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Ecological networks are more sensitive to plant than to animal extinction under climate change
(2016)
Impacts of climate change on individual species are increasingly well documented, but we lack understanding of how these effects propagate through ecological communities. Here we combine species distribution models with ecological network analyses to test potential impacts of climate change on >700 plant and animal species in pollination and seed-dispersal networks from central Europe. We discover that animal species that interact with a low diversity of plant species have narrow climatic niches and are most vulnerable to climate change. In contrast, biotic specialization of plants is not related to climatic niche breadth and vulnerability. A simulation model incorporating different scenarios of species coextinction and capacities for partner switches shows that projected plant extinctions under climate change are more likely to trigger animal coextinctions than vice versa. This result demonstrates that impacts of climate change on biodiversity can be amplified via extinction cascades from plants to animals in ecological networks.
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time‐of‐day dependent changes of proliferation and DNA damage in HCC. Using transgenic c‐myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ‐H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev‐erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ‐H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time‐of‐day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.
Background: Bone age (BA) assessment performed by artificial intelligence (AI) is of growing interest due to improved accuracy, precision and time efficiency in daily routine. The aim of this study was to investigate the accuracy and efficiency of a novel AI software version for automated BA assessment in comparison to the Greulich-Pyle method.
Methods: Radiographs of 514 patients were analysed in this retrospective study. Total BA was assessed independently by three blinded radiologists applying the GP method and by the AI software. Overall and gender-specific BA assessment results, as well as reading times of both approaches, were compared, while the reference BA was defined by two blinded experienced paediatric radiologists in consensus by application of the Greulich-Pyle method.
Results: Mean absolute deviation (MAD) and root mean square deviation (RSMD) were significantly lower between AI-derived BA and reference BA (MAD 0.34 years, RSMD 0.38 years) than between reader-calculated BA and reference BA (MAD 0.79 years, RSMD 0.89 years; p < 0.001). The correlation between AI-derived BA and reference BA (r = 0.99) was significantly higher than between reader-calculated BA and reference BA (r = 0.90; p < 0.001). No statistical difference was found in reader agreement and correlation analyses regarding gender (p = 0.241). Mean reading times were reduced by 87% using the AI system.
Conclusions: A novel AI software enabled highly accurate automated BA assessment. It may improve efficiency in clinical routine by reducing reading times without compromising the accuracy compared with the Greulich-Pyle method.
Dual-energy CT (DECT) has emerged into clinical routine as an imaging technique with unique postprocessing utilities that improve the evaluation of different body areas. The virtual non-calcium (VNCa) reconstruction algorithm has shown beneficial effects on the depiction of bone marrow pathologies such as bone marrow edema. Its main advantage is the ability to substantially increase the image contrast of structures that are usually covered with calcium mineral, such as calcified vessels or bone marrow, and to depict a large number of traumatic, inflammatory, infiltrative, and degenerative disorders affecting either the spine or the appendicular skeleton. Therefore, VNCa imaging represents another step forward for DECT to image conditions and disorders that usually require the use of more expensive and time-consuming techniques such as magnetic resonance imaging, positron emission tomography/CT, or bone scintigraphy. The aim of this review article is to explain the technical background of VNCa imaging, showcase its applicability in the different body regions, and provide an updated outlook on the clinical impact of this technique, which goes beyond the sole improvement in image quality.
