JAK‐STAT signaling shapes the NF‐κB response in CLL towards venetoclax sensitivity or resistance via Bcl‐XL

Preventing or overcoming resistance to the Bcl-2 inhibitor venetoclax is an emerging unmet clinical need in patients with chronic lymphocytic leukemia (CLL). The upregulation of anti-apoptotic Bcl-2 members through signaling pathways within the tumor microenvironment appears as a major factor leading to resistance to venetoclax. Previously, we reported that T cells can drive resistance through CD40 and non-canonical NF-κB activation and subsequent Bcl-XL induction. Moreover, the T cell-derived cytokines IL-21 and IL-4 differentially affect Bcl-XL expression and sensitivity to venetoclax via unknown mechanisms. Here, we mechanistically dissected how Bcl-XL is regulated in the context of JAK-STAT signaling in primary CLL. First, we demonstrated a clear antagonistic role of IL-21/STAT3 signaling in the NF-κB-mediated expression of Bcl-XL, whereas IL-4/STAT6 further promoted the expression of Bcl-XL. In comparison, Bfl-1, another NF-κB target, was not differentially affected by either cytokine. Second, STAT3 and STAT6 affected Bcl-XL transcription by binding to its promoter without disrupting the DNA-binding activity of NF-κB. Third, in situ proximity ligation assays (isPLAs) indicated crosstalk between JAK-STAT signaling and NF-κB, in which STAT3 inhibited canonical NF-κB by accelerating nuclear export, and STAT6 promoted non-canonical NF-κB. Finally, NF-κB inducing kinase (NIK) inhibition interrupted the NF-κB/STAT crosstalk and re-sensitized CLL cells to venetoclax. In conclusion, we uncovered distinct crosstalk mechanisms that shape the NF-κB response in CLL towards venetoclax sensitivity or resistance via Bcl-XL, thereby revealing new potential therapeutic targets

Carbon isotopic ratios of modern C3 and C4 vegetation on the Indian peninsula and changes along the plant–soil–river continuum – implications for vegetation reconstructions

The large difference in the fractionation of stable carbon isotopes between C3 and C4 plants is widely used in vegetation reconstructions, where the predominance of C3 plants suggests wetter and that of C4 plants drier conditions. The stable carbon isotopic composition of organic carbon (OC) preserved in soils or sediments may be a valuable (paleo-)environmental indicator, based on the assumption that plant-derived material retains the stable carbon isotopic value of its photosynthetic pathway during transfer from plant to sediment. In this study, we investigated the bulk carbon isotopic values of C3 and C4 plants (δ13C) and of organic carbon (δ13Corg) in soils, river suspended particulate matter (SPM) and riverbed sediments to gain insight into the control of precipitation on C3 and C4 plant δ13C values and to assess changes in δ13Corg values along the plant–soil–river continuum. This information allows us to elucidate the implications of different δ13C end-members on C3 / C4 vegetation reconstructions. Our analysis was performed in the Godavari River basin, located in the core monsoon zone in peninsular India, a region that integrates the hydroclimatic and vegetation changes caused by variation in monsoonal strength. The basin has distinct wet and dry seasons and is characterised by natural gradients in soil type (from clay-rich to sandy), precipitation (∼ 500 to 1500 mm yr−1) and vegetation type (from mixed C3 / C4 to primarily C3) from the upper to the lower basin. The δ13C values of Godavari C3 plants were strongly controlled by mean annual precipitation (MAP), showing an isotopic enrichment of ∼ 2.2 ‰ from ∼ 1500 to 500 mm yr−1. Tracing δ13Corg values from plant to soils and rivers revealed that soils and riverbed sediments reflected the transition from mixed C3 and C4 vegetation in the dry upper basin to more C3 vegetation in the humid lower basin. Soil degradation and stabilisation processes and hydrodynamic sorting within the river altered the plant-derived δ13C signal. Phytoplankton dominated the δ13Corg signal carried by SPM in the dry season and year-round in the upper basin. Application of a linear mixing model showed that the %C4 plants in the different subbasins was ∼ 7 %–15 % higher using plant end-members based on measurement of the Godavari vegetation and tailored to local moisture availability than using those derived from data compilations of global vegetation. Including a correction for the 13C enrichment in Godavari C3 plants due to drought resulted in maximally 6 % lower estimated C4 plant cover. Our results from the Godavari basin underline the importance of making informed choices about the plant δ13C end-members for vegetation reconstructions, considering characteristics of the regional vegetation and environmental factors such as MAP in monsoonal regions

