-xx variable, the transverse momentum of the pair and the fraction of the energy zz carried by the pair. Indications for positive Collins and Sivers asymmetries are observed

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

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    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

    Peculiarities of electron transport and resistive switching in point contacts on TiSe2, TiSeS and CuxTiSe2

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    TiSe2 has received much attention among the transition metals chalcogenides because of its thrilling physical properties concerning atypical resistivity behavior, emerging of charge density wave (CDW) state, induced superconductivity etc. Here, we report discovery of new feature of TiSe2, namely, observation of resistive switching in voltage biased point contacts (PCs) based on TiSe2 and its derivatives doped by S and Cu (TiSeS, CuxTiSe2). The switching is taking place between a low resistive mainly metallic-type state and a high resistive semiconducting-type state by applying bias voltage (usually below 0.5V), while reverse switching takes place by applying voltage of opposite polarity (usually below 0.5V). The difference in resistance between these two states can reach up to two orders of magnitude at the room temperature. The origin of the effect can be attributed to the variation of stoichiometry in PC core due to drift/displacement of Se/Ti vacancies under high electric field. Additionally, we demonstrated, that heating takes place in PC core, which can facilitate the electric field induced effect. At the same time, we did not found any evidence for CDW spectral features in our PC spectra for TiSe2. The observed resistive switching allows to propose TiSe2 and their derivatives as the promising materials, e.g., for non-volatile resistive random access memory (ReRAM) engineering.Comment: 11 pages, 6 figure

    Hypotension-Avoidance Versus Hypertension-Avoidance Strategies in Noncardiac Surgery : An International Randomized Controlled Trial

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    Background: Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively. Objective: To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery. Design: Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723) Setting: 110 hospitals in 22 countries. Patients: 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications. Intervention: In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80mm Hg or greater; before and for 2 days after surgery, renin– angiotensin–aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60mm Hg or greater; all antihypertensive medications were continued before and after surgery. Measurements: The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment. Results: The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P =0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term. Limitation: Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels. Conclusion: In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications.Maura Marcucci, Thomas W. Painter, David Conen, Vladimir Lomivorotov, Daniel I. Sessler, Matthew T.V. Chan, Flavia K. Borges, Kate Leslie, Emmanuelle Duceppe, María Jose Martínez-Zapata, Chew Yin Wang, Denis Xavier, Sandra N. Ofori, Michael Ke Wang, Sergey Efremov, Giovanni Landoni, Ydo V. Kleinlugtenbelt, Wojciech Szczeklik, Denis Schmartz, Amit X. Garg, Timothy G. Short, Maria Wittmann, Christian S. Meyhoff, Mohammed Amir, David Torres, Ameen Patel, Kurt Ruetzler, Joel L. Parlow, Vikas Tandon, Edith Fleischmann, Carisi A. Polanczyk, Andre Lamy, Raja Jayaram, Sergey V. Astrakov, William Ka Kei Wu, Chao Chia Cheong, Sabry Ayad, Mikhail Kirov, Miriam de Nadal, Valery V. Likhvantsev, Pilar Paniagua, Hector J. Aguado, Kamal Maheshwari, Richard P. Whitlock, Michael H. McGillion, Jessica Vincent, Ingrid Copland, Kumar Balasubramanian, Bruce M. Biccard, Sadeesh Srinathan, Samandar Ismoilov, Shirley Pettit, David Stillo, Andrea Kurz, Emilie P. Belley-Côte, Jessica Spence, William F. McIntyre, Shrikant I. Bangdiwala, Gordon Guyatt, Salim Yusuf, and P.J. Devereaux, on behalf of the POISE-3 Trial Investigators and Study Group

