Cellular forgetting, desensitisation, stress and ageing in signalling networks. When do cells refuse to learn more?

Recent findings show that single, non-neuronal cells are also able to learn signalling responses developing cellular memory. In cellular learning nodes of signalling networks strengthen their interactions e.g. by the conformational memory of intrinsically disordered proteins, protein translocation, miRNAs, lncRNAs, chromatin memory and signalling cascades. This can be described by a generalized, unicellular Hebbian learning process, where those signalling connections, which participate in learning, become stronger. Here we review those scenarios, where cellular signalling is not only repeated in a few times (when learning occurs), but becomes too frequent, too large, or too complex and overloads the cell. This leads to desensitisation of signalling networks by decoupling signalling components, receptor internalization, and consequent downregulation. These molecular processes are examples of anti-Hebbian learning and 'forgetting' of signalling networks. Stress can be perceived as signalling overload inducing the desensitisation of signalling pathways. Ageing occurs by the summative effects of cumulative stress downregulating signalling. We propose that cellular learning desensitisation, stress and ageing may be placed along the same axis of more and more intensive (prolonged or repeated) signalling. We discuss how cells might discriminate between repeated and unexpected signals, and highlight the Hebbian and anti-Hebbian mechanisms behind the fold-change detection in the NF-κB signalling pathway. We list drug design methods using Hebbian learning (such as chemically-induced proximity) and clinical treatment modalities inducing (cancer, drug allergies) desensitisation or avoiding drug-induced desensitisation. A better discrimination between cellular learning, desensitisation and stress may open novel directions in drug design, e.g. helping to overcome drug resistance.

Learning of Signaling Networks: Molecular Mechanisms.

Molecular processes of neuronal learning have been well described. However, learning mechanisms of non-neuronal cells are not yet fully understood at the molecular level. Here, we discuss molecular mechanisms of cellular learning, including conformational memory of intrinsically disordered proteins (IDPs) and prions, signaling cascades, protein translocation, RNAs [miRNA and long noncoding RNA (lncRNA)], and chromatin memory. We hypothesize that these processes constitute the learning of signaling networks and correspond to a generalized Hebbian learning process of single, non-neuronal cells, and we discuss how cellular learning may open novel directions in drug design and inspire new artificial intelligence methods.

One third of cases of new-onset diabetic ketosis in adults are associated with ketosis-prone type 2 diabetes-A systematic review and meta-analysis.

AIMS: Ketosis-prone type 2 diabetes was defined by the World Health Organization in 2019. According to the literature, the diagnosis is based on the presence of ketosis, islet autoantibody negativity and preserved insulin secretion. Our meta-analysis assessed the prevalence and clinical characteristics of ketosis-prone type 2 diabetes among patients hospitalised with diabetic ketoacidosis (DKA) or ketosis. METHODS: The systematic search was performed in five main databases as of 15 October 2021 without restrictions. We calculated the pooled prevalence of ketosis-prone type 2 diabetes (exposed group) within the diabetic population under examination, patients with ketoacidosis or ketosis, to identify the clinical characteristics, and we compared it to type 1 diabetes (the comparator group). The random effects model provided pooled estimates as prevalence, odds ratio and mean difference (MD) with 95% confidence intervals. RESULTS: Eleven articles were eligible for meta-analysis, thus incorporating 2010 patients of various ethnic backgrounds. Among patients presenting with DKA or ketosis at the onset of diabetes, 35% (95% CI: 24%-49%) had ketosis-prone type 2 diabetes. These patients were older (MD = 11.55 years; 95% CI: 5.5-17.6) and had a significantly higher body mass index (BMI) (MD = 5.48 kg/m2 ; 95% CI: 3.25-7.72) than those with type 1 diabetes. CONCLUSIONS: Ketosis-prone type 2 diabetes accounts for one third of DKA or ketosis at the onset of diabetes in adults. These patients are characterised by islet autoantibody negativity and preserved insulin secretion. They are older and have a higher BMI compared with type 1 diabetes. C-peptide and diabetes-related autoantibody measurement is essential to identify this subgroup among patients with ketosis at the onset of diabetes.

