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Introduction: There is still an ongoing debate whether a transrectal ultrasound (TRUS) approach for prostate biopsies is associated with higher (infectious) complications rates compared to transperineal biopsies. This is especially of great interests in settings with elevated frequencies of multidrug resistant organisms (MDRO).
Materials and Methods: Between 01/2018 and 05/2019 230 patients underwent a TRUS-guided prostate biopsy at the department of Urology at University Hospital Frankfurt. Patients were followed up within the clinical routine that was not conducted earlier than 6 weeks after the biopsy. Among 230 biopsies, 180 patients took part in the follow-up. No patients were excluded. Patients were analyzed retrospectively regarding complications, infections and underlying infectious agents or needed interventions.
Results: Of all patients with follow up, 84 patients underwent a systematic biopsy (SB) and 96 a targeted biopsy (TB) after MRI of the prostate with additional SB. 74.8% of the patients were biopsy-naïve. The most frequent objective complications (classified by Clavien-Dindo) lasting longer than one day after biopsy were hematuria (17.9%, n = 32), hematospermia (13.9%, n = 25), rectal bleeding (2.8%, n = 5), and pain (2.2%, n = 4). Besides a known high MDRO prevalence in the Rhine-Main region, only one patient (0.6%) developed fever after biopsy. One patient each (0.6%) consulted a physician due to urinary retention, rectal bleeding or gross hematuria. There were no significant differences in complications seen between SB and SB + TB patients. The rate of patients who consulted a physician was significantly higher for patients with one or more prior biopsies compared to biopsy-naïve patients.
Conclusion: Complications after transrectal prostate biopsies are rare and often self-limiting. Infections were seen in <1% of all patients, regardless of an elevated local prevalence of MDROs. Severe complications (Clavien-Dindo ≥ IIIa) were only seen in 3 (1.7%) of the patients. Repeated biopsy is associated with higher complication rates in general.
Objective: To analyze the effect of adverse preoperative patient and tumor characteristics on perioperative outcomes of open (ORP) and robot-assisted radical prostatectomy (RARP).
Material and Methods: We retrospectively analyzed 656 patients who underwent ORP or RARP according to intraoperative blood loss (BL), operation time (OR time), neurovascular bundle preservation (NVBP) and positive surgical margins (PSM). Univariable and multivariable logistic regression models were used to identify risk factors for impaired perioperative outcomes.
Results: Of all included 619 patients, median age was 66 years. BMI (<25 vs. 25-30 vs. ≥30) had no influence on blood loss. Prostate size >40cc recorded increased BL compared to prostate size ≤ 40cc in patients undergoing ORP (800 vs. 1200 ml, p < 0.001), but not in patients undergoing RARP (300 vs. 300 ml, p = 0.2). Similarly, longer OR time was observed for ORP in prostates >40cc, but not for RARP. Overweight (BMI 25-30) and obese ORP patients (BMI ≥30) showed longer OR time compared to normal weight (BMI <25). Only obese patients, who underwent RARP showed longer OR time compared to normal weight. NVBP was less frequent in obese patients, who underwent ORP, relative to normal weight (25.8% vs. 14.0%, p < 0.01). BMI did not affect NVPB at RARP. No differences in PSM were recorded according to prostate volume or BMI in ORP or RARP. In multivariable analyses, patient characteristics such as prostate volume and BMI was an independent predictor for prolonged OR time. Moreover, tumor characteristics (stage and grade) predicted worse perioperative outcome.
Conclusion: Patients with larger prostates and obese patients undergoing ORP are at risk of higher BL, OR time or non-nervesparing procedure. Conversely, in patients undergoing RARP only obesity is associated with increased OR time. Patients with larger prostates or increased BMI might benefit most from RARP compared to ORP.
Introduction: Ischemic and hemorrhagic strokes in the brainstem and cerebellum with injury to the functional loop of the Guillain-Mollaret triangle (GMT) can trigger a series of events that result in secondary trans-synaptic neurodegeneration of the inferior olivary nucleus. In an unknown percentage of patients, this leads to a condition called hypertrophic olivary degeneration (HOD). Characteristic clinical symptoms of HOD progress slowly over months and consist of a rhythmic palatal tremor, vertical pendular nystagmus, and Holmes tremor of the upper limbs. Diffusion Tensor Imaging (DTI) with tractography is a promising method to identify functional pathway lesions along the cerebello-thalamo-cortical connectivity and to generate a deeper understanding of the HOD pathophysiology. The incidence of HOD development following stroke and the timeline of clinical symptoms have not yet been determined in prospective studies—a prerequisite for the surveillance of patients at risk. Methods and Analysis: Patients with ischemic and hemorrhagic strokes in the brainstem and cerebellum with a topo-anatomical relation to the GMT are recruited within certified stroke units of the Interdisciplinary Neurovascular Network of the Rhine-Main. Matching lesions are identified using a predefined MRI template. Eligible patients are prospectively followed up and present at 4 and 8 months after the index event. During study visits, a clinical neurological examination and brain MRI, including high-resolution T2-, proton-density-weighted imaging, and DTI tractography, are performed. Fiberoptic endoscopic evaluation of swallowing is optional if palatal tremor is encountered. Study Outcomes: The primary endpoint of this prospective clinical multicenter study is to determine the frequency of radiological HOD development in patients with a posterior fossa stroke affecting the GMT at 8 months after the index event. Secondary endpoints are identification of (1) the timeline and relevance of clinical symptoms, (2) lesion localizations more prone to HOD occurrence, and (3) the best MR-imaging regimen for HOD identification. Additionally, (4) DTI tractography data are used to analyze individual pathway lesions. The aim is to contribute to the epidemiological and pathophysiological understanding of HOD and hereby facilitate future research on therapeutic and prophylactic measures.
Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis
(2019)
Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option.
Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection.
Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers.
Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.
Background: To evaluate the impact of time to castration resistance (TTCR) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies for mHSPC.
Material and Methods: Of 213 mHSPC patients diagnosed between 01/2013-12/2020 who subsequently developed metastatic castration resistant prostate cancer (mCRPC), 204 eligible patients were analyzed after having applied exclusion criteria. mHSPC patients were classified into TTCR <12, 12-18, 18-24, and >24 months and analyzed regarding OS. Moreover, further OS analyses were performed after having developed mCRPC status according to TTCR. Logistic regression models predicted the value of TTCR on OS.
