Reactive Events Research Articles

Herpes Simplex Virus 1 Small Noncoding RNAs 1 and 2 Activate the Herpesvirus Entry Mediator Promoter.

Herpes simplex virus 1 (HSV-1) latency-associated transcript (LAT) plays a significant role in efficient establishment of latency and reactivation. LAT has antiapoptotic activity and downregulates expression of components of the type I interferon pathway. LAT also specifically activates expression of the herpesvirus entry mediator (HVEM), one of seven known receptors used by HSV-1 for cell entry that is crucial for latency and reactivation. However, the mechanism by which LAT regulates HVEM expression is not known. LAT has two small noncoding RNAs (sncRNAs) that are not microRNAs (miRNAs), within its 1.5-kb stable transcript, which also have antiapoptotic activity. These sncRNAs may encode short peptides, but experimental evidence is lacking. Here, we demonstrate that these two sncRNAs control HVEM expression by activating its promoter. Both sncRNAs are required for wild-type (WT) levels of activation of HVEM, and sncRNA1 is more important in HVEM activation than sncRNA2. Disruption of a putative start codon in sncRNA1 and sncRNA2 sequences reduced HVEM promoter activity, suggesting that sncRNAs encode a protein. However, we did not detect peptide binding using two chromatin immunoprecipitation (ChIP) approaches, and a web-based algorithm predicts low probability that the putative peptides bind to DNA. In addition, computational modeling predicts that sncRNA molecules bind with high affinity to the HVEM promoter, and deletion of these binding sites to sncRNA1, sncRNA2, or both reduced HVEM promoter activity. Together, our data suggest that sncRNAs exert their function as RNA molecules, not as proteins, and we provide a model for the predicted binding affinities and binding sites of sncRNA1 and sncRNA2 in the HVEM promoter. IMPORTANCE HSV-1 causes recurrent ocular infections, which is the leading cause of corneal scarring and blindness. Corneal scarring is caused by the host immune response to repeated reactivation events. LAT functions by regulating latency and reactivation, in part by inhibiting apoptosis and activating HVEM expression. However, the mechanism used by LAT to control HVEM expression is unclear. Here, we demonstrate that two sncRNAs within the 1.5-kb LAT transcript activate HVEM expression by binding to two regions of its promoter. Interfering with these interactions may reduce latency and thereby eye disease associated with reactivation.

Abstract P252: IMM-1-104: a novel, oral, selective dual-MEK inhibitor that displays broad antitumor activity and high tolerability across RAS and RAF mutant tumors in vivo

Abstract Background: Inappropriate activation of the MAPK pathway, often stemming from mutations in RAS or RAF, represents one of the most common oncogenic events in human cancer. Therefore, MEK1 and MEK2 (MEK), which lie downstream of RAS and RAF but upstream of ERK, have represented an attractive drug target for over two decades. Unfortunately, first generation MEK inhibitors have been limited by pathway reactivation events and serious on-target drug toxicities that restrain clinical utility, especially in patients with RAS mutant tumors. We sought to develop a new approach to MEK inhibition that would be more effective in RAS mutant tumors and with improved tolerability. IMM-1-104 is a novel dual-MEK inhibitor that is designed to disrupt phosphorylation of MEK and subsequently prevent activation of ERK1 and ERK2 (ERK). IMM-1-104’s dual-MEK mechanism resists RAF activation of MEK, and its short drug half-life allows for chronic dosing while maintaining a near-zero drug trough for improved tolerability. Materials & Methods: IMM-1-104 was profiled across a series of preclinical experiments to assess its physicochemical and drug-like properties. Cell-free and cell-based in vitro as well as in vivo characteristics were evaluated, including four independent in vivo pharmacology rodent studies in lung, colon and skin tumor models. Results: IMM-1-104 is a highly selective, orally bioavailable, non-ATP competitive, allosteric dual-MEK inhibitor. At drug exposures up to 1 micromolar (uM) in cell-free and in situ kinome screens, thermodynamic interactions and altered activity levels were observed for MEK1 and MEK2. At higher drug exposures up to 10 uM, IMM-1-104 also thermodynamically interacted with RAF1 (CRAF) and prompted reduction of KSR1 and KSR2 activation markers. IMM-1-104 displayed dual-MEK activity (i.e., RAS mutant tumor cell reductions in both ERK and MEK phosphorylation) across multiple human tumor cell-based models including A549 (KRAS-G12S) lung, A375 (BRAF-V600E) and SK-MEL-2 (NRAS-Q61R) melanoma. Pharmacokinetic studies in rodent models revealed a drug plasma half-life for IMM-1-104 of approximately 1.3 hours. In vivo tumor pharmacology studies in A549 and A375 achieved tumor stasis (i.e., 85% to 95% Tumor Growth Inhibition) with regressions observed in Colon-26 and SK-MEL-2. Conclusions: The dual-MEK mechanism and short half-life of IMM-1-104 has proven to be broadly active and well-tolerated in multiple RAS and RAF mutant preclinical tumor models in rodents. IMM-1-104 drives deep, cyclic inhibition of the MAPK pathway (improving tolerability) while resisting pathway bypass mechanisms (improving activity). Our collective data suggest that RAS and RAF mutant tumor cells are not able to tolerate periods of deep but cyclic MAPK pathway inhibition. Overall, these results are consistent with on and off signaling events that can significantly impact cell fate decisions (i.e. signaling dynamics). Citation Format: Peter J. King, Kevin D. Fowler, Sarah E. Kolitz, Scott Barrett, Benjamin J. Zeskind, Brett M. Hall. IMM-1-104: a novel, oral, selective dual-MEK inhibitor that displays broad antitumor activity and high tolerability across RAS and RAF mutant tumors in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P252.