Contrast-enhanced endoscopic ultrasound likely does not improve diagnostic adequacy during endoscopic ultrasound guided tissue acquisition: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Solid pancreatic masses are sampled through tissue acquisition by endoscopic ultrasound (EUS). Inadequate samples may significantly delay diagnosis, increasing costs and carrying risks to the patients. AIM: assess the diagnostic adequacy of tissue acquisition using contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) compared to conventional EUS. METHODS: Five databases (PubMed, Embase, CENTRAL, Scopus and Web of Science) were searched in November 2023. Studies comparing diagnostic adequacy, accuracy and safety using CEH-EUS versus conventional EUS for tissue acquisition of solid pancreatic masses were included. Risk of bias was assessed using the Risk of Bias tool for randomized controlled trials (RoB2) and the Risk Of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) tool for non-randomized studies, level of evidence using the GRADE approach, Odds Ratios (RR) with 95 % Confidence Intervals (CI) calculated and pooled using a random-effects model. I2 quantified heterogeneity. RESULTS: The search identified 3858 records; nine studies (1160 patients) were included. OR for achieving an adequate sample was 1.467 (CI: 0.850-2.533), for randomized trials 0.902 (CI: 0.541-1.505), for non-randomized 2.396 (CI: 0.916-6.264), with significant subgroup difference. OR for diagnostic accuracy was 1.326 (CI: 0.890-1977), for randomized trials 0.997 (CI: 0.593-1.977) and for non-randomized studies 1.928 (CI: 1.096-3.393), significant subgroup difference (p = 0.0467). No differences were observed for technical failures or adverse events. Heterogeneity was low, risk of bias "low" to "some concerns" for most outcomes, mostly moderate for non-randomized studies. CONCLUSION: Non-randomized studies indicated differences in favor of contrast-enhanced EUS, randomized studies showed no difference in diagnostic adequacy, accuracy or sensitivity when using CEH-EUS.

Umbilical cord management in newborn resuscitation: a systematic review and meta-analysis.

BACKGROUND: Evidence supporting the benefits of delayed cord clamping is increasing; however, there is no clear recommendation on cord management during newborn resuscitation. This study aimed to investigate the effects of resuscitation initiated with an intact umbilical cord, hypothesizing it is a safe stabilization procedure that improves neonatal outcomes. METHODS: Systematic search was conducted in MEDLINE, Embase, CENTRAL, and Web of Science from inception to March 1, 2024. Eligible articles compared neonatal outcomes in newborns receiving initial stabilization steps before and after cord clamping. RESULTS: Twelve studies met our inclusion criteria, with six RCTs included in the quantitative analysis. No statistically significant differences were found in delivery room parameters, in-hospital mortality, or neonatal outcomes between the examined groups. However, intact cord resuscitation group showed higher SpO2 at 5 min after birth compared to cord clamping prior to resuscitation group (MD 6.67%, 95% CI [-1.16%, 14.50%]). There were no significant differences in early complications of prematurity (NEC ≥ stage 2: RR 2.05, 95% CI [0.34, 12.30], IVH: RR 1.25, 95% CI [0.77, 2.00]). CONCLUSION: Intact cord management during resuscitation appears to be a safe intervention; its effect on early complications of prematurity remains unclear. Further high-quality RCTs with larger patient numbers are urgently needed. IMPACT: Initiating resuscitation with an intact umbilical cord appears to be a safe intervention for newborns. No statistically significant differences were found in delivery room parameters, in-hospital mortality, and neonatal outcomes between the examined groups. The utilization of specialized resuscitation trolleys appears to be promising to reduce the risk of intraventricular hemorrhage in preterm infants. Further high-quality RCTs with larger sample sizes are urgently needed to refine recommendations.