Results: Median follow-up was 34 months. Among 204 mHSPC patients, 41.2% harbored TTCR <12 months, 18.1% for 12-18 months, 15.2% for 18-24 months, and 25.5% for >24 months. Median age was 67 years and median PSA at prostate cancer diagnosis was 61 ng/ml. No differences in patient characteristics were observed (all p>0.05). According to OS, TTCR <12 months patients had the worst OS, followed by TTCR 12-18 months, 18-24 months, and >24 months, in that order (p<0.001). After multivariable adjustment, a 4.07-, 3.31-, and 6.40-fold higher mortality was observed for TTCR 18-24 months, 12-18 months, and <12 months patients, relative to TTCR >24 months (all p<0.05). Conversely, OS after development of mCRPC was not influenced by TTCR stratification (all p>0.05).
Conclusion: Patients with TTCR <12 months are at the highest OS disadvantage in mHSPC. This OS disadvantage persisted even after multivariable adjustment. Interestingly, TTCR stratified analyses did not influence OS in mCRPC patients.
Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections.
Materials and methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study.
Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0–19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6–30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002).
Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections.
The transverse mass mt distributions for deuterons and protons are measured in Pb+Pb reactions near midrapidity and in the range 0<mt–m<1.0 (1.5) GeV/c2 for minimum bias collisions at 158A GeV and for central collisions at 40 and 80 A GeV beam energies. The rapidity density dn/dy, inverse slope parameter T and mean transverse mass <mt> derived from mt distributions as well as the coalescence parameter B2 are studied as a function of the incident energy and the collision centrality. The deuteron mt spectra are significantly harder than those of protons, especially in central collisions. The coalescence factor B2 shows three systematic trends. First, it decreases strongly with increasing centrality reflecting an enlargement of the deuteron coalescence volume in central Pb+Pb collisions. Second, it increases with mt. Finally, B2 shows an increase with decreasing incident beam energy even within the SPS energy range. The results are discussed and compared to the predictions of models that include the collective expansion of the source created in Pb+Pb collisions.
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.
Background: Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement ‘hotspot’ loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained.
Objective: To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype.
Methods: We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls.
Results: When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10−6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10−12, OR 7.45, 95% CI 4.20–13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10−3,OR 2.85, 95% CI 1.62–4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls.
Conclusions: Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE.
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Quasifree one-proton knockout reactions have been employed in inverse kinematics for a systematic study of the structure of stable and exotic oxygen isotopes at the R3B/LAND setup with incident beam energies in the range of 300–450 MeV/u. The oxygen isotopic chain offers a large variation of separation energies that allows for a quantitative understanding of single-particle strength with changing isospin asymmetry. Quasifree knockout reactions provide a complementary approach to intermediate-energy one-nucleon removal reactions. Inclusive cross sections for quasifree knockout reactions of the type AO(p,2p)A−1N have been determined and compared to calculations based on the eikonal reaction theory. The reduction factors for the single-particle strength with respect to the independent-particle model were obtained and compared to state-of-the-art ab initio predictions. The results do not show any significant dependence on proton-neutron asymmetry.
The ability of hematopoietic stem cells (HSCs) to self-renew is a prerequisite for the establishment of definitive hematopoiesis and life-long blood regeneration. Here, we report the single-stranded DNA-binding transcriptional regulator far upstream element (FUSE)-binding protein 1 (FUBP1) as an essential factor of HSC self-renewal. Functional inactivation of FUBP1 in two different mouse models resulted in embryonic lethal anemia at around E15.5 caused by severely diminished HSCs. Fetal and adult HSCs lacking FUBP1 revealed an HSC-intrinsic defect in their maintenance, expansion, and long-term blood reconstitution, but could differentiate into all hematopoietic lineages. FUBP1-deficient adult HSCs exhibit significant transcriptional changes, including upregulation of the cell-cycle inhibitor p21 and the pro-apoptotic Noxa molecule. These changes caused an increase in generation time and death of HSCs as determined by video-microscopy-based tracking. Our data establish FUBP1 and its recognition of single-stranded genomic DNA as an important element in the transcriptional regulation of HSC self-renewal.
We have sampled atmospheric ice nuclei (IN) and aerosol in Germany and in Israel during spring 2010. IN were analyzed by the static vapor diffusion chamber FRIDGE, as well as by electron microscopy. During the Eyjafjallajökull volcanic eruption of April 2010 we have measured the highest ice nucleus number concentrations (>600 l−1) in our record of 2 yr of daily IN measurements in central Germany. Even in Israel, located about 5000 km away from Iceland, IN were as high as otherwise only during desert dust storms. The fraction of aerosol activated as ice nuclei at −18 °C and 119% rhice and the corresponding area density of ice-active sites per aerosol surface were considerably higher than what we observed during an intense outbreak of Saharan dust over Europe in May 2008.
Pure volcanic ash accounts for at least 53–68% of the 239 individual ice nucleating particles that we collected in aerosol samples from the event and analyzed by electron microscopy. Volcanic ash samples that had been collected close to the eruption site were aerosolized in the laboratory and measured by FRIDGE. Our analysis confirms the relatively poor ice nucleating efficiency (at −18 °C and 119% ice-saturation) of such "fresh" volcanic ash, as it had recently been found by other workers. We find that both the fraction of the aerosol that is active as ice nuclei as well as the density of ice-active sites on the aerosol surface are three orders of magnitude larger in the samples collected from ambient air during the volcanic peaks than in the aerosolized samples from the ash collected close to the eruption site. From this we conclude that the ice-nucleating properties of volcanic ash may be altered substantially by aging and processing during long-range transport in the atmosphere, and that global volcanism deserves further attention as a potential source of atmospheric ice nuclei.
Surface measurements of aerosol and ice nuclei (IN) at a Central European mountain site during an episode of dust transport from the Sahara are presented. Ice nuclei were sampled by electrostatic precipitation on silicon wafers and were analyzed in an isothermal static vapor diffusion chamber. The transport of mineral dust is simulated by the Eulerian regional dust model DREAM. Ice nuclei and mineral dust are significantly correlated, in particular IN number concentration and aerosol surface area. The ice nucleating characteristics of the aerosol as analyzed with respect to temperature and supersaturation are similar during the dust episode than during the course of the year. This suggests that dust may be a main constituent of ice nucleating aerosols in Central Europe.