Single-cell transcriptomics identifies Gadd45b as a regulator of herpesvirus-reactivating neurons.

Single-cell RNA sequencing (scRNA-seq) is a powerful technique for dissecting the complexity of normal and diseased tissues, enabling characterization of cell diversity and heterogeneous phenotypic states in unprecedented detail. However, this technology has been underutilized for exploring the interactions between the host cell and viral pathogens in latently infected cells. Herein, we use scRNA-seq and single-molecule sensitivity fluorescent in situ hybridization (smFISH) technologies to investigate host single-cell transcriptome changes upon the reactivation of a human neurotropic virus, herpes simplex virus-1 (HSV-1). We identify the stress sensor growth arrest and DNA damage-inducible 45 beta (Gadd45b) as a critical antiviral host factor that regulates HSV-1 reactivation events in a subpopulation of latently infected primary neurons. We show that distinct subcellular localization of Gadd45b correlates with the viral late gene expression program, as well as the expression of the viral transcription factor, ICP4. We propose that a hallmark of a "successful" or "aborted" HSV-1 reactivation state in primary neurons is determined by a unique subcellular localization signature of the stress sensor Gadd45b.

Serum thromboxane B2 but not soluble P-selectin levels identify ischemic stroke patients with persistent platelet reactivity while on aspirin therapy

BackgroundAspirin non-response due to persistent platelet reactivity has been associated with adverse vascular events. Light transmission aggregometry (LTA), the ‘gold standard’ for measuring the platelet response to aspirin therapy, is a cumbersome procedure and a simple and reliable alternative is required. Our aim was to explore whether serum thromboxane B2 (sTXB2) and soluble P-selectin can be used to identify patients who are at risk of increased platelet reactivity while on aspirin. Methods and resultsWe recruited 293 ischemic stroke patients, taking aspirin for more than seven days, and performed LTA to classify them. Based on therapeutic serum salicylate levels, 63 patients were excluded due to suspected non-compliance, followed by ELISA measurement of TXB2 and P-selectin in serum. Accordingly, patients were classified into ‘Responders’ (n = 122, 53%), ‘Semi-responders’ (n = 76, 33%) and ‘Non-responders’ (n=32, 14%) by LTA. Patients who had platelet aggregation of ≥70% with 10μM ADP and ≥20% with 0.5mM AA were defined as ‘Non-responders’. In comparison with ‘Responders’, ‘Non-responders’ had 8.63-fold increased risk of secondary vascular events (p = 0.008). ROC curve analysis revealed that sTXB2, at a cut-off level of >4.15 ng/mL, could distinguish the patient group with elevated platelet reactivity with a sensitivity of 84.3% (AUC = 0.84), and was in fair agreement with the LTA-based classification of patients. Soluble P-selectin levels, on the other hand, had no discriminatory ability. ConclusionWe suggest sTXB2 measurement as an alternative to the LTA approach for identifying aspirin-treated ischemic stroke patients who are at risk of enhanced platelet reactivity and subsequent vascular events.