Sugammadex reverses neuromuscular block induced by 3-desacetyl-vecuronium, an active metabolite of vecuronium, in the anaesthetised rhesus monkey

Item does not contain fulltextBACKGROUND AND OBJECTIVE: 3-Desacetyl-vecuronium is an active metabolite of the neuromuscular blocking agent (NMBA) vecuronium, which might lead to residual paralysis after prolonged administration of vecuronium in critically ill patients with renal failure. This study investigated the ability of sugammadex to reverse 3-desacetyl-vecuronium-induced neuromuscular block (NMB) in the anaesthetised rhesus monkey. METHODS: Experiments were performed in anaesthetised female rhesus monkeys. After bolus intravenous injection of vecuronium (n = 8) or 3-desacetyl-vecuronium (n = 8) 10 mug kg(-1) (ED90), a continuous infusion of the same NMBA was started to maintain the first twitch of the train-of-four (TOF) at 10% of baseline value. The infusion was stopped and NMB recovered spontaneously. The procedure was repeated, but immediately after stopping the infusion, an intravenous bolus dose of sugammadex 0.5 or 1.0 mg kg(-1) was given. For each NMBA, four placebo experiments were performed, in which the second recovery from NMB was also spontaneous. For all experiments, time to recovery of the TOF ratio to 90% was retrieved. RESULTS: After administration of sugammadex for reversal of 3-desacetyl-vecuronium-induced NMB, recovery was significantly faster than spontaneous recovery. Mean time to recovery of TOF to 90% was 3.2 min (sugammadex 0.5 mg kg(-1)) and 2.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (17.6 min). For vecuronium-induced NMB, mean time to recovery of TOF to 90% was 17.1 min (0.5 mg kg(-1)) and 4.6 min (1.0 mg kg(-1)), compared to spontaneous recovery (23.4 min). CONCLUSION: Sugammadex rapidly and effectively reversed 3-desacetyl-vecuronium-induced NMB in the rhesus monkey, at a lower dose than that needed to reverse vecuronium-induced NMB

Carbon and nitrogen (isotopic) signatures in C3 and C4 plants, soils, SPM and riverbed sediments in the Godavari River basin (India) in 2015

%OC, %TN, δ13C and δ15N analysed in C3 and C4 plants, soils, SPM and riverbed sediments in the Godavari River basin (India), located in the Core Monsoon Zone. Above-ground plant parts of C3 and C4 vegetation were collected at the end of the dry season (February/March 2015) across the Godavari basin, including trees, shrubs, herbaceous plants, grasses and dominant crops. Surface soils (0-10 cm) were collected near the Godavari River, and SPM (10-80 L, filtered over 0.7 μm GFF filters) and bulk and fine (≤63 μm) riverbed sediments were collected in a dry (February/March 2015) and wet season (July/August 2015). Mean Annual Precipitation (MAP) data were retrieved from Dearing Crampton-Flood et al. (2019) (https://doi.org/10.1594/PANGAEA.907818) and India Water Resources Information System (https://indiawris.gov.in/

Characteristics of the Children's Revised Impact of Event Scale in a clinically referred Dutch sample