Surface measurements of aerosol and ice nuclei (IN) at a Central European mountain site during an episode of dust transport from the Sahara are presented. Transport is simulated by the Eulerian regional dust model DREAM. Ice nuclei and mineral dust are significantly correlated. The highest correlation is found between IN concentration and aerosol surface area. The ice nucleating characteristics of the aerosol with respect to temperature and supersaturation are similar during the dust episode than during the course of the year. This suggests that dust is always a dominant constituent of ice nucleating aerosols in Central Europe.
Purpose: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) replicates predominantly in the upper respiratory tract and is primarily transmitted by droplets and aerosols. Taking the medical history for typical COVID-19 symptoms and PCR-based SARS-CoV-2 testing have become established as screening procedures. The aim of this work was to describe the clinical appearance of SARS-CoV-2-PCR positive patients and to determine the SARS-CoV-2 contact risk for health care workers (HCW).
Methods: The retrospective study included n = 2283 SARS-CoV-2 PCR tests from n = 1725 patients with otorhinolaryngological (ORL) diseases performed from March to November 2020 prior to inpatient treatment. In addition, demographic data and medical history were assessed.
Results: n = 13 PCR tests (0.6%) were positive for SARS-CoV-2 RNA. The positive rate showed a significant increase during the observation period (p < 0.01). None of the patients had clinical symptoms that led to a suspected diagnosis of COVID-19 before PCR testing. The patients were either asymptomatic (n = 4) or had symptoms that were interpreted as symptoms typical of the ORL disease or secondary diagnoses (n = 9).
Conclusion: The identification of SARS-CoV-2-positive patients is a considerable challenge in clinical practice. Our findings illustrate that taking a medical history alone is of limited value and cannot replace molecular SARS-CoV-2 testing, especially for patients with ORL diseases. Our data also demonstrate that there is a high probability of contact with SARS-CoV-2-positive patients in everyday clinical practice, so that the use of personal protective equipment, even in apparently “routine cases”, is highly recommended.
Targeted protein degradation is a drug modality represented by compounds that recruit a target to an E3 ubiquitin ligase to promote target ubiquitination and proteasomal degradation. Historically, the field distinguishes monovalent degraders from bifunctional degraders (PROTACs) that connect target and ligase via separate binding ligands joined via a linker1–4. Here, we elucidate the mechanism of action of a PROTAC-like degrader of the transcriptional coactivator BRD4, composed of a BRD4 ligand linked to a ligand for the E3 ligase CRL4DCAF15. Using orthogonal CRISPR/Cas9 screens we identify the degrader activity is independent of DCAF15, and relies on a different CRL4 substrate receptor, DCAF16. We demonstrate an intrinsic affinity between BRD4 and DCAF16, which is dependent on the tandem bromodomains of BRD4 and further increased by the degrader without physically engaging DCAF16 in isolation. Structural characterization of the resulting ternary complex reveals both BRD4 bromodomains are bivalently engaged in cis by the degrader and are bound to DCAF16 through several interfacial BRD4-DCAF16 and degrader-DCAF16 contacts. Our findings demonstrate that intramolecularly bridging domains can confer glue-type stabilization of intrinsic target-E3 interactions, and we propose this as a general strategy to modulate the surface topology of target proteins to nucleate co-opting of E3 ligases or other cellular effector proteins for effective proximity-based pharmacology.
Vampire bats are the only mammals that feed exclusively on blood. To uncover genomic changes associated with this dietary adaptation, we generated a haplotype-resolved genome of the common vampire bat and screened 27 bat species for genes that were specifically lost in the vampire bat lineage. We found previously unknown gene losses that relate to reduced insulin secretion (FFAR1 and SLC30A8), limited glycogen stores (PPP1R3E), and a unique gastric physiology (CTSE). Other gene losses likely reflect the biased nutrient composition (ERN2 and CTRL) and distinct pathogen diversity of blood (RNASE7) and predict the complete lack of cone-based vision in these strictly nocturnal bats (PDE6H and PDE6C). Notably, REP15 loss likely helped vampire bats adapt to high dietary iron levels by enhancing iron excretion, and the loss of CYP39A1 could have contributed to their exceptional cognitive abilities. These findings enhance our understanding of vampire bat biology and the genomic underpinnings of adaptations to blood feeding.
Background Drug resistance to chemotherapy is often associated with increased malignancy in neuroblastoma (NB). One explanation for the link between resistance and malignancy might be that resistance facilitates cancer progression and invasion. To investigate this hypothesis, adhesion, transendothelial penetration and NCAM (CD56) adhesion receptor expression of drug-resistant versus drug-sensitive NB tumor cells were evaluated. Methods Acquired drug resistance was mimicked by exposing parental UKF-NB-2, UKF-NB-3 or IMR-32 tumor cells to increasing concentrations of vincristine- (VCR) or doxorubicin (DOX) to establish the resistant tumor cell sublines UKF-NB-2VCR, UKF-NB-2DOX, UKF-NB-3VCR, UKF-NB-3DOX, IMR-32VCR and IMR-32DOX. Additionally, the malignant behaviour of UKF-NB-4, which already possessed the intrinsic multidrug resistance (MDR) phenotype, was analyzed. UKF-NB-4 exposed to VCR or DOX were designated UKF-NB-4VCR or UKF-NB-4DOX. Combined phase contrast - reflection interference contrast microscopy was used to separately evaluate NB cell adhesion and penetration. NCAM was analyzed by flow cytometry, western blot and RT-PCR. Results VCR and DOX resistant tumor sublines showed enhanced adhesion and penetration capacity, compared to their drug naive controls. Strongest effects were seen with UKF-NB-2VCR, UKF-NB-3VCR and IMR-32DOX. DOX or VCR treatment also evoked increased invasive behaviour of UKF-NB-4. The process of accelerated tumor invasion was accompanied by decreased NCAM surface and protein expression, and down-regulation of NCAM coding mRNA. Transfection of UKF-NB-4VCR cells with NCAM cDNA led to a significant receptor up-regulation, paralleled by diminished adhesion to an endothelial cell monolayer. Conclusions It is concluded that NB cells resistant to anticancer drugs acquire increased invasive capacity relative to non-resistant parental cells, and that enhanced invasion is caused by strong down-regulation of NCAM adhesion receptors.