Volcanological evolution of Montagne Pelée (Martinique): A textbook case of alternating Plinian and dome-forming eruptions

Montagne Pelée is one of the most active volcanoes of the Lesser Antilles arc, with two to three magmatic eruptions per millennium and an estimated magmatic production rate in the order of 0.7 km3/1000 years. Montagne Pelée is also infamous for the very large number of people (30000) killed by an eruptive phenomenon at the onset of the 1902–1905 dome-forming eruption. Active for ~550 kyrs, Montagne Pelée has undergone two major flank collapses that influenced its volcanological as well as magmatic evolution. The last one occurred at around 36 ka. Due to changes in the threshold effect following the decrease in load of the volcanic edifice due to flank collapse, there was a switch in emitted magma from generally andesitic to basaltic andesites. After 10 kyrs of intense activity, the load exerted by the new edifice once again prevented dense basaltic andesite magma from reaching the surface, whereas andesitic magmas, similar to the initial ones, continued to be emitted. All the magmas come from a common magma ponding zone at 200 ± 50 MPa, 875 ± 25 °C, an oxygen fugacity (fO2) between 0.4 and 0.8 log unit above the nickel‑nickel oxide (NNO) oxygen buffer, and melt H2O contents of 5.3–6.3 wt%. Based on comparative on-land and marine tephrochronological studies, we have reconstructed a detailed eruptive history of the volcano over the last 25 kyrs. The volcano produced a succession of Plinian-SubPlinian and dome-forming eruptions, making it a textbook case for studying this duality, which sometimes occurred during a single eruption. We identified more than 55 magmatic eruptions, with a ratio of 2/3 for dome-forming vs. Plinian eruptions. An unusual feature of this volcano is that dome-forming eruptions often start with violent, superficial and laterally directed explosions. These generate highly devastating dilute and turbulent pyroclastic density currents on the southwestern and southern flanks of the volcano, as illustrated by the seven events of this type during the first months of the 1902–1905 eruption. On the basis of the past eruptions over the last millennia, a series of scenarios can be proposed in the event of reactivation, including no magmatic eruption, a phreatic event or a magmatic eruption (Plinian or dome-forming eruption, with or without an explosive phase).

Reinforcement learning of rare diffusive dynamics.

We present a method to probe rare molecular dynamics trajectories directly using reinforcement learning. We consider trajectories that are conditioned to transition between regions of configuration space in finite time, such as those relevant in the study of reactive events, and trajectories exhibiting rare fluctuations of time-integrated quantities in the long time limit, such as those relevant in the calculation of large deviation functions. In both cases, reinforcement learning techniques are used to optimize an added force that minimizes the Kullback-Leibler divergence between the conditioned trajectory ensemble and a driven one. Under the optimized added force, the system evolves the rare fluctuation as a typical one, affording a variational estimate of its likelihood in the original trajectory ensemble. Low variance gradients employing value functions are proposed to increase the convergence of the optimal force. The method we develop employing these gradients leads to efficient and accurate estimates of both the optimal force and the likelihood of the rare event for a variety of model systems.

Rational Design of Live-Attenuated Vaccines against Herpes Simplex Viruses.

Diseases caused by human herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) affect millions of people worldwide and range from fatal encephalitis in neonates and herpes keratitis to orofacial and genital herpes, among other manifestations. The viruses can be shed efficiently by asymptomatic carriers, causing increased rates of infection. Viral transmission occurs through direct contact of mucosal surfaces followed by initial replication of the incoming virus in skin tissues. Subsequently, the viruses infect sensory neurons in the trigeminal and lumbosacral dorsal root ganglia, where they are primarily maintained in a transcriptionally repressed state termed “latency”, which persists for the lifetime of the host. HSV DNA has also been detected in other sympathetic ganglia. Periodically, latent viruses can reactivate, causing ulcerative and often painful lesions primarily at the site of primary infection and proximal sites. In the United States, recurrent genital herpes alone accounts for more than a billion dollars in direct medical costs per year, while there are much higher costs associated with the socio-economic aspects of diseased patients, such as loss of productivity due to mental anguish. Currently, there are no effective FDA-approved vaccines for either prophylactic or therapeutic treatment of human herpes simplex infections, while several recent clinical trials have failed to achieve their endpoint goals. Historically, live-attenuated vaccines have successfully combated viral diseases, including polio, influenza, measles, and smallpox. Vaccines aimed to protect against the devastation of smallpox led to the most significant achievement in medical history: the eradication of human disease by vaccination. Recently, novel approaches toward developing safe and effective live-attenuated vaccines have demonstrated high efficacy in various preclinical models of herpetic disease. This next generation of live-attenuated vaccines has been tailored to minimize vaccine-associated side effects and promote effective and long-lasting immune responses. The ultimate goal is to prevent or reduce primary infections (prophylactic vaccines) or reduce the frequency and severity of disease associated with reactivation events (therapeutic vaccines). These vaccines’ “rational” design is based on our current understanding of the immunopathogenesis of herpesviral infections that guide the development of vaccines that generate robust and protective immune responses. This review covers recent advances in the development of herpes simplex vaccines and the current state of ongoing clinical trials in pursuit of an effective vaccine against herpes simplex virus infections and associated diseases.