Probiotic supplementation during antibiotic treatment is unjustified in maintaining the gut microbiome diversity: a systematic review and meta-analysis.

BACKGROUND: Probiotics are often used to prevent antibiotic-induced low-diversity dysbiosis, however their effect is not yet sufficiently summarized in this regard. We aimed to investigate the effects of concurrent probiotic supplementation on gut microbiome composition during antibiotic therapy. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials reporting the differences in gut microbiome diversity between patients on antibiotic therapy with and without concomitant probiotic supplementation. The systematic search was performed in three databases (MEDLINE (via PubMed), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL)) without filters on 15 October 2021. A random-effects model was used to estimate pooled mean differences (MD) with 95% confidence intervals (CI). This review was registered on PROSPERO (CRD42021282983). RESULTS: Of 11,769 identified articles, 15 were eligible in the systematic review and 5 in the meta-analyses. Quantitative data synthesis for Shannon (MD = 0.23, 95% CI: [(-)0.06-0.51]), Chao1 (MD = 11.59 [(-)18.42-41.60]) and observed OTUs (operational taxonomic unit) (MD = 17.15 [(-)9.43-43.73]) diversity indices revealed no significant difference between probiotic supplemented and control groups. Lacking data prevented meta-analyzing other diversity indices; however, most of the included studies reported no difference in the other reported α- and ß-diversity indices between the groups. Changes in the taxonomic composition varied across the eligible studies but tended to be similar in both groups. However, they showed a potential tendency to restore baseline levels in both groups after 3-8 weeks. This is the first meta-analysis and the most comprehensive review of the topic to date using high quality methods. The limited number of studies and low sample sizes are the main limitations of our study. Moreover, there was high variability across the studies regarding the indication of antibiotic therapy and the type, dose, and duration of antimicrobials and probiotics. CONCLUSIONS: Our results showed that probiotic supplementation during antibiotic therapy was not found to be influential on gut microbiome diversity indices. Defining appropriate microbiome diversity indices, their standard ranges, and their clinical relevance would be crucial.

Clinical assessment of children with long COVID syndrome.

BACKGROUND: There is a need for further understanding pediatric long COVID syndrome (LCS) to be able to create specific case definitions and guidelines for providing good clinical care. METHODS: Medical records of all LCS patients who presented at our designated LC clinic were collected. We carried out descriptive analyses summarizing the history, clinical presentation, and findings of children, while doing a diagnosis of exclusion with multi-disciplinary medical examinations (physical, laboratory, and radiological examinations, specialist consultations, etc.) without a control group. RESULTS: Most children reported at least minor impairment to their quality of life, of which 17 (23%) had moderate or severe difficulties. Findings that could be directly connected to the linked complaint category were observed in an average of 18%, respiratory symptoms with objective alterations being the most frequent (37%). Despite our detecting mostly non-specific conditions, in a smaller number we identified well-described causes such as autoimmune thyroiditis (7%). CONCLUSIONS: The majority of children stated an impairment in their quality of life, while symptom-related conditions were detected only in a minority. Controlled studies are needed to separate the effect of the pandemic era from the infection itself. Evidence-based pediatric guidelines could aid to rationalize the list of recommended examinations. IMPACT: Long COVID syndrome is a complex entity with a great impact on children's everyday lives. Still, there is no clear guidance for pediatric clinical management. Systematic, detailed studies with medical assessment findings could aid the process of creating evidence-based guidelines. We present validated systematic information collected during in-person medical assessments with detailed medical findings and quality of life changes. While making a diagnosis of exclusion, we could confirm symptom-related conditions only in a minority of children; however, the majority reported at least minor impairment to their quality of life.

Maternal age is highly associated with non-chromosomal congenital anomalies: Analysis of a population-based case-control database.