Background: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter.
Methods: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150–200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS.
Results: A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively.
Conclusions: The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.
ClinicalTrials.gov NCT02617589
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here, we show in awake macaque area V1 that both repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects show some persistence on the timescale of minutes. Gamma increases are specific to the presented stimulus location. Further, repetition effects on gamma and on firing rates generalize to images of natural objects. These findings support the notion that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters.
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here we show in awake macaque area V1 that both, repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects showed some persistence on the timescale of minutes. Further, gamma increases were specific to the presented stimulus location. Importantly, repetition effects on gamma and on firing rates generalized to natural images. These findings suggest that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters, both for generating efficient stimulus responses and possibly for memory formation.
Purpose: Prostate specific antigen is not reliable in diagnosing prostate cancer (PCa), making the identification of novel, precise diagnostic biomarkers important. Since chemokines are associated with more aggressive disease and poor prognosis in diverse malignancies, we aimed to investigate the diagnostic relevance of chemokines in PCa.
Materials and methods: Preoperative and early postoperative serum samples were obtained from 39 consecutive PCa patients undergoing radical prostatectomy. Serum from 15 healthy volunteers served as controls. Concentrations of CXCL12, CXCL13, CX3CL1, CCL2, CCL5, and CCL20 were measured in serum by Luminex. The expression activity of CXCR3, CXCR4, CXCR5, CXCR7, CXCL12, CXCL13, CX3CR1, CXCL1, CCR2, CCR5, CCR6, CCR7, CCL2, and CCL5 mRNA was assessed in tumor and adjacent normal tissue of prostatectomy specimens by quantitative real-time polymerase chain reaction. The associations of these chemokines with clinical and histological parameters were tested.
Results: The gene expression activity of CCL2 and CCR6 was significantly higher in tumor tissue compared to adjacent normal tissue. CCL2 was also significantly higher in the blood samples of PCa patients, compared to controls. CCL5, CCL20, and CX3CL1 were lower in patient serum, compared to controls. CCR2 tissue mRNA was negatively correlated with the Gleason score and grading.
Conclusion: Chemokines are significantly modified during tumorigenesis of PCa, and CCL2 is a promising diagnostic biomarker.
The new heavy ion superconducting continuous wave HElmholtz LInear ACcelerator (HELIAC) is under construction at GSI. A normal conducting injector, comprising an ECR ion source, an RFQ and a DTL, is recently in development. The new Interdigital H-mode DTL, presented in this paper, accelerates the heavy ion beam from 300 to 1400 keV/u, applying an Alternating Phase Focusing (APF) beam dynamics scheme. This APF section, consisting of two separately controlled tanks, has to provide for stable routine operation with assistance of dedicated beam diagnostics devices in the Intertank section. The installed quadrupole lenses and beam steerers installed there ensure full transmission in a wide range of input beam parameters.
Sex differences in the relationship between conduct disorder and cortical structure in adolescents
(2017)
Objective: Previous studies have reported reduced cortical thickness and surface area and altered gyrification in frontal and temporal regions in adolescents with conduct disorder (CD). Although there is evidence that the clinical phenotype of CD differs between males and females, no studies have examined whether such sex differences extend to cortical and subcortical structure.
Method: As part of a European multisite study (FemNAT-CD), structural magnetic resonance imaging (MRI) data were collected from 48 female and 48 male participants with CD and from 104 sex-, age-, and pubertal-status−matched controls (14–18 years of age). Data were analyzed using surface-based morphometry, testing for effects of sex, diagnosis, and sex-by-diagnosis interactions, while controlling for age, IQ, scan site, and total gray matter volume.
Results: CD was associated with cortical thinning and higher gyrification in ventromedial prefrontal cortex in both sexes. Males with CD showed lower, and females with CD showed higher, supramarginal gyrus cortical thickness compared with controls. Relative to controls, males with CD showed higher gyrification and surface area in superior frontal gyrus, whereas the opposite pattern was seen in females. There were no effects of diagnosis or sex-by-diagnosis interactions on subcortical volumes. Results are discussed with regard to attention-deficit/hyperactivity disorder, depression, and substance abuse comorbidity, medication use, handedness, and CD age of onset.
Conclusion: We found both similarities and differences between males and females in CD–cortical structure associations. This initial evidence that the pathophysiological basis of CD may be partly sex-specific highlights the need to consider sex in future neuroimaging studies and suggests that males and females may require different treatments.
Objective: Studies using diffusion tensor imaging (DTI) to investigate white matter (WM) microstructure in youths with conduct disorder (CD) have reported disparate findings. We investigated WM alterations in a large sample of youths with CD, and examined the influence of sex and callous-unemotional (CU) traits.
Method: DTI data were acquired from 124 youths with CD (59 female) and 174 typically developing (TD) youths (103 female) 9 to 18 years of age. Tract-based spatial statistics tested for effects of diagnosis and sex-by-diagnosis interactions. Associations with CD symptoms, CU traits, a task measuring impulsivity, and the impact of comorbidity, and age- and puberty-related effects were examined.
Results: Youths with CD exhibited higher axial diffusivity in the corpus callosum and lower radial diffusivity and mean diffusivity in the anterior thalamic radiation relative to TD youths. Female and male youths with CD exhibited opposite changes within the internal capsule, fornix, posterior thalamic radiation, and uncinate fasciculus. Within the CD group, CD symptoms and callous traits exerted opposing influences on corpus callosum axial diffusivity, with callous traits identified as the unique clinical feature predicting higher axial diffusivity and lower radial diffusivity within the corpus callosum and anterior thalamic radiation, respectively. In an exploratory analysis, corpus callosum axial diffusivity partially mediated the association between callous traits and impulsive responses to emotional faces. Results were not influenced by symptoms of comorbid disorders, and no age- or puberty-related interactions were observed.