The role of intracratonic crustal reworking in the tectonic compartmentalization of the Juruena Terrane, SW Amazonas Craton: the Roosevelt-Guariba Transpressive Belt

The multiscale structural analysis carried out in the NNW sector of the Juruena Terrane, SE of the State of Amazonas combines structural mapping, microtectonic analysis and aeromagnetic data analysis. It shows a complex structural and metamorphic history composed of successive deformation events, responsible by the formation of its tectonic framework. Event D2 (1520-1460 Ma) is responsible for the main structure of the NNW sector of the Juruena Terrane, and it generates a dextral transpressive shear zone NW-SE, called Roosevelt-Guariba Transpressive Belt (RGTB). This is an intracontinental high-temperature, medium-pressure tectonothermal event, compatible with the conditions of the upper amphibolite to granulite facies. The RGTB controls the tectonic compartmentation of the region, particularly affecting the Granitic Gneiss Domain (1760-1750 Ma). Other sectors, such as the Supracrustal Rock Domain (1800-1730 Ma) and the Pre-Juruena geological-structural association (>1830 Ma), are subordinately affected. Event D2 overlaps the regional structure E-W (ENE-WSW) attributed to Event D1 (1690-1630 Ma), which is restricted to the deep basement in the NNW sector, but dominant in the south central sector of the Juruena Terrane. There are also two late brittle-ductile to brittle deformation events (events D3 and D4). Event D3 (1320-1300 Ma) is represented by NE-SW cataclastic and shear zones, commonly serving as conduits for hydrothermal fluids relative to gold mineralizations. Event D4 is constituted by normal faults and fractures that reactivate RGTB shear zones, limiting Neoproterozoic and Paleozoic-Mesozoic sedimentary exposures. The tectonic structural model proposed in this study reinforces the interpretation that the Juruena Terrane evolved from a foreland basin, which was formed during the Juruena Orogen and whose basement is the Tapajos Crust. This basin was preserved from the tectono-thermal effects of the end of the Statherian (D1), and it was only during event D2, after emplacement of the RGTB, that it underwent high-grade deformation and metamorphism, whose driving force is attributed to the propagation of stresses in pericratonic regions, associated with Calymmian orogens. The successive events are related to the cratonization of the Juruena Terrane, represented by late crust reactivation (D3) and neotectonic events (D4).

Structure and Composition of Basement and Sedimentary Cover in the Southwestern Part of the Siljan Ring, Central Sweden: New Data from the C-C-1 Drill Core

The results from the geological and geophysical investigations of the Siljan Ring impact structure (central Sweden) have shown that the Paleozoic sedimentary succession and the Precambrian basement were strongly affected by complex deformational processes. Studies of a new drill core from the C-C-1 well provide valuable additional information necessary for the reconstruction of the geological setting in the southwestern part of the Siljan Ring. It was found that the contact between the basement and the sedimentary cover is tectonic, not normal sedimentary, in origin. The basement interval comprises Precambrian metavolcanic and metasedimentary rocks with a single mafic intrusion (gabbro-dolerite) in the upper part. The rocks have only been partially metamorphosed. The intercalation of calcareous mudstones, skeletal wackstones, and black shales in the sedimentary cover interval is not consistent with the regional lithostratigraphy scheme. Thus, more likely that the sedimentary sequence is not complete as a result of tectonic displacements, and a significant part of the Lower and Middle Ordovician succession is missing. The Post-Proterozoic tectonic reactivation and impact event also caused the formation of four types of fracture. The third type of fracture is accompanied by cataclastic zones and probably have an impact-related nature. In the highly fractured basement rocks, a dissolution along the second type of fracture has resulted in the development of open vugs. Open vugs and microporosity in cataclastic zones have been considered to be an effective storage space for hydrocarbons.