OBJECTIVE: The role of maternal age in the development of non-chromosomal congenital anomalies (NCAs) is under debate. Therefore, the primary aim of this study was to identify the age groups at risk for NCAs. The secondary aim was to perform a detailed analysis of the relative frequency of various anomalies. DESIGN: National population-based study. SETTING: The Hungarian Case-Control Surveillance of Congenital Anomalies (CAs) between 1980 and 2009. POPULATION OR SAMPLE: A cohort of 31 128 cases with confirmed NCAs was compared with Hungary's total of 2 808 345 live births. METHODS: Clinicians prospectively reported cases after delivery. Data were analysed by non-linear logistic regression. Risk-increasing effect of young and advanced maternal age was determined by each NCA group. MAIN OUTCOME MEASURES: These were the total number of NCAs: cleft lip and palate, circulatory, genital, musculoskeletal, digestive, urinary, eye, ear, face, and neck, nervous system, and respiratory system anomalies. RESULTS: The occurrence of NCAs in our database was lowest between 23 and 32 years of maternal age at childbirth. The relative risk (RR) of any NCA was 1.2 (95% CI 1.17-1.23) and 1.15 (95% CI 1.11-1.19) in the very young and advanced age groups, respectively. The respective results for the circulatory system were RR = 1.07 (95% CI 1.01-1.13) and RR = 1.33 (95% CI 1.24-1.42); for cleft lip and palate RR = 1.09 (95% CI 1.01-1.19) and RR = 1.45 (95% CI 1.26-1.67); for genital organs RR = 1.15 (95% CI 1.08-1.22) and RR = 1.16 (95% CI 1.04-1.29); for the musculoskeletal system RR = 1.17 (95% CI 1.12-1.23) and RR = 1.29 (95% CI 1.14-1.44); and for the digestive system RR = 1.23 (95% CI 1.14-1.31) and RR = 1.16 (95% CI 1.04-1.29). CONCLUSION: Very young and advanced maternal ages are associated with different types of NCAs. Therefore, screening protocols should be adjusted for these risk groups.

Impact of COVID-19 on neurotrauma cases, mortality rates, and rebound effect: a monocenter retrospective study.

Background and purpose:

We retro­spec­tively studied the development of neuro­trauma case numbers during the COVID-19 pandemic in the largest trauma center in Hun­gary and compared them to the data of the previous year. We hypothesized that the decrease in the number of neurotrauma cases during the restrictions would sub­sequently lead to a significant increase in a so-called rebound phenomenon. Our goal was to better understand the effect of the pandemic and the restrictive measures on neurotrauma admissions to help better pre­pare for a new pandemic or for other mobility restrictions. 

We compiled daily case numbers from January 1, 2019, to April 30, 2021, which included the treatment of 861 patients with spinal trauma and 1244 patients with head injuries from 2019 to 2020, and 871 and 1255 patients with spinal trauma and head injuries, respectively, from March 2020 to April 30, 2021. The parameters studied were patients’ age, admission date and time from injury to admission. We also conducted a minimum 3-month follow-up study with pa­tients admitted during the pandemic to determine the changes in the hazard ratio of mortality. 

We found that in each wave of the pandemic, during the restrictive measures, neurotrauma case numbers decreased. After the first restrictions, we observed a clinically relevant rebound effect among spinal trauma patients. The main findings of the follow-up were that the hazard ratio of mortality for COVID-19 infected patients was 2.5 (p < 0.001), compared with the mortality hazard ratio of COVID-19-negative patients.

Restrictions during the pandemic significantly reduced population mobility helping slow down the spread of the virus and give time to healthcare systems to better prepare. At the same time, it also reduced the number of new neurotrauma cases. In case of spinal trauma patients, a rebound effect was observed after the restrictions, which may be due to increased mobility, activity and travel. The restrictive measures reduced trauma cases effectively, while not increased the time from injury to admission. 

Translocatome: a novel resource for the analysis of protein translocation between cellular organelles.