Background: Dual-source dual-energy computed tomography (DECT) offers the potential for opportunistic osteoporosis screening by enabling phantomless bone mineral density (BMD) quantification. This study sought to assess the accuracy and precision of volumetric BMD measurement using dual-source DECT in comparison to quantitative CT (QCT). Methods: A validated spine phantom consisting of three lumbar vertebra equivalents with 50 (L1), 100 (L2), and 200 mg/cm3 (L3) calcium hydroxyapatite (HA) concentrations was scanned employing third-generation dual-source DECT and QCT. While BMD assessment based on QCT required an additional standardised bone density calibration phantom, the DECT technique operated by using a dedicated postprocessing software based on material decomposition without requiring calibration phantoms. Accuracy and precision of both modalities were compared by calculating measurement errors. In addition, correlation and agreement analyses were performed using Pearson correlation, linear regression, and Bland-Altman plots. Results: DECT-derived BMD values differed significantly from those obtained by QCT (p < 0.001) and were found to be closer to true HA concentrations. Relative measurement errors were significantly smaller for DECT in comparison to QCT (L1, 0.94% versus 9.68%; L2, 0.28% versus 5.74%; L3, 0.24% versus 3.67%, respectively). DECT demonstrated better BMD measurement repeatability compared to QCT (coefficient of variance < 4.29% for DECT, < 6.74% for QCT). Both methods correlated well to each other (r = 0.9993; 95% confidence interval 0.9984–0.9997; p < 0.001) and revealed substantial agreement in Bland-Altman plots. Conclusions: Phantomless dual-source DECT-based BMD assessment of lumbar vertebra equivalents using material decomposition showed higher diagnostic accuracy compared to QCT.
Tumor progression largely depends on the presence of alternatively polarized (M2) tumor-associated macrophages (TAMs), whereas the classical M1-polarized macrophages can promote anti-tumorigenic immune responses. Thus, selective inhibition of M2-TAMs is a desirable anti-cancer approach in highly resistant tumor entities such as hepatocellular carcinoma (HCC) or breast cancer. We here examined whether a peptide that selectively binds to and is internalized by in vitro-differentiated murine M2 macrophages as compared to M1 macrophages, termed M2pep, could be used to selectively target TAMs in HCC and breast carcinoma. We confirmed selectivity of M2pep for in vitro M2 polarized macrophages. Upon incubation of suspended mixed 4T1 tumor cells with M2pep, high amounts of the TAMs were found to be associated with M2pep, whereas in mixed tumor cell suspensions from two HCC mouse models, M2pep showed only low-degree binding to TAMs. M2pep also showed low-degree targeting of liver macrophages. This indicates that the TAMs in different tumor entities show different targeting of M2pep and that M2pep is a very promising approach to develop selective M2-TAM-targeting in tumor entities containing M2-TAMs with significant amounts of the so far elusive M2pep receptor(s).
Background: This prospective randomized trial is designed to compare the performance of conventional transarterial chemoembolization (cTACE) using Lipiodol-only with additional use of degradable starch microspheres (DSM) for hepatocellular carcinoma (HCC) in BCLC-stage-B based on metric tumor response. Methods: Sixty-one patients (44 men; 17 women; range 44–85) with HCC were evaluated in this IRB-approved HIPPA compliant study. The treatment protocol included three TACE-sessions in 4-week intervals, in all cases with Mitomycin C as a chemotherapeutic agent. Multiparametric magnetic resonance imaging (MRI) was performed prior to the first and 4 weeks after the last TACE. Two treatment groups were determined using a randomization sheet: In 30 patients, TACE was performed using Lipiodol only (group 1). In 31 cases Lipiodol was combined with DSMs (group 2). Response according to tumor volume, diameter, mRECIST criteria, and the development of necrotic areas were analyzed and compared using the Mann–Whitney-U, Kruskal–Wallis-H-test, and Spearman-Rho. Survival data were analyzed using the Kaplan–Meier estimator. Results: A mean overall tumor volume reduction of 21.45% (± 62.34%) was observed with an average tumor volume reduction of 19.95% in group 1 vs. 22.95% in group 2 (p = 0.653). Mean diameter reduction was measured with 6.26% (± 34.75%), for group 1 with 11.86% vs. 4.06% in group 2 (p = 0.678). Regarding mRECIST criteria, group 1 versus group 2 showed complete response in 0 versus 3 cases, partial response in 2 versus 7 cases, stable disease in 21 versus 17 cases, and progressive disease in 3 versus 1 cases (p = 0.010). Estimated overall survival was in mean 33.4 months (95% CI 25.5–41.4) for cTACE with Lipiosol plus DSM, and 32.5 months (95% CI 26.6–38.4), for cTACE with Lipiodol-only (p = 0.844), respectively. Conclusions: The additional application of DSM during cTACE showed a significant benefit in tumor response according to mRECIST compared to cTACE with Lipiodol-only. No benefit in survival time was observed.