Diels–Alder Reaction in a Molecular Junction

We computationally investigate the utility of molecular junctions to probe chemical reactivity at the single-molecule limit. To do so, we employ molecular dynamics (MD) coupled to quantum transport simulations to investigate the classic Diels–Alder reaction but in the context of nanoscale junctions where the reactants are nanoconfined and the reactive pair is mechanically brought to proximity. To capture reactive events, the MD employs the density functional tight binding method to account for interatomic interactions. To understand the thermodynamic driving forces behind the reaction in this novel chemical environment, we reconstruct the potential of mean force along the reaction coordinate and decompose it into energetic and entropic contributions. The analysis demonstrates that the process is entropically penalized, which makes the reaction barrier sensitive to changes in the temperature and reactant rigidity. The simulations further show that in nanojunctions the degree of reactivity can be mechanically manipulated simply by controlling the proximity of the electrodes. Surprisingly, for optimal electrode separations, the entropic and energetic cost in the nanoconfined reaction coincides with that observed in bulk, establishing a clear connection between measurements performed in these two vastly different reactive environments. Finally, we show how conductance measurements can be used to experimentally monitor the process at the single-entity limit.

Risk of Hepatitis B Virus Reactivation in Patients Treated With Immunotherapy for Anti-cancer Treatment

Background & AimsHepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology. MethodsThis historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment. ResultsThe mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3–4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients. ConclusionsIn general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.

Clinical Impact of the Immune Reconstitution Status on 100 Day after Allogeneic Stem Cell Transplantation with Fludarabine Based Conditioning

Background: Immune reconstitution following allogeneic stem cell transplantation (SCT) can be affected by many variables in the transplant process such as the particular conditioning regimen, donor type, GVHD prophylaxis, and so on. We assessed clinical factors to contribute to the immune reconstitution status at 100 days after allogeneic SCT in patients received fludarabine based conditioning.Methods: 114 patients received allogeneic SCT were divided into two groups according to the immune recovery status at D+100 days after SCT. Immunophenotypic analysis using flowcytometry was performed to evaluate the percentage and the absolute numbers of T cell subsets (CD3+, CD4+, and CD8+ cells), NK cells (CD16+CD56+ cells), and B cells (CD19+ cells) with serum immunoglobulin levels as well as clinical outcomes were investigated.Results: Disease status at the time of SCT (HR 2.54, p=0.034), risk stratification by HCI-CI (HR 2.94, p=0.000), and chronic GVHD (HR 0.30, p=0.006) were significantly associated with survival outcome, while grade II~IV GVHD tended to have a negative effect on overall survival without statistical significance (HR 1.74, p=0.068). Tacrolimus based GVHD prophylactic regimen and T cell depletion with anti-thymocyte globulin or alemtuzumab (HR 6.71, p < 0.001) were significantly associated with delayed immune reconstitution of T cell subsets. T cell depletion seemed to be associated with worse overall survival. The incidence of chronic GVHD was significantly increased in normal recovery group compared to that of abnormal group (p=0.01). In addition, Ebstein-Barr virus reactivation was more frequent in abnormal group of T cell subsets (p=0.045). Events of all viral reactivation including CMV reactivation seemed to be more frequent in abnormal group of T cell subsets.Conclusions: Immune reconstitution after SCT was affected by tacrolimus based GVHD prophylasis and T cell depletion. Delayed immune reconstitution might cause increased morbidity from viral reactivation. We need strategies to prevent infectious complications and enhance immune reconstitution according the immune recovery status following SCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