Here we present Translocatome, the first dedicated database of human translocating proteins (URL: http://translocatome.linkgroup.hu). The core of the Translocatome database is the manually curated data set of 213 human translocating proteins listing the source of their experimental validation, several details of their translocation mechanism, their local compartmentalized interactome, as well as their involvement in signalling pathways and disease development. In addition, using the well-established and widely used gradient boosting machine learning tool, XGBoost, Translocatome provides translocation probability values for 13 066 human proteins identifying 1133 and 3268 high- and low-confidence translocating proteins, respectively. The database has user-friendly search options with a UniProt autocomplete quick search and advanced search for proteins filtered by their localization, UniProt identifiers, translocation likelihood or data complexity. Download options of search results, manually curated and predicted translocating protein sets are available on its website. The update of the database is helped by its manual curation framework and connection to the previously published ComPPI compartmentalized protein-protein interaction database (http://comppi.linkgroup.hu). As shown by the application examples of merlin (NF2) and tumor protein 63 (TP63) Translocatome allows a better comprehension of protein translocation as a systems biology phenomenon and can be used as a discovery-tool in the protein translocation field.

Exceptionally high levels of lead pollution in the Balkans from the Early Bronze Age to the Industrial Revolution.

The Balkans are considered the birthplace of mineral resource exploitation and metalworking in Europe. However, since knowledge of the timing and extent of metallurgy in southeastern Europe is largely constrained by discontinuous archaeological findings, the long-term environmental impact of past mineral resource exploitation is not fully understood. Here, we present a high-resolution and continuous geochemical record from a peat bog in western Serbia, providing a clear indication of the extent and magnitude of environmental pollution in this region, and a context in which to place archaeological findings. We observe initial evidence of anthropogenic lead (Pb) pollution during the earliest part of the Bronze Age [∼3,600 years before Common Era (BCE)], the earliest such evidence documented in European environmental records. A steady, almost linear increase in Pb concentration after 600 BCE, until ∼1,600 CE is observed, documenting the development in both sophistication and extent of southeastern European metallurgical activity throughout Antiquity and the medieval period. This provides an alternative view on the history of mineral exploitation in Europe, with metal-related pollution not ceasing at the fall of the western Roman Empire, as was the case in western Europe. Further comparison with other Pb pollution records indicates the amount of Pb deposited in the Balkans during the medieval period was, if not greater, at least similar to records located close to western European mining regions, suggestive of the key role the Balkans have played in mineral resource exploitation in Europe over the last 5,600 years.

Impact of climate change on the transition of Neanderthals to modern humans in Europe.

Two speleothem stable isotope records from East-Central Europe demonstrate that Greenland Stadial 12 (GS12) and GS10-at 44.3-43.3 and 40.8-40.2 ka-were prominent intervals of cold and arid conditions. GS12, GS11, and GS10 are coeval with a regional pattern of culturally (near-)sterile layers within Europe's diachronous archeologic transition from Neanderthals to modern human Aurignacian. Sterile layers coeval with GS12 precede the Aurignacian throughout the middle and upper Danube region. In some records from the northern Iberian Peninsula, such layers are coeval with GS11 and separate the Châtelperronian from the Aurignacian. Sterile layers preceding the Aurignacian in the remaining Châtelperronian domain are coeval with GS10 and the previously reported 40.0- to 40.8-ka cal BP [calendar years before present (1950)] time range of Neanderthals' disappearance from most of Europe. This suggests that ecologic stress during stadial expansion of steppe landscape caused a diachronous pattern of depopulation of Neanderthals, which facilitated repopulation by modern humans who appear to have been better adapted to this environment. Consecutive depopulation-repopulation cycles during severe stadials of the middle pleniglacial may principally explain the repeated replacement of Europe's population and its genetic composition.

Living with a Brain AVM: A Quality of Life Assessment.