Conclusion: WM alterations within the corpus callosum represent a reliable neuroimaging marker of CD. Sex and callous traits are important factors to consider when examining WM in CD.
Sex differences in psychiatric comorbidity and clinical presentation in youths with conduct disorder
(2021)
Background: Conduct disorder (CD) rarely occurs alone but is typically accompanied by comorbid psychiatric disorders, which complicates the clinical presentation and treatment of affected youths. The aim of this study was to investigate sex differences in comorbidity pattern in CD and to systematically explore the ‘gender paradox’ and ‘delayed-onset pathway’ hypotheses of female CD.
Methods: As part of the FemNAT-CD multisite study, semistructured clinical interviews and rating scales were used to perform a comprehensive phenotypic characterization of 454 girls and 295 boys with CD (9–18 years), compared to 864 sex- and age-matched typically developing controls.
Results: Girls with CD exhibited higher rates of current major depression, anxiety disorders, post-traumatic stress disorder and borderline personality disorder, whereas boys with CD had higher rates of current attention-deficit/hyperactivity disorder. In line with the ‘gender paradox’ hypothesis, relative to boys, girls with CD showed significantly more lifetime psychiatric comorbidities (incl. Alcohol Use Disorder), which were accompanied by more severe CD symptoms. Female and male youths with CD also differed significantly in their CD symptom profiles and distribution of age-of-onset subtypes of CD (i.e. fewer girls with childhood-onset CD). In line with the ‘delayed-onset pathway’ hypothesis, girls with adolescent-onset CD showed similar levels of dimensional psychopathology like boys with childhood-onset CD, while boys with adolescent-onset CD had the lowest levels of internalizing psychopathology.
Conclusions: Within the largest study of CD in girls performed to date, we found compelling evidence for sex differences in comorbidity patterns and clinical presentation of CD. Our findings further support aspects of the ‘gender paradox’ and ‘delayed-onset pathway’ hypotheses by showing that girls with CD had higher rates of comorbid lifetime mental disorders and functional impairments, and they usually developed CD during adolescence. These novel data on sex-specific clinical profiles of CD will be critical in informing intervention and prevention programmes.
Callous-unemotional traits are characterized by a lack of empathy, a disregard for others' feelings and shallow or deficient affect, such as a lack of remorse or guilt. Neuroanatomical correlates of callous-unemotional traits have been demonstrated in clinical samples (i.e., adolescents with disruptive behavior disorders). However, it is unknown whether callous-unemotional traits are associated with neuroanatomical correlates within normative populations without clinical levels of aggression or antisocial behavior. Here we investigated the relationship between callous-unemotional traits and gray matter volume using voxel-based morphometry in a large sample of typically-developing boys and girls (N = 189). Whole-brain multiple regression analyses controlling for site, total intracranial volume, and age were conducted in the whole sample and in boys and girls individually. Results revealed that sex and callous-unemotional traits interacted to predict gray matter volume when considering the whole sample. This interaction was driven by a significant positive correlation between callous-unemotional traits and bilateral anterior insula volume in boys, but not girls. Insula gray matter volume explained 19% of the variance in callous-unemotional traits for boys. Our results demonstrate that callous-unemotional traits are related to variations in brain structure beyond psychiatric samples. This association was observed for boys only, underlining the importance of considering sex as a factor in future research designs. Future longitudinal studies should determine whether these findings hold over childhood and adolescence, and whether the neuroanatomical correlates of callous-unemotional traits are predictive of future psychiatric vulnerability.
Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.
Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.
Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
The transition to a future electricity system based primarily on wind and solar PV is examined for all regions in the contiguous US. We present optimized pathways for the build-up of wind and solar power for least backup energy needs as well as for least cost obtained with a simplified, lightweight model based on long-term high resolution weather-determined generation data. In the absence of storage, the pathway which achieves the best match of generation and load, thus resulting in the least backup energy requirements, generally favors a combination of both technologies, with a wind/solar PV (photovoltaics) energy mix of about 80/20 in a fully renewable scenario. The least cost development is seen to start with 100% of the technology with the lowest average generation costs first, but with increasing renewable installations, economically unfavorable excess generation pushes it toward the minimal backup pathway. Surplus generation and the entailed costs can be reduced significantly by combining wind and solar power, and/or absorbing excess generation, for example with storage or transmission, or by coupling the electricity system to other energy sectors.
Objectives: Stenosis of the biliary anastomosis predisposes liver graft recipients to bacterial cholangitis. Antibiotic therapy (AT) is performed according to individual clinical judgment, but duration of AT remains unclear.
Methods: All liver graft recipients with acute cholangitis according to the Tokyo criteria grade 1 and 2 after endoscopic retrograde cholangiography (ERC) were included. Outcome of patients treated with short AT (<7 days) was compared to long AT (>6 days). Recurrent cholangitis (RC) within 28 days was the primary end point.
Results: In total, 30 patients were included with a median of 313 (range 34–9849) days after liver transplantation until first proven cholangitis. Among 62 cases in total, 51/62 (82%) were graded as Tokyo-1 and 11/62 (18%) as Tokyo-2. Overall median duration of AT was 6 days (1–14) with 36 cases (58%) receiving short AT and 26 (42%) receiving long AT. RC was observed in 10 (16%) cases, without significant difference in occurrence of RC in short versus long AT cases. CRP and bilirubin were significantly higher in patients with long AT, while low serum albumin and low platelets were associated with risk of RC.
Conclusion: A shorter antibiotic course than 7 days shows good results in selected, ERC-treated patients for post-transplantation biliary strictures.
Accurate spectroscopy of highly-charged high-Z ions in a storage ring is demonstrated to be feasible by the use of specially adapted crystal optics. The method has been applied for the measurement of the 1s Lamb shift in hydrogen-like gold (Au+78) in a storage ring through spectroscopy of the Lyman x-rays. This measurement represents the first result obtained for a high-Z element using high-resolution wavelength-dispersive spectroscopy in the hard x-ray regime, paving the way for sensitivity to higher- order QED effects.