HBV Care Map for Patients Receiving Anti-CD20 Therapy

Background:Chronic Hepatitis B Virus (HBV) and so-called “resolved” HBV infections (HBsAg negative and anti-HBc positive) can be reactivated secondary to anti-CD20 therapy mediated immunosuppression used in the treatment of cancer and many non-malignant conditions. HBV reactivation can lead to delays in curative chemotherapy as well as HBV specific complications including liver failure and death. Appropriate screening, monitoring and treatment of HBV is integral to the safe administration of anti-CD20 therapies. However, current available guidelines for the management of HBV in patients receiving anti-CD20 therapies rely on a weak body of evidence and provide recommendations that do not adequately address all aspects of care.Objective:To provide a unified care map for the management of HBV in patients undergoing treatment with anti-CD20 therapies.Methods:A Delphi consensus technique was applied to a multidisciplinary panel of 10 North American experts in HBV or anti-CD20 therapy. The processed occurred over a 20-month period culminating in November 2014. To achieve a comprehensive overview, pharmacists, physicians and a nurse practitioner were included as team members. A preliminary HBV care map was generated based on literature review in conjunction with iterative questionnaires completed by panel members. Panelists were asked to rate their level of agreement across multiple domains of HBV care including screening, treatment and monitoring of patients. Consensus was achieved when there was greater than 75% agreement for all HBV care map elements. The HBV care map was subsequently revised and approved by all members at a face-to-face panel meeting.Results:The HBV care map recommends universal screening for all patients receiving anti-CD20 therapy. Patients with positive screening results are stratified into parallel, chronic and resolved HBV tracks. Both patients with chronic and resolved HBV should be started on antiviral treatment (or prophylaxis) prior to beginning anti-CD20 therapy. Entecavir is recommended as first line therapy over tenofovir disoproxil fumarate or lamuvidine. Where cost is a major factor, lamuvidine may be acceptable with close monitoring for viral resistance. Patients require routine monitoring for HBV reactivation (q3-6 months depending on care approach) from the initiation of anti-CD20 therapy until at least one year following discontinuation of immunosuppression. HBV DNA is recommended as the optimal test for HBV reactivation status as it is sensitive and can identify early reactivation events. Monitoring for HBsAg reverse seroconversion can also be used in resolved HBV but is not prioritized in the care map due to limited data demonstrating the safety of this approach.Conclusion:The HBV care map incorporates best available evidence and expert consensus building to provide clear and pragmatic guidance to clinicians managing HBV in patients receiving anti-CD20 therapies. In the rapidly changing clinical environment there is a need to quickly respond to growing risks associated with the development of new immunosuppressive treatments. The development of specific and valid guidelines in areas with limited published studies is an i2mportant step in improving the safe delivery of cancer care. This will also serve as the foundation for current and future prospective studies in the care of HBV among immunosuppressed patients. [Display omitted] DisclosuresCrump:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Ortho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hwang:Gilead Sciences: Research Funding; Merck: Research Funding. Yim:Gilead Sciences: Consultancy, Honoraria. Zelenetz:Celgene: Consultancy; Amgen: Consultancy. Feld:Gilead Sciences: Research Funding. Hicks:Gilead Sciences: Research Funding.

The Safety and Immunogenicity of the mRNA-BNT162b2 SARS-CoV-2 Vaccine in Hemodialysis Patients.

BackgroundHemodialysis patients are at high risk for severe COVID-19. SARS-CoV-2 vaccination related safety and immunogenicity data in these patients are rare.MethodsIn this observational study SARS-CoV-2-seronegative hemodialysis patients were vaccinated with two doses of the Pfizer/BioNTech mRNA-BNT162b2 vaccine (COMIRNATY® 30 µg) and followed for 90 days. Local and systemic side effects were assessed at every dialysis session during the first post-vaccination week after the first and second vaccine dose. Immunogenicity was determined four weeks after vaccination by quantifying anti-SARS-CoV-2 spike protein IgG antibodies (LIAISON® SARS-CoV-2-TrimericS IgG chemiluminescent immunoassay) expressed in binding activity units per milliliter (BAU/mL) adapted to the WHO International standard.ResultsFifty patients (32% women, 68% men) with a mean (SD) age of 67.6 (14.8) years were included. Mild local reactions occurred in 38% after the first injection, and in 29.2% with mild, in 2.1% with moderate and in 2.1% with severe degree after the second injection. Systemic reactive events occurred less often, with diarrhea (4% mild, 4% moderate) and fatigue (8% mild) being the most frequent ones. After the first injection 42% of the patients developed a positive response using the assay specific cut-off value of 33.8 binding activity units per milliliter (BAU/mL) with a median (Q1, Q3) anti-SARS-CoV-2 spike IgG concentration of 20.0 (11.7, 51.0) BAU/mL. After the second injection the percentage of seropositive patients increased to 97.9% with an anti-SARS-CoV-2 spike IgG concentration of 1075 (290.8, 1735) BAU/mL. Higher age and immunosuppression were associated with lower, calcitriol treatment and prior seroconversion to hepatitis B vaccination with significantly higher antibody concentration.ConclusionsThe mRNA-BNT162b2 SARS-CoV-2 vaccine appears to be safe and well-tolerated and shows a high immunogenicity in hemodialysis patients.