BACKGROUND AND PURPOSE: Brain arteriovenous malformations (AVM) are uncommon vascular lesions with the risk of hemorrhage, epileptic seizures, neurological deficits, and headache. Comparing the risks of the natural history and that of preventive treatment, a recent study has found observation more beneficial than treatment for unruptured AVMs. This study, however, did not consider the long-term impact of carrying a brain AVM on everyday activities. In this study we analyzed the Quality Of Life (QOL) of patients with untreated AVMs, a measure increasingly used in clinical trials to asses this kind of impact. METHODS: We enrolled 36 patients with unruptured, untreated brain AVM from our hospital database and measured their QOL retrospectively using the EQ-5D-5L questionnaire. As a control group we used the results of the Research Report, a nationwide study based on the quality of life of 5534 healthy Hungarians in 2002. Due to the low number of cases, statistical analysis could not be made. RESULTS: Headache proved to be the most common AVM-related sign in our cohort (40%, n = 17), with a female predominance; neurological deficit was detected in 33% (n = 14), while epileptic seizures occurred in 26% (n = 11), more commonly affecting male subjects. Anxiety and discomfort seemed to be the most prevalent influencing factors on QOL, especially in the youngest age group (18-34 years). Female subjects showed a greater dependence than men in all age groups, though males had a more significant impairment in their usual activities. Older patients were affected more significantly in their self-care and usual activities compared with the younger population. CONCLUSIONS: Untreated AVMs have a significant negative impact on patients carrying unruptured brain AVMs, as proved by QOL assessment. Beside neurological deficits, this impact should also be considered in the therapeutic decision.

Folate-Targeted Monodisperse PEG-Based Conjugates Made by Chemo-Enzymatic Methods for Cancer Diagnosis and Treatment.

This paper focuses on preliminary in vitro and in vivo testing of new bivalent folate-targeted PEGylated doxorubicin (DOX) made by modular chemo-enzymatic processes (FA2-dPEG-DOX2). A unique feature is the use of monodisperse PEG (dPEG). The modular approach with enzyme catalysis ensures exclusive γ-conjugation of folic acid, full conversion and selectivity, and no metal catalyst residues. Flow cytometry analysis showed that at 10 µM concentration, both free DOX and FA2-dPEG-DOX2 would be taken up by 99.9% of triple-negative breast cancer cells in 2 h. Intratumoral injection to mice seemed to delay tumor growth more than intravenous delivery. The mouse health status, food, water consumption, and behavior remained unchanged during the observation.

The EntOptLayout Cytoscape plug-in for the efficient visualization of major protein complexes in protein-protein interaction and signalling networks.

MOTIVATION: Network visualizations of complex biological datasets usually result in 'hairball' images, which do not discriminate network modules. RESULTS: We present the EntOptLayout Cytoscape plug-in based on a recently developed network representation theory. The plug-in provides an efficient visualization of network modules, which represent major protein complexes in protein-protein interaction and signalling networks. Importantly, the tool gives a quality score of the network visualization by calculating the information loss between the input data and the visual representation showing a 3- to 25-fold improvement over conventional methods. AVAILABILITY AND IMPLEMENTATION: The plug-in (running on Windows, Linux, or Mac OS) and its tutorial (both in written and video forms) can be downloaded freely under the terms of the MIT license from: http://apps.cytoscape.org/apps/entoptlayout. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Thrombocytosis and Effects of IL-6 Knock-Out in a Colitis-Associated Cancer Model.