    Spin Density Matrix Elements in Exclusive ρ0\rho ^0 Meson Muoproduction

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    We report on a measurement of Spin Density Matrix Elements (SDMEs) in hard exclusive ρ0\rho ^0 meson muoproduction at COMPASS using 160~GeV/cc polarised μ+ \mu ^{+} and μ \mu ^{-} beams impinging on a liquid hydrogen target. The measurement covers the kinematic range 5.0~GeV/c2c^2 <W<< W < 17.0~GeV/c2c^2, 1.0 (GeV/cc)2^2 <Q2<< Q^2 < 10.0 (GeV/cc)2^2 and 0.01 (GeV/cc)2^2 <pT2<< p_{\rm{T}}^2 < 0.5 (GeV/cc)2^2. Here, WW denotes the mass of the final hadronic system, Q2Q^2 the virtuality of the exchanged photon, and pTp_{\rm{T}} the transverse momentum of the ρ0\rho ^0 meson with respect to the virtual-photon direction. The measured non-zero SDMEs for the transitions of transversely polarised virtual photons to longitudinally polarised vector mesons (γTVL\gamma^*_T \to V^{ }_L) indicate a violation of ss-channel helicity conservation. Additionally, we observe a dominant contribution of natural-parity-exchange transitions and a very small contribution of unnatural-parity-exchange transitions, which is compatible with zero within experimental uncertainties. The results provide important input for modelling Generalised Parton Distributions (GPDs). In particular, they may allow one to evaluate in a model-dependent way the role of parton helicity-flip GPDs in exclusive ρ0\rho ^0 production

    Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity

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    Amphipathic perylene derivatives are broad-spectrum antivirals against enveloped viruses that act as fusion inhibitors in a light-dependent manner. The compounds target the lipid bilayer of the viral envelope using the lipophilic perylene moiety and photogenerating singlet oxygen, thereby causing damage to unsaturated lipids. Previous studies show that variation of the polar part of the molecule is important for antiviral activity. Here, we report modification of the lipophilic part of the molecule, perylene, by the introduction of 4-, 8-, and 12-carbon alkyls into position 9(10) of the perylene residue. Using Friedel–Crafts acylation and Wolff–Kishner reduction, three 3-acetyl-9(10)-alkylperylenes were synthesized from perylene and used to prepare 9 nucleoside and 12 non-nucleoside amphipathic derivatives. These compounds were characterized as fluorophores and singlet oxygen generators, as well as tested as antivirals against herpes virus-1 (HSV-1) and vesicular stomatitis virus (VSV), both known for causing superficial skin/mucosa lesions and thus serving as suitable candidates for photodynamic therapy. The results suggest that derivatives with a short alkyl chain (butyl) have strong antiviral activity, whereas the introduction of longer alkyl substituents (n = 8 and 12) to the perylenyethynyl scaffold results in a dramatic reduction of antiviral activity. This phenomenon is likely attributable to the increased lipophilicity of the compounds and their ability to form insoluble aggregates. Moreover, molecular dynamic studies revealed that alkylated perylene derivatives are predominately located closer to the middle of the bilayer compared to non-alkylated derivatives. The predicted probability of superficial positioning correlated with antiviral activity, suggesting that singlet oxygen generation is achieved in the subsurface layer of the membrane, where the perylene group is more accessible to dissolved oxygen

    Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as therapeutic strategy in CLL

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    Dysregulation of messenger RNA (mRNA) translation, including preferential translation of mRNA with complex 5′ untranslated regions such as the MYC oncogene, is recognized as an important mechanism in cancer. Here, we show that both human and murine chronic lymphocytic leukemia (CLL) cells display a high translation rate, which is inhibited by the synthetic flavagline FL3, a prohibitin (PHB)-binding drug. A multiomics analysis performed in samples from patients with CLL and cell lines treated with FL3 revealed the decreased translation of the MYC oncogene and of proteins involved in cell cycle and metabolism. Furthermore, inhibiting translation induced a proliferation arrest and a rewiring of MYC-driven metabolism. Interestingly, contrary to other models, the RAS-RAF-(PHBs)-MAPK pathway is neither impaired by FL3 nor implicated in translation regulation in CLL cells. Here, we rather show that PHBs are directly associated with the eukaryotic initiation factor (eIF)4F translation complex and are targeted by FL3. Knockdown of PHBs resembled FL3 treatment. Importantly, inhibition of translation controlled CLL development in vivo, either alone or combined with immunotherapy. Finally, high expression of translation initiation–related genes and PHBs genes correlated with poor survival and unfavorable clinical parameters in patients with CLL. Overall, we demonstrated that translation inhibition is a valuable strategy to control CLL development by blocking the translation of several oncogenic pathways including MYC. We also unraveled a new and direct role of PHBs in translation initiation, thus creating new therapeutic opportunities for patients with CLL