Chemical pollution caused by synthetic organic chemicals at low concentrations in the environment poses a growing threat to the ecological status of aquatic ecosystems. These chemicals are regularly released into surface waters through both treated and untreated effluents from wastewater treatment plants (WWTPs), agricultural runoff, and industrial discharges. Consequently, they accumulate in surface waters, distribute amongst environmental compartments according to their physicochemical properties, and cause adverse effects on aquatic organisms. Unfortunately, there is a lack of data regarding the occurrence of synthetic organic chemicals, henceforth micropollutants, in South American freshwater ecosystems, especially in Chile.
To address this research gap, we present a comprehensive dataset comprising concentrations of 153 emerging chemicals, including pesticides, pharmaceutical and personal care products (PPCPs), surfactants, and industrial chemicals. These chemicals were found to co-occur in surface waters within Central Chile, specifically in the River Aconcagua Basin. Our sampling strategy involved collecting surface water samples from streams and rivers with diverse land uses, such as agriculture, urban areas, and natural reserves. For sample extraction, we employed an on-site large-volume solid phase extraction (LVSPE) device. The resulting environmental extracts were then subjected to wide-scope chemical target screening using gas chromatography and liquid chromatography high-resolution mass spectrometry (GC- and LCsingle bondHRMS).
The dataset we present holds significant value in assessing the chemical status of water bodies. It enables comparative analysis of pollution fingerprints associated with emerging chemicals across different freshwater systems. Moreover, the data can be reused for environmental risk assessment studies. Its utilisation will contribute to a better understanding of the impact and extent of chemical pollution in aquatic ecosystems, facilitating the development of effective mitigation strategies.
Results are presented on event-by-event fluctuations in transverse momentum of charged particles, produced at forward rapidities in p+p, C+C, Si+Si and Pb+Pb collisions at 158 AGeV. Three different characteristics are discussed: the average transverse momentum of the event, the Phi_pT fluctuation measure and two-particle transverse momentum correlations. In the kinematic region explored, the dynamical fluctuations are found to be small. However, a significant system size dependence of Phi_pT is observed, with the largest value measured in peripheral Pb+Pb interactions. The data are compared with predictions of several models. PACS numbers: 14.20.Jn, 13.75.Cs, 12.39.-x
Evidence for an exotic S=-2, Q=-2 baryon resonance in proton-proton collisions at the CERN SPS
(2004)
Results of resonance searches in the Xi - pi -, Xi - pi +, Xi -bar+ pi -, and Xi -bar+ pi + invariant mass spectra in proton-proton collisions at sqrt[s]=17.2 GeV are presented. Evidence is shown for the existence of a narrow Xi - pi - baryon resonance with mass of 1.862±0.002 GeV/c2 and width below the detector resolution of about 0.018 GeV/c2. The significance is estimated to be above 4.2 sigma . This state is a candidate for the hypothetical exotic Xi --3/2 baryon with S=-2, I=3 / 2, and a quark content of (dsdsu-bar). At the same mass, a peak is observed in the Xi - pi + spectrum which is a candidate for the Xi 03/2 member of this isospin quartet with a quark content of (dsusd-bar). The corresponding antibaryon spectra also show enhancements at the same invariant mass.
Observation of an exotic S = -2, Q = -2 baryon resonance in proton-proton collisions at the CERN SPS
(2003)
Results of resonance searches in the Xi- pi-, Xi- pi+, antiXi+ pi- and antiXi+ pi+ invariant mass spectra in proton-proton collisions at sqrt s=17.2 GeV are presented. Evidence is shown for the existence of a narrow Xi- pi- baryon resonance with mass of 1.862+/-0.002 GeV/c^2 and width below the detector resolution of about 0.018 GeV/c^2. The significance is estimated to be 4.0 sigma. This state is a candidate for the hypothetical exotic Xi_(3/2)^-- baryon with S = -2, I = 3/2 and a quark content of (d s d s ubar). At the same mass a peak is observed in the Xi- pi+ spectrum which is a candidate for the Xi_(3/2)^0 member of this isospin quartet with a quark content of (d s u s dbar). The corresponding antibaryon spectra also show enhancements at the same invariant mass.
Report from NA49
(2004)
The most recent data of NA49 on hadron production in nuclear collisions at CERN SPS energies are presented. Anomalies in the energy dependence of pion and kaon production in central Pb+Pb collisions are observed. They suggest that the onset of deconfinement is located at about 30 AGeV. Large multiplicity and transverse momentum fluctuations are measured for collisions of intermediate mass systems at 158 AGeV. The need for a new experimental programme at the CERN SPS is underlined.
Event-by-event fluctuations of particle ratios in central Pb + Pb collisions at 20 to 158 AGeV
(2004)
In the vicinity of the QCD phase transition, critical fluctuations have been predicted to lead to non-statistical fluctuations of particle ratios, depending on the nature of the phase transition. Recent results of the NA49 energy scan program show a sharp maximum of the ratio of K+ to Pi+ yields in central Pb+Pb collisions at beam energies of 20-30 AGeV. This observation has been interpreted as an indication of a phase transition at low SPS energies. We present first results on event-by-event fluctuations of the kaon to pion and proton to pion ratios at beam energies close to this maximum.
A non-monotonic energy dependence of the K + / pi + ratio with a sharp maximum close to 30 A GeV is observed in central Pb+Pb collisions. Within a statistical model of the early stage, this is interpreted as a sign of the phase transition to a QGP, which causes a sharp change in the energy dependence of the strangeness to entropy ratio. This observation naturally motivates us to study the production of multistrange hyperons (Xi, Omega) as a function of the beam energy. Furthermore it was suggested that the kinematic freeze-out of Omega takes place directly at QGP hadronization. If this is indeed the case, the transverse momentum spectra of the Omega directly reflect the transverse expansion velocity of a hadronizing QGP. In this report we show preliminary NA49 results on Omega - and Omega + production in central Pb+Pb collisions at 40 and 158 A GeV and compare them to measurements of Xi - and Xi + production in central Pb+Pb collisions at 30, 40, 80 and 158 A GeV.
Objective: To assess predictive factors for poststroke pneumonia (PSP) in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) of the anterior circulation, with special regard to the impact of intravenous thrombolysis (IVT) and endovascular treatment (EVT) on the risk of PSP. As a secondary goal, the validity of the A2DS2, PNEUMONIA, and ISAN scores in LVO will be determined.
