Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of ...pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue Tyr3-octreotate and Chlorin e6 (Ce6): Ce6-K3-Tyr3-octreotate (1) and Ce6-Tyr3-octreotate-K3-Tyr3-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of Tyr3-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2+ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An increasing number of studies of above‐belowground interactions provide a fundamental basis for our understanding of the coexistence between plant and soil communities. However, we lack empirical ...evidence to understand the directionality of drivers of plant and soil communities under natural conditions: ‘Are soil microorganisms driving plant community functioning or do they adapt to the plant community?’ In a field experiment in an early successional dune ecosystem, we manipulated soil communities by adding living (i.e., natural microbial communities) and sterile soil inocula, originating from natural ecosystems, and examined the annual responses of soil and plant communities. The experimental manipulations had a persistent effect on the soil microbial community with divergent impacts for living and sterile soil inocula. The plant community was also affected by soil inoculation, but there was no difference between the impacts of living and sterile inocula. We also observed an increasing convergence of plant and soil microbial composition over time. Our results show that alterations in soil abiotic and biotic conditions have long‐term effects on the composition of both plant and soil microbial communities. Importantly, our study provides direct evidence that soil microorganisms are not “drivers” of plant community dynamics. We found that soil fungi and bacteria manifest different community assemblies in response to treatments. Soil fungi act as “passengers,” that is, soil microorganisms reflect plant community dynamics but do not alter it, whereas soil bacteria are neither “drivers” nor “passengers” of plant community dynamics in early successional ecosystems. These results are critical for understanding the community assembly of plant and soil microbial communities under natural conditions and are directly relevant for ecosystem management and restoration.
Purpose
Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alphaherpesviruses endemic worldwide. Upon primary infection, both viruses establish lifelong latency in ...neurons and reactivate intermittently to cause a variety of mild to severe diseases. Acute retinal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infection. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying genetic defect in at least part of ARN cases.
Methods
We collected blood from 17 patients with HSV-or VZV-induced ARN, isolated DNA and performed Whole Exome Sequencing by Illumina followed by analysis in Varseq with criteria of CADD score > 15 and frequency in GnomAD < 0.1% combined with biological filters. Gene modifications relative to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predictions and biological relevance.
Results
We identified a total of 50 potentially disease-causing genetic variants, including missense, frameshift and splice site variants and on in-frame deletion in 16 of the 17 patients. The vast majority of these genes are involved in innate immunity, followed by adaptive immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was identified in several patients.
Discussion
We propose that the identified variants may contribute to insufficient viral control and increased necrosis ocular disease presentation in the patients and serve as a knowledge base and starting point for the development of improved diagnostic, prophylactic, and therapeutic applications.
Introduction
Radiofrequency (RF) atrial fibrillation (AF) ablation using a catheter dragging technique may shorten procedural duration and improve durability of pulmonary vein isolation (PVI) by ...creating uninterrupted linear ablation lesions. We compared a novel AF ablation approach guided by Grid annotation allowing for “drag lesions” with a standard point‐by‐point ablation approach in a single‐center randomized study.
Methods
Eighty‐eight paroxysmal or persistent AF patients were randomized 1:1 to undergo RF‐PVI with either a catheter dragging ablation technique guided by Grid annotation or point‐by‐point ablation guided by Ablation Index (AI) annotation. In the Grid annotation arm, ablation was visualized using 1 mm³ grid points coloring red after meeting predefined stability and contact force criteria. In the AI annotation arm, ablation lesions were created in a point‐by‐point fashion with AI target values set at 380 and 500 for posterior/inferior and anterior/roof segments, respectively. Patients were followed up for 12 months after PVI using ECGs, 24‐h Holter monitoring and a mobile‐based one‐lead ECG device.
Results
Procedure time was not different between the two randomization arms (Grid annotation 71 ± 19 min, AI annotation 72 ± 26 min, p = .765). RF time was significantly longer in the Grid annotation arm compared with the AI annotation arm (49 ± 8 min vs. 37 ± 8 min, respectively, p < .001). Atrial tachyarrhythmia recurrence was documented in 10 patients (23%) in the Grid annotation arm compared with 19 patients (42%) in the AI annotation arm with time to recurrence not reaching statistical significance (p = .074).
Conclusions
This study shows that a Grid annotation‐guided dragging approach provides an alternative to point‐by‐point RF‐PVI using AI annotation.
Plant functional traits are increasingly recognised as being impacted by soil abiotic and biotic factors. Yet, the question to what extent the coupling between community‐level above‐ and below‐ground ...traits is affected by soil conditions remains open.