Reconstructing craton‐scale tectonic events via in situ Rb‐Sr geochronology of poly‐phased vein mineralization

AbstractFault‐ and fracture‐hosted multi‐stage mineral assemblages that formed by fracture reactivation and fluid migration, constitute archives of the tectonic evolution of Precambrian cratons. Complex intergrowth patterns of these mineral records often hinder absolute dating of mineralization events for geological models. We apply LA‐ICP‐MS/MS in situ Rb‐Sr dating of single crystal growth zones in sub‐mm‐wide vein mineralization assemblages including illite, K‐feldspar, albite, calcite, mica, zeolites, fluorite and/or epidote at three Palaeoproterozoic crystalline bedrock sites over 300 km apart in the Fennoscandian Shield. The dating campaign reveals multiple age clusters between ca. 1757 ± 15 and 355 ± 12 Ma correlating with fluid flow and fracture reactivation events initiated by far‐field orogens and their foreland basin evolution. This new approach for reconstructing geological histories of Precambrian cratons connects micro‐scale age determinations of different mineral growth zones in fractures with regional‐scale crustal dynamic responses to tectonic events.

Use of Local Seismic Network in Analysis of Volcano-Tectonic (VT) Events Preceding the 2017 Agung Volcano Eruption (Bali, Indonesia)

This study provides an attempt to analyze the pre-eruptive seismicity events for volcano eruption forecasting. After more than 50 years of slumber, Agung volcano on Bali Island erupted explosively, starting on November 21, 2017. The eruption was preceded by almost 2 months of significant increase of recorded seismicity, herein defined as “seismic crisis.” Our study provides the first analysis of VT events using data from eight local seismic stations deployed by the Center for Volcanology and Geological Hazard Mitigation of Indonesia (CVGHM) to monitor the Agung Volcano activity. In total, 2,726 Volcano-Tectonic (VT) events, with 13,023 P waves and 11,823 S wave phases, were successfully identified between October 18 and November 30, 2017. We increased the accuracy of the hypocenter locations of these VT events using a double-difference (DD) relative relocation and a new velocity model appropriate to the subsurface geological conditions of Agung volcano. We found two types of seismicity during the recording period that represent the VT events relating to fracture network reactivation due to stress changes (during the seismic crisis) and magma intrusion (after the seismic crisis). The characteristics of each event type are discussed in terms of Vp/Vs values, phase delay times, seismic cluster shapes, and waveform similarity. We interpret that the upward migrating magma reached a barrier (probably a stiff layer) which prohibited further ascent. Consequently, magma pressurized the zone above the magma chamber and beneath the barrier, reactivated the fracture zone between Agung and Batur volcanoes, and caused the seismic crisis since September 2017. In early November 2017, the barrier was finally intruded, and magma and seismicity propagated toward the Agung summit. This reconstruction provides a better depth constraint as to the previous conceptual models and explains the long delay (∼10 weeks) between the onset of the seismic crisis and the eruption. The distinction between the fracture reactivation and magma intrusion VT events observed in this study is significant for eruption forecasting and understanding the subsurface structure of the magmatic system. Based on the results obtained in this study, we emphasize the importance of prompt analysis (location and basic seismic characteristics) of the seismic crisis preceding the Agung eruption.

Ansa-Zirconocene Catalysts for Isotactic-Selective Propene Polymerization at High Temperature: A Long Story Finds a Happy Ending

Absolute rigidity is rare in the "soft" world of organometallics. Here we introduce two cyclopenta[a]triptycyl ansa-zirconocene catalysts for isotactic-selective propene polymerization, designed by means of an integrated high-throughput experimentation/quantitative structure-activity relationship modeling approach. An ultrarigid ligand precisely wrapped around the Zr center enforces an enzyme-like lock and key fit, effectively hampering undesired reactive events, even at high temperature. Stereodefective units are hardly detectable by 13C NMR in the polymer produced at 120 °C; this corresponds to an enantioselectivity exceeding 6-7 kcal/mol: i.e., less than 1 propene misinsertion every 4000 (and at room temperature, one every ∼40000!).