Early identification of posttraumatic stress disorder (PTSD) in children is important to offer them appropriate and timely treatment. The Children's Revised Impact of Event Scale (CRIES) is a brief self-report measure designed to screen children for PTSD. Research regarding the diagnostic validity of the CRIES is still insufficient, has been restricted to specific populations, and sample sizes have often been small. This study evaluated the reliability and validity of the 8-item (CRIES-8) and 13-item (CRIES-13) versions of the CRIES in a large clinically referred sample. The measure was completed by 395 Dutch children (7-18 years) who had experienced a wide variety of traumatic events. PTSD was assessed using the Anxiety Disorders Interview Schedule for DSM-IV: Child and Parent version. A cutoff score of 17 on the CRIES-8 and 30 on the CRIES-13 emerged as the best balance between sensitivity and specificity, and correctly classified 78%-81% of all children. The CRIES-13 outperformed the CRIES-8, in that the overall efficiency of the CRIES-13 was slightly superior (.81 and .78, respectively). The CRIES appears to be a reliable and valid measure, which gives clinicians a brief and user-friendly instrument to identify children who may have PTSD and offer them appropriate and timely treatmen

Enhanced screening for posttraumatic stress disorder and comorbid diagnoses in children and adolescents

BACKGROUND: Posttraumatic stress disorder (PTSD) can be a debilitating disorder and often co-occurs with other psychiatric disorders, such as mood, behavioral, and anxiety disorders. Early identification of PTSD and psychiatric comorbidity is highly relevant in order to offer children appropriate and timely treatment. The Children's Revised Impact of Event Scale (CRIES-13) is a reliable and valid self-report measure designed to screen children for PTSD. However, this measure is not useful as a screen for psychiatric comorbidity in children with probable PTSD. OBJECTIVE: This study evaluated the screening accuracy of the CRIES-Plus, that is, the CRIES-13 combined with 12 additional items to detect psychiatric comorbidity. METHOD: The CRIES-Plus was completed by 398 Dutch children (7-18 years) exposed to various traumatic events. Psychiatric diagnoses were assessed using the Anxiety Disorders Interview Schedule for DSM-IV: Child version. RESULTS: Six additional items were significantly associated with mood disorders, three items were associated with behavioral disorders, and five items with anxiety disorders. Additional items associated with mood and anxiety disorders demonstrated good discriminatory ability, with cut-off scores of ≥14 and ≥10, respectively. Items associated with behavioral disorders had poor to fair discriminatory ability, with no clear cut-off point. CONCLUSIONS: Our findings support the use of the CRIES-Plus to screen for PTSD and comorbid disorders which may help clinicians in assigning appropriate follow-up diagnostic and clinical care

Reversal of rocuronium-induced neuromuscular block by sugammadex is independent of renal perfusion in anesthetized cats

Item does not contain fulltextPURPOSE: Sugammadex is a selective relaxant binding agent designed to encapsulate the aminosteroidal neuromuscular blocking agent rocuronium, thereby reversing its effect. Both sugammadex and the sugammadex-rocuronium complex are eliminated by the kidneys. This study investigated the effect of sugammadex on recovery of rocuronium-induced neuromuscular block in cats with clamped renal pedicles, as a model for acute renal failure. METHODS: Twelve male cats were divided into two groups and anesthetized with medetomidine, ketamine, and alpha-chloralose. The cats were intubated and ventilated with a mixture of oxygen and air. Neuromuscular monitoring was performed by single twitch monitoring. Rocuronium 0.5 mg/kg i.v. was administered. After spontaneous recovery from neuromuscular block, both renal pedicles were ligated. A second dose of rocuronium 0.5 mg/kg i.v. was given. One minute after disappearance of the twitches, in Group 1 placebo (0.9% saline) and in Group 2 sugammadex 5.0 mg/kg i.v. was administered. Onset time, duration of neuromuscular block, and time to recovery to 25, 50, 75, and 90% were determined. Results : After renal pedicle ligation, sugammadex reversed rocuronium-induced neuromuscular block significantly faster than spontaneous recovery. Mean time (SEM) to 90% recovery of the twitch response was 4.7 (0.25) min (Group 2) versus 31.1 (5.0) min (Group 1) (p < 0.0001). No signs of recurrence of neuromuscular block were observed for 90 min after complete twitch restoration. Sugammadex caused no significant cardiovascular effects. CONCLUSION: Sugammadex rapidly and effectively reversed rocuronium-induced neuromuscular block in anesthetized cats, even when both renal pedicles were ligated and renal elimination of the drugs was no longer possible