There is an increasing number of studies showing that thrombocytosis-accompanying a variety of solid tumors including colorectal cancer (CRC)-is associated with shorter survival and earlier development of metastases. The mechanisms of cancer-associated thrombocytosis are not completely understood yet. The aim of our study was to evaluate the role of IL-6 in tumor development and thrombocytosis in mice with inflammation-induced CRC, using a CRISPR/cas9 IL-6 knockout (KO) strain. Adult male FB/Ant mice (n = 39) were divided into four groups: (1) IL-6 KO controls (n = 5); (2) IL-6 KO CRC model group (n = 18); (3) Wild-type (WT) controls (n = 6); and (4) WT CRC model group (n = 10). CRC model animals in (2) and (4) received azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment to induce inflammation-related CRC. Plasma and liver tissues were obtained to determine platelet counts, IL-6 and thrombopoietin-1 (TPO) levels. In 1 WT and 2 IL-6 KO mice in vivo confocal endomicroscopy and 18F-fluorodeoxyglucose (FDG) PET/MRI examinations were performed to evaluate the inflammatory burden and neoplastic transformation. At the end of the study, tumorous foci could be observed macroscopically in both CRC model groups. Platelet counts were significantly elevated in the WT CRC group compared to the IL-6 KO CRC group. TPO levels moved parallelly with platelet counts. In vivo fluorescent microscopy showed signs of disordered and multi-nuclear crypt morphology with increased mucus production in a WT animal, while regular mucosal structure was prominent in the IL-6 KO animals. The WT animal presented more intense and larger colonic FDG uptake than IL-6 KO animals. Our study confirmed thrombocytosis accompanying inflammation-related CRC and the crucial role of IL-6 in this process. Significantly higher platelet counts were found in the WT CRC group compared to both the control group and the IL-6 KO group. Concomitantly, the tumor burden of WT mice was also greater than that of IL-6 KO mice. Our findings are in line with earlier paraneoplastic IL-6 effect suggestions.

Stent Protrusion >20 mm Into the Aorta: A New Predictor for Restenosis After Kissing Stent Reconstruction of the Aortoiliac Bifurcation.

PURPOSE: To determine the long-term patency of aortoiliac kissing stents and to identify predisposing factors for the development of in-stent restenosis (ISR). METHODS: A retrospective analysis was conducted of 105 patients (median age 60.9 years; 64 women) with symptomatic aortoiliac occlusive disease who had kissing stents implanted between 2001 and 2015. The indication for kissing stents was severe claudication in 91 (86.7%) patients and critical limb ischemia in 14 (13.3%). Lesions were TASC A in 52 (49.5%), B in 29 (27.6%), C in 4 (3.8%), and D in 20 (19%) patients. Twenty-five (23.8%) patients had heavily calcified lesions. In all, 210 stents were deployed [180 (85.7%) self-expanding and 30 (14.3%) balloon-expandable]. Follow-up included clinical evaluation, ankle-brachial index measurement, and duplex ultrasonography. RESULTS: The median follow-up was 45 months. The primary patency rates were 93%, 86%, and 77% at 12, 24, and 60 months, respectively. Significant ISR developed in 23 (21.9%) patients (12 unilateral and 11 bilateral). Univariate Cox regression analysis revealed older age [hazard ratio (HR) 0.5, 95% confidence interval (CI) 0.31 to 0.81, p=0.004] and larger aortic diameter (HR 0.42, 95% CI 0.25 to 0.7, p<0.001) to be variables favoring long-term patency, while a longer aortic stent segment (HR 1.56, 95% CI 1.16 to 2.09, p=0.003) and a larger discrepancy between the summed stent diameters and the aortic diameter (HR 1.64, 95% CI 1.01 to 2.65, p=0.043) were associated with ISR development. Multivariate analysis showed a longer aortic stent segment to be the only significant determinant of ISR (HR 1.44, 95% CI 1.02 to 2.01, p=0.035). CONCLUSION: The kissing stent technique can be performed with good long-term patency. Patients whose iliac stents protrude too far into the aorta need closer follow-up.

ComPPI: a cellular compartment-specific database for protein-protein interaction network analysis.