Methods: Analysis was based on consecutive data for the years 2017 to 2019 from the prospective inpatient stroke registry covering the entire federal state of Hesse, Germany, using the Kruskal-Wallis test and binary logistic regression.
Results: Data from 4,281 patients with LVO were included in the analysis (54.8% female, median age = 78 years, range = 18–102), of whom 66.4% (n = 2,843) received recanalization therapy (RCT). In total, 19.4% (n = 832) of all LVO patients developed PSP. Development of PSP was associated with an increase in overall in-hospital mortality of 32.1% compared with LVO patients without PSP (16.4%; p < 0.001). Incidence of PSP was increased in 2132 patients with either EVT (n = 928; 25.9% PSP incidence) or combined EVT plus IVT (n = 1,204; 24.1%), compared with 2,149 patients with IVT alone (n = 711; 15.2%) or conservative treatment only (n = 1,438; 13.5%; p < 0.001). Multivariate analysis identified EVT (OR 1.5) and combined EVT plus IVT (OR 1.5) as significant independent risk factors for PSP. Furthermore, male sex (OR 1.9), age ≥ 65 years (OR 1.7), dysphagia (OR 3.2) as well as impaired consciousness at arrival (OR 1.7) and the comorbidities diabetes (OR 1.4) and atrial fibrillation (OR 1.3) were significantly associated risk factors (each p < 0.001). Minor stroke (NIHSS ≤ 4) was associated with a significant lower risk of PSP (OR 0.5). Performance of risk stratification scores varied between A2DS2 (96.1% sensitivity, 20.7% specificity), PNEUMONIA (78.2% sensitivity and 45.1% specificity) and ISAN score (98.0% sensitivity, 20.0% specificity).
Conclusion: Nearly one in five stroke patients with LVO develops PSP during acute care. This risk of PSP is further increased if an EVT is performed. Other predictive factors are consistent with those previously described for all AIS patients. Available risk stratification scores proved to be sensitive tools in LVO patients but lack specificity.
Meeting Abstract : Deutsche Gesellschaft für Chirurgie. 125. Kongress der Deutschen Gesellschaft für Chirurgie. Berlin, 22.-25.04.2008 Einleitung: Beim follikulären Schilddrüsenkarzinom ist die prae- und intraoperative Diagnose nur eingeschränkkt möglich. Immunhistochemische und immuncytologische Marker können hier hilfreich sein. Bei Patienten mit follikulären Karzinomen ist auf mRNA-Ebene eine up-Regulation für qprt (quinolinate-phosphoribosyltransferase) zu beobachten. Material und Methoden: Seit Januar 2004 werden bei Patienten mit prae- und intraoperativem Verdacht auf Schilddrüsenkarzinom, Frischgewebeproben zur Genexpressions-Analyse asserviert. Die so gewonnen Ergebnisse wurden an prospektiv und retrospektiv gewonnenen Präparaten von follikulären Adenomen und follikulären Karzinomen überprüft [Gruppe A]. Bei 20 prospektiven Punktionscytologien mit follikulärer Neoplasie werden aktuell zusätzliche immuncytologische Färbungen auf qprt durchgeführt und mit den nachfolgenden histologischen und immunhistochemischen Ergebnissen der Operationspräparate verglichen. Ergebnisse: Gruppe A (151 Patienten): bei 79 follikulären Adenomen und 72 follikulären Karzinomen wurden immunhistochemische Färbungen auf qprt durchgeführt. Hier zeigten sich 60 der 79 Adenome richtig negativ (76%) und 47 der 72 Karzinome richtig positiv (66%). Dies ergab eine Treffsicherheit zwischen Adenom und Karzinom von 71%. Gruppe B (20 Patienten): Die Ergebnisse der Korrelation zwischen präoperativer Immuncytochemie und postoperativer Diagnose und Immunhistochemie stehen derzeit noch aus. Schlussfolgerung: qprt ist ein immunhistochemischer Marker für follikuläre Schilddrüsenkarzinome mit einer befriedigenden Trennschärfe zwischen Adenom und Karzinom. Zusätzlich stellt qprt möglicherweise einen aussagekräftigen präoperativen immuncytochemischen Marker mit Auswirkung auf OP-Zeitpunkt, OP-Verfahren und OP-Taktik dar.
Results are presented on event-by-event electric charge fluctuations in central Pb+Pb collisions at 20, 30, 40, 80 and 158 AGeV. The observed fluctuations are close to those expected for a gas of pions correlated by global charge conservation only. These fluctuations are considerably larger than those calculated for an ideal gas of deconfined quarks and gluons. The present measurements do not necessarily exclude reduced fluctuations from a quark-gluon plasma because these might be masked by contributions from resonance decays.
System-size dependence of strangeness production in nucleus-nucleus collisions at √sNN = 17.3 GeV
(2005)
Emission of pi, K, phi and Lambda was measured in near-central C+C and Si+Si collisions at 158 AGeV beam energy. Together with earlier data for p+p, S+S and Pb+Pb, the system-size dependence of relative strangeness production in nucleus-nucleus collisions is obtained. Its fast rise and the saturation observed at about 60 participating nucleons can be understood as onset of the formation of coherent partonic subsystems of increasing size. PACS numbers: 25.75.-q
Production of Lambda and Antilambda hyperons was measured in central Pb-Pb collisions at 40, 80, and 158 A GeV beam energy on a fixed target. Transverse mass spectra and rapidity distributions are given for all three energies. The Lambda/pi ratio at mid-rapidity and in full phase space shows a pronounced maximum between the highest AGS and 40 A GeV SPS energies, whereas the anti-Lambda}/pi ratio exhibits a monotonic increase. PACS numbers: 25.75.-q
Results are presented on Omega production in central Pb+Pb collisions at 40 and 158 AGeV beam energy. Given are transverse-mass spectra, rapidity distributions, and total yields for the sum Omega+Antiomega at 40 AGeV and for Omega and Antiomega separately at 158 AGeV. The yields are strongly under-predicted by the string-hadronic UrQMD model and are in better agreement with predictions from a hadron gas models. PACS numbers: 25.75.Dw
Particle production in central Pb+Pb collisions was studied with the NA49 large acceptance spectrometer at the CERN SPS at beam energies of 20, 30, 40, 80, and 158 GeV per nucleon. A change of the energy dependence is observed around 30A GeV for the yields of pions and strange particles as well as for the shapes of the transverse mass spectra. At present only a reaction scenario with onset of deconfinement is able to reproduce the measurements.