A parental tool to screen for posttraumatic stress in children: first psychometric results

The Children's Revised Impact of Event Scale (CRIES-13) is a brief self-report measure designed to screen children for posttraumatic stress disorder (PTSD). This study investigates the psychometric properties of a Dutch version of the CRIES-13-parent version and evaluates its correlation with the child version. A sample of 59 trauma-exposed children (8 years-18 years) and their parents completed an assessment including the CRIES-13 (child/parent version) along with the Anxiety Disorders Interview Schedule for DSM-IV: Parent version. Results demonstrated good internal consistency (α = .87) with acceptable values for the 3 subscales. A strong correlation (r = .73) with another measure of PTSD and lower correlations with a behavioral measure (r = .15 to .38) were found, confirming the convergent/divergent validity. A cutoff score ≥ 31 emerged as the best balance between sensitivity and specificity, and correctly classified 83.6% of all children as having a diagnosis of PTSD. This study provides support for the reliability and validity of the CRIES-13-parent version as a screening measure for posttraumatic stress in childre

Carbon isotopic ratios of modern C3 and C4 vegetation on the Indian peninsula and changes along the plant–soil–river continuum – implications for vegetation reconstructions

The large difference in the fractionation of stable carbon isotopes between C3 and C4 plants is widely used in vegetation reconstructions, where the predominance of C3 plants suggests wetter and that of C4 plants drier conditions. The stable carbon isotopic composition of organic carbon (OC) preserved in soils or sediments may be a valuable (paleo-)environmental indicator, based on the assumption that plant-derived material retains the stable carbon isotopic value of its photosynthetic pathway during transfer from plant to sediment. In this study, we investigated the bulk carbon isotopic values of C3 and C4 plants (δ13C) and of organic carbon (δ13Corg) in soils, river suspended particulate matter (SPM) and riverbed sediments to gain insight into the control of precipitation on C3 and C4 plant δ13C values and to assess changes in δ13Corg values along the plant–soil–river continuum. This information allows us to elucidate the implications of different δ13C end-members on C3 / C4 vegetation reconstructions. Our analysis was performed in the Godavari River basin, located in the core monsoon zone in peninsular India, a region that integrates the hydroclimatic and vegetation changes caused by variation in monsoonal strength. The basin has distinct wet and dry seasons and is characterised by natural gradients in soil type (from clay-rich to sandy), precipitation (∼ 500 to 1500 mm yr−1) and vegetation type (from mixed C3 / C4 to primarily C3) from the upper to the lower basin. The δ13C values of Godavari C3 plants were strongly controlled by mean annual precipitation (MAP), showing an isotopic enrichment of ∼ 2.2 ‰ from ∼ 1500 to 500 mm yr−1. Tracing δ13Corg values from plant to soils and rivers revealed that soils and riverbed sediments reflected the transition from mixed C3 and C4 vegetation in the dry upper basin to more C3 vegetation in the humid lower basin. Soil degradation and stabilisation processes and hydrodynamic sorting within the river altered the plant-derived δ13C signal. Phytoplankton dominated the δ13Corg signal carried by SPM in the dry season and year-round in the upper basin. Application of a linear mixing model showed that the %C4 plants in the different subbasins was ∼ 7 %–15 % higher using plant end-members based on measurement of the Godavari vegetation and tailored to local moisture availability than using those derived from data compilations of global vegetation. Including a correction for the 13C enrichment in Godavari C3 plants due to drought resulted in maximally 6 % lower estimated C4 plant cover. Our results from the Godavari basin underline the importance of making informed choices about the plant δ13C end-members for vegetation reconstructions, considering characteristics of the regional vegetation and environmental factors such as MAP in monsoonal regions