We give a report of the fourth annual symposium of the Dry Grassland Working Group, which was organized in conjunction with the second workshop ‘Floristics and geobotany - Contributions to applied questions’, from 6 to 8 Sept. 2007 in Freising-Weihenstephan. The symposium was entitled ‘Restoration and spontaneous establishment of dry and semi-dry grasslands at traditional and urban-industrial sites’. Additionally, the aims of the Dry Grassland Working Group are shortly outlined and the next symposia of both groups are announced.
Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved.
Traditional chinese medicine and herbal hepatotoxicity: a tabular compilation of reported cases
(2015)
Traditional Chinese Medicine (TCM) with its focus on herbal use became popular worldwide. Treatment was perceived as safe, with neglect of rare adverse reactions including liver injury. To compile worldwide cases of liver injury by herbal TCM, we undertook a selective literature search in the PubMed database and searched for the items Traditional Chinese Medicine, TCM, Traditional Asian Medicine, and Traditional Oriental Medicine, also combined with the terms herbal hepatotoxicity or herb induced liver injury. The search focused primarily on English-language case reports, case series, and clinical reviews. We identified reported hepatotoxicity cases in 77 relevant publications with 57 different herbs and herbal mixtures of TCM, which were further analyzed for causality by the Council for International Organizations of Medical Sciences (CIOMS) scale, positive reexposure test results, or both. Causality was established for 28/57 different herbs or herbal mixtures, Bai Xian Pi, Bo He, Ci Wu Jia, Chuan Lian Zi, Da Huang, Gan Cao, Ge Gen, Ho Shou Wu, Huang Qin, Hwang Geun Cho, Ji Gu Cao, Ji Xue Cao, Jin Bu Huan, Jue Ming Zi, Jiguja, Kudzu, Ling Yang Qing Fei Keli, Lu Cha, Rhen Shen, Ma Huang, Shou Wu Pian, Shan Chi, Shen Min, Syo Saiko To, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, and Zhen Chu Cao. In conclusion, this compilation of liver injury cases establishes causality for 28/57 different TCM herbs and herbal mixtures, aiding diagnosis for physicians who care for patients with liver disease possibly related to herbal TCM.
Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the “real-world” setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany.
Patients and methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1.
Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4–10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9–9.2) with druggable ALK alterations.
Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.
Objectives: To compare radiation dose and image quality of single-energy (SECT) and dual-energy (DECT) head and neck CT examinations performed with second- and third-generation dual-source CT (DSCT) in matched patient cohorts. Methods: 200 patients (mean age 55.1 ± 16.9 years) who underwent venous phase head and neck CT with a vendor-preset protocol were retrospectively divided into four equal groups (n = 50) matched by gender and BMI: second (Group A, SECT, 100-kV; Group B, DECT, 80/Sn140-kV), and third-generation DSCT (Group C, SECT, 100-kV; Group D, DECT, 90/Sn150-kV). Assess- ment of radiation dose was performed for an average scan length of 27 cm. Contrast-to-noise ratio measure- ments and dose-independent figure-of-merit calcu- lations of the submandibular gland, thyroid, internal jugular vein, and common carotid artery were analyzed quantitatively. Qualitative image parameters were evalu- ated regarding overall image quality, artifacts and reader confidence using 5-point Likert scales. Results: Effective radiation dose (ED) was not signifi- cantly different between SECT and DECT acquisition for each scanner generation (p = 0.10). Significantly lower effective radiation dose (p < 0.01) values were observed for third-generation DSCT groups C (1.1 ± 0.2 mSv) and D (1.0 ± 0.3 mSv) compared to second-generation DSCT groups A (1.8 ± 0.1 mSv) and B (1.6 ± 0.2 mSv). Figure-of- merit/contrast-to-noise ratio analysis revealed superior results for third-generation DECT Group D compared to all other groups. Qualitative image parameters showed non-significant differences between all groups (p > 0.06). Conclusion: Contrast-enhanced head and neck DECT can be performed with second- and third-generation DSCT systems without radiation penalty or impaired image quality compared with SECT, while third-generation DSCT is the most dose efficient acquisition method. Advances in knowledge: Differences in radiation dose between SECT and DECT of the dose-vulnerable head and neck region using DSCT systems have not been evaluated so far. Therefore, this study directly compares radiation dose and image quality of standard SECT and DECT protocols of second- and third-generation DSCT platforms.