    Protein compactness and interaction valency define the architecture of a biomolecular condensate across scales

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    Non-membrane-bound biomolecular condensates have been proposed to represent an important mode of subcellular organization in diverse biological settings. However, the fundamental principles governing the spatial organization and dynamics of condensates at the atomistic level remain unclear. The Saccharomyces cerevisiae Lge1 protein is required for histone H2B ubiquitination and its N-terminal intrinsically disordered fragment (Lge11-80) undergoes robust phase separation. This study connects single- and multi-chain all-atom molecular dynamics simulations of Lge11-80 with the in vitro behavior of Lge11-80 condensates. Analysis of modeled protein-protein interactions elucidates the key determinants of Lge11-80 condensate formation and links configurational entropy, valency, and compactness of proteins inside the condensates. A newly derived analytical formalism, related to colloid fractal cluster formation, describes condensate architecture across length scales as a function of protein valency and compactness. In particular, the formalism provides an atomistically resolved model of Lge11-80 condensates on the scale of hundreds of nanometers starting from individual protein conformers captured in simulations. The simulation-derived fractal dimensions of condensates of Lge11-80 and its mutants agree with their in vitro morphologies. The presented framework enables a multiscale description of biomolecular condensates and embeds their study in a wider context of colloid self-organization

    Клинический случай экстрагастроинтестинальной стромальной опухоли в сочетании с синдромом тестикулярной феминизации (синдром Морриса)

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    Background. According to literature data, errors in the diagnosis of gastrointestinal tumors (GIST) are uncommon, accounting for approximately 6% of cases that results in treatment failure. Case report. Here, we describe a rare case of a 58-year-old female patient with extragastrointestinal stromal tumor (EGIST) in the evidence of testicular feminisation syndrome (TFS) – Morris syndrome. This hereditary pathology is associated with complete insensitivity of target organs to androgens and was described in 1953 by the American gynaecologist John Morris. The patient was referred to the cancer clinic, where she was wrongly diagnosed with uterine leiomyoma. Interdisciplinary approach, cancer alarm, active surgical tactics, additional immunohistochemical (IHC) and molecular genetic studies (MGI) allowed verifcation of the true diagnosis. There are reported cases of EGIST of the bladder, prostate, retroperitoneum, mesentery, omentum, and posterior mediastinum. However, we were not able to fnd publications regarding the cases of EGIST originating from the vaginal wall. Combination of TFS and EGIST is a unique case in our clinical practice. Conclusion. The study of rare cases expands the understanding of the molecular pathogenesis of malignancies. Patients with rare types of malignant tumors should be obligatorily examined and treated in specialized cancer clinics with involvement of certifed oncologists, surgeons, chemotherapists, geneticists.Актуальность. В клинической практике встречаются ошибки при диагностике гастроинтестинальных опухолей (GIST), которые, по литературным данным, составляют около 6 %. Описание клинического случая. Представлено редкое клиническое наблюдение манифестации экстрагастроинтестинальной стромальной опухоли на фоне синдрома тестикулярной феминизации (СТФ) – синдрома Морриса. Эта наследственная патология ассоциирована с полной нечувствительностью органов-мишеней к андрогенам и описана американским гинекологом Д. Моррисом в 1953 г. Самостоятельное обращение пациентки в специализированное медицинское учреждение, междисциплинарный подход, онконастороженность, активная хирургическая тактика, выполнение дополнительных иммуногистохимического (ИГХ) и молекулярно-генетических исследований (МГИ) позволили верифицировать диагноз, который ранее был расценен как лейомиома матки. В медицинской литературе описаны единичные случаи экстрагастроинтестинальной опухоли (ЕGIST) мочевого пузыря, предстательной железы, забрюшинного пространства, брыжейки кишки, сальника, заднего средостения, однако ни одного случая ЕGIST, происходящей из стенки влагалища. СТФ в сочетании с ЕGIST является уникальным случаем в нашей клинической практике. Заключение. Изучение редких случаев расширяет представление о природе злокачественных новообразований. Пациенты с редкими видами злокачественных опухолей должны в обязательном порядке проходить обследование и лечение в специализированных онкологических учреждениях с привлечением сертифицированных специалистов: онкологов, хирургов, химиотерапевтов, генетиков
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