β2 adrenergic receptor desensitization through chronic stimulation of Natural Killer cells

Stress is a ubiquitous phenomenon that impacts the health of populations across all social strata. While acute stress can be beneficial, chronic stress elevates the risk for various diseases. A major part of the body’s stress response operates through the Sympathetic-Adrenal-Medullary (SAM) axis, leading to the release of epinephrine. This stress mediator can impact the immune system and alter the immune defense response. Natural Killer (NK) cells play a critical role in early immune responses, defending against pathogens and malignant cells. During stressful situations, NK cells are recruited to the blood circulation within minutes. The expression of adrenergic receptors, particularly β2 adrenergic receptors (β2AR), renders them sensitive to epinephrine. This study analyzed the response of NK cells to acute and chronic β2AR stimulation. We confirmed that acute β2AR stimulation inhibits NK cell functions in vitro. Epinephrine showed potent inhibitory effects, suppressing the activation of NK cells independent of the activation signal. The β2AR stimulation reduced NK cell adhesion, IFNγ secretion, degranulation, and cytotoxicity. We could show that β2AR stimulation effectively blocked the LFA-1 activity and led to the detachment from its ligand ICAM-1. The effect was rescued through the addition of Propranolol, a beta blocker, or ADRB2 knock out implicating LFA-1 inhibition as critical role for NK cell mobilization. The metabolic analysis revealed that β2AR agonists influenced the metabolic profile upon NK cell activation, leading to a prolonged glycolysis activity displayed by Seahorse ECAR values. In contrast, chronic β2AR stimulation nullified NK cell inhibition. After five days of β2AR treatment, NK cells were no longer responsive to a β2AR agonist. Chronic β2AR stimulation did not alter protein translation but led to receptor phosphorylation through the PKA feedback loop, initiating a G-protein switch and receptor desensitization. The β2AR treatment with long-acting β2 agonist (LABA) Indacaterol and epinephrine displayed different properties. While epinephrine inhibited NK cells only transiently as long as the β2AR agonist was abundant, Indacaterol could not be washed away and continuously stimulated the receptor. For this reason, a single LABA treatment was sufficient to induce NK cell desensitization. However, peripheral NK cells from LABA-treated patients remained responsive to epinephrine. They did not exhibit inhibition but showed an overall correlation in NK cell fitness with asthma severity. Taken together, the transient, inhibitory effect of epinephrine indicate that the hormone plays a crucial role in NK cell recruitment during acute stressful situations while repeated β2AR stimulation leads to desensitization

The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells

Background: Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Methods: Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. Results: HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Conclusion: Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.<br

A time-resolved proteomic and prognostic map of COVID-19.

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version

The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells

BACKGROUND: Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. METHODS: Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. RESULTS: HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. CONCLUSION: Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors

Studying the abnormal formation pressure zones by analyzing seismic field attributes on the example of Western Siberia deposits

Бурение глубоких скважин во многих районах мира, особенно в трещинно-кавернозных коллекторах сталкивается с рядом проблем, часть из которых имеет геологическую природу, а часть - техническую. В частности, осложнения могут вызывать аномально высокие пластовые давления. В настоящее время зафиксирован рост числа скважин (в том числе и аварийных) с установленным аномально высоким пластовым давлением. По этой причине актуальность исследований в области прогноза зон с аномально высоким пластовым давлением, в частности для предотвращения аварийных ситуаций, возросла. Повышенное внимание к изучению зон аномально высокого пластового давления и формированию механизма их прогноза начало уделяться в последней трети 20-го столетия. Изучалась геологическая природа и механизмы возникновения этих зон, пространственные закономерности их локализации. Кроме того, были предложены способы прогноза их появления, которые можно было бы использовать при проектировании скважин и в процессе бурения. Авторами приведѐн анализ известной геологической информации о формировании и пространственной приуроченности зон аномально высокого пластового давления. Кроме того, показано, что с зонами аномально высоких пластовых давлений могут быть связаны значительные изменения сейсмических атрибутов. Обобщенный анализ приведѐнных данных позволяет нам сказать, что зоны аномально высокого пластового давления достаточно широко распространены в осадочном чехле, в том числе и на участке нашего исследования. Существующая проблема связи аномально высокого пластового давления с сейсмическими атрибутами далека от окончательного решения. Правильный прогноз оценки пластовых давлений дает возможность вести бурение в оптимальных режимах. Задача прогнозирования зон аномально высокого пластового давления, дренирующих толщи коллекторов на этом месторождении насущна и актуальна, поскольку в настоящее время его разбуривание продолжается по сети эксплуатационных скважин Цель: использование сейсмические атрибуты для контроля и уточнения динамической модели резервуара; выявление зон аномально высокого пластового давления в разрезах месторождения углеводородов по данным сейсморазведки (сейсмическим атрибутам). Объекты: породы со сложным строением пустотного пространства, обусловленным повышенными трещиноватостью и кавернозностью, которые образовались за счет тектонических дислокаций в осадочном чехле. Методы: теоретическое и экспериментально обоснование связи зон аномально высокого пластового давления и сейсмических данных. Результаты. Были построены карты вероятностей распределения пластового давления по площади в межскважинном пространстве на изучаемое месторождение.Deep wells drilling in many parts of the world, especially in fractured cavernous reservoirs, faces a number of difficulties, both of technical and geological nature such as, the manifestations of abnormally high formation pressure. With the increase in the number of wells with abnormally high formation pressure, and the number of cases of emergency situations, it became absolutely necessary to study this problem in order to prevent negative consequences. The proper study of abnormally high formation pressure started in the late 70-s to the 90-s of the last century. The geological features, patterns, mechanisms for formation of abnormally high formation pressure were studied and various techniques and methods for assessment of reservoir pressures both before and during well drilling were developed. This article analyzes geological information on the development and distribution of abnormal pressures. It is shown that zones of abnormally high formation pressures can be associated with significant changes in the seismic field, that is, seismic attributes. The generalized analysis of presented data allows determining that the zones of abnormally high formation pressure are quite widespread in the sedimentary cover, including in the area of the study. The existing problem of the connection of abnormally high formation pressure with seismic attributes is far from the final solution. A correct forecast of formation pressure assessment makes it possible to conduct drilling in optimal conditions. The task of the prediction of abnormally high formation pressure zones draining reservoir strata in this field is relevant and urgent, since at present it is being drilled through a network of production wells. The aim of the research is the use of seismic attributes to control the development and refinement of a dynamic tank model; identification of abnormally high formation pressure zones in the sections of the hydrocarbon field according to seismic data (seismic attributes). Objects: rocks with a complex structure of the void space due to intense cavernosity and fracturing formed at the expense of tectonic dislocations in the sedimentary cover. Methodology: theoretical and experimental justification of the connection of abnormally high formation pressure zones and seismic data. Results. The authors have constructed the maps of reservoir pressure distribution across the area in the interwell space for gas condensate field under study