Here we present ComPPI, a cellular compartment-specific database of proteins and their interactions enabling an extensive, compartmentalized protein-protein interaction network analysis (URL: http://ComPPI.LinkGroup.hu). ComPPI enables the user to filter biologically unlikely interactions, where the two interacting proteins have no common subcellular localizations and to predict novel properties, such as compartment-specific biological functions. ComPPI is an integrated database covering four species (S. cerevisiae, C. elegans, D. melanogaster and H. sapiens). The compilation of nine protein-protein interaction and eight subcellular localization data sets had four curation steps including a manually built, comprehensive hierarchical structure of >1600 subcellular localizations. ComPPI provides confidence scores for protein subcellular localizations and protein-protein interactions. ComPPI has user-friendly search options for individual proteins giving their subcellular localization, their interactions and the likelihood of their interactions considering the subcellular localization of their interacting partners. Download options of search results, whole-proteomes, organelle-specific interactomes and subcellular localization data are available on its website. Due to its novel features, ComPPI is useful for the analysis of experimental results in biochemistry and molecular biology, as well as for proteome-wide studies in bioinformatics and network science helping cellular biology, medicine and drug design.

Cancer stem cells display extremely large evolvability: alternating plastic and rigid networks as a potential Mechanism: network models, novel therapeutic target strategies, and the contributions of hypoxia, inflammation and cellular senescence.

Cancer is increasingly perceived as a systems-level, network phenomenon. The major trend of malignant transformation can be described as a two-phase process, where an initial increase of network plasticity is followed by a decrease of plasticity at late stages of tumor development. The fluctuating intensity of stress factors, like hypoxia, inflammation and the either cooperative or hostile interactions of tumor inter-cellular networks, all increase the adaptation potential of cancer cells. This may lead to the bypass of cellular senescence, and to the development of cancer stem cells. We propose that the central tenet of cancer stem cell definition lies exactly in the indefinability of cancer stem cells. Actual properties of cancer stem cells depend on the individual "stress-history" of the given tumor. Cancer stem cells are characterized by an extremely large evolvability (i.e. a capacity to generate heritable phenotypic variation), which corresponds well with the defining hallmarks of cancer stem cells: the possession of the capacity to self-renew and to repeatedly re-build the heterogeneous lineages of cancer cells that comprise a tumor in new environments. Cancer stem cells represent a cell population, which is adapted to adapt. We argue that the high evolvability of cancer stem cells is helped by their repeated transitions between plastic (proliferative, symmetrically dividing) and rigid (quiescent, asymmetrically dividing, often more invasive) phenotypes having plastic and rigid networks. Thus, cancer stem cells reverse and replay cancer development multiple times. We describe network models potentially explaining cancer stem cell-like behavior. Finally, we propose novel strategies including combination therapies and multi-target drugs to overcome the Nietzschean dilemma of cancer stem cell targeting: "what does not kill me makes me stronger".

Synthesis, Characterization, and Application of Core-Shell Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm) Nanoparticle as Trimodal (MRI, PET/SPECT, and Optical) Imaging Agents.

Multimodal nanoparticulate materials are described, offering magnetic, radionuclide, and fluorescent imaging capabilities to exploit the complementary advantages of magnetic resonance imaging (MRI), positron emission tomography/single-photon emission commuted tomography (PET/SPECT), and optical imaging. They comprise Fe3O4@NaYF4 core/shell nanoparticles (NPs) with different cation dopants in the shell or core, including Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm). These NPs are stabilized by bisphosphonate polyethylene glycol conjugates (BP-PEG), and then show a high transverse relaxivity (r2) up to 326 mM(-1) s(-1) at 3T, a high affinity to [(18)F]-fluoride or radiometal-bisphosphonate conjugates (e.g., (64)Cu and (99m)Tc), and fluorescent emissions from 500 to 800 nm under excitation at 980 nm. The biodistribution of intravenously administered particles determined by PET/MR imaging suggests that negatively charged Co0.16Fe2.84O4@NaYF4(Yb, Er)-BP-PEG (10K) NPs cleared from the blood pool more slowly than positively charged NPs Fe3O4@NaYF4(Yb, Tm)-BP-PEG (2K). Preliminary results in sentinel lymph node imaging in mice indicate the advantages of multimodal imaging.