The hadronic final state of central Pb+Pb collisions at 20, 30, 40, 80, and 158 AGeV has been measured by the CERN NA49 collaboration. The mean transverse mass of pions and kaons at midrapidity stays nearly constant in this energy range, whereas at lower energies, at the AGS, a steep increase with beam energy was measured. Compared to p+p collisions as well as to model calculations, anomalies in the energy dependence of pion and kaon production at lower SPS energies are observed. These findings can be explained, assuming that the energy density reached in central A+A collisions at lower SPS energies is sufficient to transform the hot and dense nuclear matter into a deconfined phase.
The hadronic final state of central Pb+Pb collisions at 20, 30, 40, 80, and 158 AGeV has been measured by the CERN NA49 collaboration. The mean transverse mass of pions and kaons at midrapidity stays nearly constant in this energy range, whereas at lower energies, at the AGS, a steep increase with beam energy was measured. Compared to p+p collisions as well as to model calculations, anomalies in the energy dependence of pion and kaon production at lower SPS energies are observed. These findings can be explained, assuming that the energy density reached in central A+A collisions at lower SPS energies is sufficient to force the hot and dense nuclear matter into a deconfined phase.
Increasing atmospheric CO2 stimulates photosynthesis which can increase net primary production (NPP), but at longer timescales may not necessarily increase plant biomass. Here we analyse the four decade-long CO2-enrichment experiments in woody ecosystems that measured total NPP and biomass. CO2 enrichment increased biomass increment by 1.05 ± 0.26 kg C m−2 over a full decade, a 29.1 ± 11.7% stimulation of biomass gain in these early-secondary-succession temperate ecosystems. This response is predictable by combining the CO2 response of NPP (0.16 ± 0.03 kg C m−2 y−1) and the CO2-independent, linear slope between biomass increment and cumulative NPP (0.55 ± 0.17). An ensemble of terrestrial ecosystem models fail to predict both terms correctly. Allocation to wood was a driver of across-site, and across-model, response variability and together with CO2-independence of biomass retention highlights the value of understanding drivers of wood allocation under ambient conditions to correctly interpret and predict CO2 responses.
Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement “hotspot” loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted.
Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases. These microdeletion sets were assessed in a combined analysis and in sub-type specific approaches against 6,746 ethnically matched controls.
Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted-P= 2.00×10-7; OR = 1.89; 95%-CI: 1.51-2.35), where the implicated microdeletions overlapped with rarely deleted genes and those involved in neurodevelopmental processes. Sub-type specific analyses showed that hotspot deletions in the GGE subgroup contribute most of the signal (adjusted-P = 1.22×10-12; OR = 7.45; 95%-CI = 4.20-11.97). Outside hotspot loci, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted-P = 4.78×10-3; OR = 2.30; 95%-CI = 1.42-3.70), whereas no additional signal was observed for RE and AFE. Still, gene content analysis was able to identify known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes affected in more than one epilepsy sub-type but not in controls.
Conclusions Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor to negligible contribution in the etiology of RE and AFE.
From hunting and foraging to clearing land for agriculture, humans modify forest biodiversity, landscapes, and climate. Forests constantly undergo disturbance–recovery dynamics and understanding them is a major objective of ecologists and conservationists. Chronosequences are a useful tool for understanding global restoration efforts. They represent a space-for-time substitution approach suited for the quantification of the resistance of ecosystem properties to withstand disturbance and the resilience of these properties until reaching pre-disturbance levels. Here we introduce a newly established chronosequence with 62 plots (50 ⍰ 50 m) in active cacao plantations and pastures, early and late regeneration, and mature old-growth forests, across a 200 km2 area in the extremely wet Chocó rainforest. Our chronosequence covers by far the largest total area of plots compared to others in the Neotropics. Plots ranged from 159–615 masl in a forested landscape with 74 ± 2.8 % forest cover within a 1-km radius including substantial old-growth forest cover. Land-use legacy and regeneration time were not confounded by elevation. We tested how six forest structure variables (maximum tree height and DBH, basal area, number of stems, vertical vegetation heterogeneity, and light availability), aboveground biomass (AGB), and rarefied tree species richness change along our chronosequence. Forest structure variables, AGB, and tree species richness increased with regeneration time and are predicted to reach similar levels to those in old-growth forests after ca. 30–116, 202, and 108 yrs, respectively. Compared to previous work in the Neotropics, old-growth forests in Canandé accumulate high AGB that takes one of the largest time spans reported until total recovery. Our chronosequence comprises one of the largest tree species pools, covers the largest total area of regenerating and old-growth forests, and has higher forest cover than other Neotropical chronosequences. Hence, our chronosequence can be used to determine the time for recovery and stability (resistance and resilience) of different taxa and ecosystem functions, including species interaction networks. This integrative effort will ultimately help to understand how one of the most diverse forests on the planet recovers from large-scale disturbances.
Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting.
Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in the HCC4006rErlo0.5 NSCLC cell line adapted to erlotinib as a model of acquired drug resistance. Constitutive CIP2A resulted in a constitutive activation of Akt signaling. The proteasome inhibitor bortezomib was able to reduce CIP2A levels, which resulted in an activation of protein phosphatase 2A and deactivation of Akt. Combination experiments with erlotinib and bortezomib revealed a lack of interaction between the two drugs. However, the effect size of bortezomib was higher in HCC4006rErlo0.5, compared to the erlotinib-sensitive HCC4006 cells, as indicated by an increase in Emax (0.911 (95%CI 0.867–0.954) vs. 0.585 (95%CI 0.568–0.622), respectively) and decrease in EC50 (52.4 µM (95%CI 46.1–58.8 µM) vs. 73.0 µM (95%CI 60.4–111 µM), respectively) in the concentration–effect model, an earlier onset of cell death induction, and a reduced colony surviving fraction (0.38 ± 0.18 vs. 0.95 ± 0.25, respectively, n = 3, p < 0.05). Therefore, modulation of CIP2A with bortezomib could be an interesting approach to overcome drug resistance to erlotinib treatment in NSCLC.