ADP-induced platelet reactivity and bleeding events in patients with acute myocardial infarction complicated by cardiogenic shock

While previous reports showed ADP-induced platelet reactivity to be an independent predictor of bleeding after PCI in stable patients, this has never been investigated in patients with cardiogenic shock. The association of bleeding events with respect to ADP-induced platelet aggregation was investigated in patients undergoing primary PCI for acute myocardial infarction complicated by cardiogenic shock and with available on-treatment ADP-induced platelet aggregation measurements. Out of 233 patients, 74 suffered from a severe BARC3 or higher bleed. ADP-induced platelet aggregation was significantly lower in patients with BARC≥3 bleedings (p < .001). Multivariate analysis identified on-treatment ADP-induced platelet aggregation as an independent risk factor for bleeding (HR = 0.968 per AU). An optimal cutoff value of <12 AU for ADP-induced platelet aggregation to predict BARC≥3 bleedings was identified via ROC analysis. Moreover, the use of VA-ECMO (HR 1.972) or coaxial left ventricular pump (HR 2.593), first lactate (HR 1.093 per mmol/l) and thrombocyte count (HR 0.994 per G/l) were independent predictors of BARC≥3 bleedings. In conclusion, lower on-treatment ADP-induced platelet aggregation was independently associated with severe bleeding events in patients with AMI-CS. The value of platelet function testing for bleeding risk prediction and guidance of anti-thrombotic treatment in cardiogenic shock warrants further investigation.

Closing the protein gap in plant chronobiology.

Our modern understanding of diel cell regulation in plants stems from foundational work in the late 1990s that analysed the dynamics of selected genes and mutants in Arabidopsis thaliana. The subsequent rise of transcriptomics technologies such as microarrays and RNA sequencing has substantially increased our understanding of anticipatory (circadian) and reactive (light- or dark-triggered) diel events in plants. However, it is also becoming clear that gene expression data fail to capture critical events in diel regulation that can only be explained by studying protein-level dynamics. Over the past decade, mass spectrometry technologies and quantitative proteomic workflows have significantly advanced, finally allowing scientists to characterise diel protein regulation at high throughput. Initial proteomic investigations suggest that the diel transcriptome and proteome generally lack synchrony and that the timing of daily regulatory events in plants is impacted by multiple levels of protein regulation (e.g., post-translational modifications [PTMs] and protein-protein interactions [PPIs]). Here, we highlight and summarise how the use of quantitative proteomics to elucidate diel plant cell regulation has advanced our understanding of these processes. We argue that this new understanding, coupled with the extraordinary developments in mass spectrometry technologies, demands greater focus on protein-level regulation of, and by, the circadian clock. This includes hitherto unexplored diel dynamics of protein turnover, PTMs, protein subcellular localisation and PPIs that can be masked by simple transcript- and protein-level changes. Finally, we propose new directions for how the latest advancements in quantitative proteomics can be utilised to answer outstanding questions in plant chronobiology.

ADP-induced platelet reactivity and bleeding events in patients with acute myocardial infarction complicated by cardiogenic shock

Abstract Funding Acknowledgements Type of funding sources: None. Background While previous reports showed ADP-induced platelet reactivity to be an independent predictor of bleeding after PCI in stable patients, this has never been investigated in patients with cardiogenic shock (CS). Methods The association of bleeding events with respect to ADP-induced platelet aggregation was investigated in patients undergoing primary PCI for acute myocardial infarction complicated by cardiogenic shock (AMI-CS) and with available on-treatment ADP-induced platelet aggregation measurements. Results Out of 233 patients, 74 suffered from a severe BARC 3 or higher bleed. ADP-induced platelet aggregation was significantly lower in patients with BARC≥3 bleedings (10 AU [IQR 3 - 13] vs. 15 AU [IQR 9 - 25], p &amp;lt; 0.001). Multivariate analysis identified on-treatment ADP-induced platelet aggregation as an independent risk factor for bleeding (HR = 0.968 per AU, 95% confidence interval (CI) 0.942-0.994). An optimal cut-off value of &amp;lt;12 AU for ADP-induced platelet aggregation to predict BARC≥3 bleedings was identified via ROC analysis. Moreover, use of VA-ECMO (HR 1.972, 95% CI 1.003-3.879) or coaxial left ventricular pump (HR 2.593, 95% CI 1.509-4.455), first lactate (HR 1.093 per mmol/l, 95% CI 1.037-1.152) and thrombocyte count (HR 0.994 per G/l, 95% CI 0.990-0.998) were independent predictors of BARC≥3 bleedings. There was no significant difference in survival nor ischemic events between patients with low and high on-treatment platelet reactivity. Conclusion: Lower on-treatment ADP-induced platelet aggregation was independently associated with severe bleeding events in patients with AMI-CS. The value of platelet function testing for bleeding risk prediction and guidance of anti-thrombotic treatment in CS warrants further investigation.