In a field experiment in dune grassland, we quantified the responses of both community‐level leaf and root traits to changes in soil abiotic and biotic conditions using soil inoculation by living and sterile soil inocula originated from different dune ecosystems.
Altered soil conditions resulted in a strong decoupling in responses of community‐level leaf and root traits. Changes in soil abiotic conditions imposed by soil inoculation were more important in determining the decoupling of the leaf vs root relationships than additions of soil biota. Altered soil abiotic factors influenced both leaf and root traits at the community level and caused the entire community‐level trait spectrum to shift, while experimental additions of living soil inocula only significantly influenced root traits towards longer and thinner roots.
Synthesis. Our results bring direct evidence that, at a plant community level, the dynamics of plant above‐ground traits are not informative of below‐ground traits. Particularly, below‐ground abiotic processes are a major driver of commonly observed trait spectra. We suggest that future study is required to test the general pattern of leaf and root correlations across different ecosystems under field conditions.
Our results bring direct evidence that, at a plant community level, the dynamics of plant above‐ground traits are not informative of below‐ground traits. Particularly, below‐ground abiotic processes are a major driver of commonly observed trait spectra. We suggest that future study is required to test the general pattern of leaf and root correlations across different ecosystems under field conditions.
The authors sought to evaluate the impact of ischemic burden reduction after chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on long-term prognosis and cardiac symptom relief.
...The clinical benefit of CTO PCI is questioned.
In a high-volume CTO PCI center, 212 patients prospectively underwent quantitative
OH
O positron emission tomography perfusion imaging before and three months after successful CTO PCI between 2013-2019. Perfusion defects (PD) (in segments) and hyperemic myocardial blood flow (hMBF) (in ml · min
· g
) allocated to CTO areas were related to prognostic outcomes using unadjusted (Kaplan-Meier curves, log-rank test) and risk-adjusted (multivariable Cox regression) analyses. The prognostic endpoint was a composite of all-cause death and nonfatal myocardial infarction.
After a median interquartile range of 2.8 years 1.8 to 4.3 years, event-free survival was superior in patients with ≥3 versus <3 segment PD reduction (p < 0.01; risk-adjusted p = 0.04; hazard ratio HR: 0.34 95% confidence interval (CI): 0.13 to 0.93) and with hMBF increase above (Δ≥1.11 ml · min
· g
) versus below the population median (p < 0.01; risk-adjusted p < 0.01; HR: 0.16 95% CI: 0.05 to 0.54) after CTO PCI. Furthermore, event-free survival was superior in patients without versus any residual PD (p < 0.01; risk-adjusted p = 0.02; HR: 0.22 95% CI: 0.06 to 0.76) or with a residual hMBF level >2.3 versus ≤2.3 ml · min
· g
(p < 0.01; risk-adjusted p = 0.03; HR: 0.25 95% CI: 0.07 to 0.91) at follow-up positron emission tomography. Patients with residual hMBF >2.3 ml · min
· g
were more frequently free of angina and dyspnea on exertion at long-term follow-up (p = 0.04).
Patients with extensive ischemic burden reduction and no residual ischemia after CTO PCI had lower rates of all-cause death and nonfatal myocardial infarction. Long-term cardiac symptom relief was associated with normalization of hMBF levels after CTO PCI.
IPOPI held its first Global Multi-Stakeholders’ Summit on 23-24 June 2022 in Cascais, Portugal. This IPOPI initiative was designed to set the stage for a stimulating forward-thinking meeting and ...brainstorming discussion among stakeholders on the future priorities of the PID community. All participants were actively engaged in the entire Summit, bringing provocative questions to ensure a high level of discussion and engagement, and partnered in identifying the outlooks, unmet needs, hurdles and opportunities of PIDs for 2030. The topics that were covered include diagnosis (e.g., newborn screening NBS, genomic sequencing— including ethical aspects on the application of genomics on NBS, the role of more accurate and timely diagnostics in impacting personalized management), treatment (e.g., the therapeutic evolution of immunoglobulins in a global environment, new therapies such as targeted therapies, new approaches in curative therapies), the interactions of Primary ID with Secondary ID, Autoinflammatory Diseases and other diseases as the field experiences an incessant evolution, and also the avenues for research in the field of humanities and human sciences such as Patient-Reported Outcome Measures (PROMs), Patient-Reported Experience Measures (PREMs), and Health-Related Quality Of Life (HRQoL). During this meeting, all participants contributed to the drafting of recommendations based on our common understanding of the future opportunities, challenges, and scenarios. As a collection of materials, perspectives and summaries, they are succinct and impactful and may help determine some of the next key steps for the PID community.
•Ablation Index-guided ablation allows for ablation lesions of consistent depth.•Ablation Index-guided ablation is limited by ignoring local wall thickness.•Local atrial wall thickness is associated ...with acute pulmonary vein reconnection.•Wall thickness adjusted Ablation Index targets may improve ablation outcomes.
Although Ablation Index (AI)-guided ablation facilitates creation of lesions of consistent depth, pulmonary vein (PV) reconnection is still commonly observed after AI-guided pulmonary vein isolation (PVI). The present study aimed to investigate the impact of local left atrial wall thickness on the incidence of acute PV reconnection after AI-guided atrial fibrillation (AF) ablation.
Seventy patients (63% paroxysmal AF, 67% male, mean age 63 ± 8 years) who underwent preprocedural CT imaging and AI-guided AF ablation were studied. Occurrence of acute PV reconnection after initial PVI was assessed after a 30-minute waiting period. Ablation procedures were retrospectively analyzed and each ablation circle was subdivided into 8 segments. Minimum AI, force-time integral, contact force, ablation duration, power, impedance drop and maximum interlesion distance were determined for each segment. PV antrum wall thickness was assessed for each segment on reconstructed CT images based on patient-specific thresholds in Hounsfield Units. Acute reconnection occurred in 27/1120 segments (2%, 15 anterior/roof, 12 posterior/inferior) in 19/140 ablation circles (14%). Reconnected segments were characterized by a greater local atrial wall thickness, both in anterior/roof (1.87 ± 0.42 vs. 1.54 ± 0.42 mm; p < 0.01) and posterior/inferior (1.43 ± 0.20 vs. 1.16 ± 0.22 mm; p < 0.01) segments. Minimum AI, force-time integral, contact force, ablation duration, power, impedance drop and maximum interlesion distance were not associated with acute reconnection.
Local atrial wall thickness is associated with acute pulmonary vein reconnection after AI-guided PVI. Individualized AI targets based on local wall thickness may be of use to create transmural ablation lesions and prevent PV reconnection after PVI.
Departments of 1 Internal Medicine,
2 Immunology, and 4 Pathology,
Josephine Nefkens Institute, Erasmus MC, 3015 GD Rotterdam, The Netherlands;
and 3 Radiology Department, Washington University
...School of Medicine, St. Louis, Missouri 63110
Submitted 3 February 2003
; accepted in final form 6 April 2003
Increasing evidence suggests that neuropeptides play a role in the
regulatory mechanisms between the neuroendocrine and immune systems. A
differential expression of the five known somatostatin (SS) receptors
(sst 15 ) has been demonstrated in human immune cells and
tissues. However, little is known concerning regulation and expression of
sst 15 and the peptide SS. Therefore, we investigated the
expression and the time-dependent regulation of sst 15 , SS,
and cortistatin (CST), a novel SS-like peptide, in human monocytes (MO),
monocyte-derived macrophages (MP), and dendritic cells (DC) in the basal and
lipopolysaccharide (LPS)-activated state. MO, MP, and DC selectively expressed
sst 2 mRNA. SS mRNA was not detectable, whereas all samples
expressed CST mRNA. Expression levels of sst 2 and CST mRNA showed
marked differences and were in the rank order of MP>>DC>>>MO.
LPS stimulation did not induce expression of SS or sst 1,3,4,5 .
However, sst 2 mRNA expression was upregulated significantly by
stimulation with LPS. CST mRNA was upregulated as well. During differentiation
of MO in MP or DC, time-dependent, significantly increasing sst 2
and CST mRNA levels were found. By confocal microscopy, the presence of
sst 2 receptors was demonstrated on MP, but not on DC. This study
demonstrates for the first time a selective and inducible expression of the
recently discovered CST, as well as sst 2 , in human monocyte-derived
cells, suggesting a role for a CST-sst 2 system rather than a
SS-sst 2 system in these immune cell types.
cellular differentiation; cellular activation; neuropeptides; messenger ribonucleic acid
Address for reprint requests and other correspondence: L. J. Hofland, Dept. of
Internal Medicine, Rm. Bd 240, Erasmus MC, Dr. Molewaterplein 40, 3015 GD,
Rotterdam, The Netherlands (E-mail:
l.hofland{at}erasmusmc.nl ).
PDF