Objectives: To determine the diagnostic accuracy of dual-energy CT (DECT) virtual noncalcium (VNCa) reconstructions for assessing thoracic disk herniation compared to standard grayscale CT. Methods: In this retrospective study, 87 patients (1131 intervertebral disks; mean age, 66 years; 47 women) who underwent third-generation dual-source DECT and 3.0-T MRI within 3 weeks between November 2016 and April 2020 were included. Five blinded radiologists analyzed standard DECT and color-coded VNCa images after a time interval of 8 weeks for the presence and degree of thoracic disk herniation and spinal nerve root impingement. Consensus reading of independently evaluated MRI series served as the reference standard, assessed by two separate experienced readers. Additionally, image ratings were carried out by using 5-point Likert scales. Results: MRI revealed a total of 133 herniated thoracic disks. Color-coded VNCa images yielded higher overall sensitivity (624/665 [94%; 95% CI, 0.89–0.96] vs 485/665 [73%; 95% CI, 0.67–0.80]), specificity (4775/4990 [96%; 95% CI, 0.90–0.98] vs 4066/4990 [82%; 95% CI, 0.79–0.84]), and accuracy (5399/5655 [96%; 95% CI, 0.93–0.98] vs 4551/5655 [81%; 95% CI, 0.74–0.86]) for the assessment of thoracic disk herniation compared to standard CT (all p < .001). Interrater agreement was excellent for VNCa and fair for standard CT (ϰ = 0.82 vs 0.37; p < .001). In addition, VNCa imaging achieved higher scores regarding diagnostic confidence, image quality, and noise compared to standard CT (all p < .001). Conclusions: Color-coded VNCa imaging yielded substantially higher diagnostic accuracy and confidence for assessing thoracic disk herniation compared to standard CT.
Purpose: To investigate the diagnostic performance of noise-optimized virtual monoenergetic images (VMI+) in dual-energy CT (DECT) of portal vein thrombosis (PVT) compared to standard reconstructions. Method: This retrospective, single-center study included 107 patients (68 men; mean age, 60.1 ± 10.7 years) with malignant or cirrhotic liver disease and suspected PVT who had undergone contrast-enhanced portal-phase DECT of the abdomen. Linearly blended (M_0.6) and virtual monoenergetic images were calculated using both standard VMI and noise-optimized VMI+ algorithms in 20 keV increments from 40 to 100 keV. Quantitative measurements were performed in the portal vein for objective contrast-to-noise ratio (CNR) calculation. The image series showing the greatest CNR were further assessed for subjective image quality and diagnostic accuracy of PVT detection by two blinded radiologists. Results: PVT was present in 38 subjects. VMI+ reconstructions at 40 keV revealed the best objective image quality (CNR, 9.6 ± 4.3) compared to all other image reconstructions (p < 0.01). In the standard VMI series, CNR peaked at 60 keV (CNR, 4.7 ± 2.1). Qualitative image parameters showed the highest image quality rating scores for the 60 keV VMI+ series (median, 4) (p ≤ 0.03). The greatest diagnostic accuracy for the diagnosis of PVT was found for the 40 keV VMI+ series (sensitivity, 96%; specificity, 96%) compared to M_0.6 images (sensitivity, 87%; specificity, 92%), 60 keV VMI (sensitivity, 87%; specificity, 97%), and 60 keV VMI+ reconstructions (sensitivity, 92%; specificity, 97%) (p ≤ 0.01). Conclusions: Low-keV VMI+ reconstructions resulted in significantly improved diagnostic performance for the detection of PVT compared to other DECT reconstruction algorithms.
Background: To evaluate clinical outcomes after either immediate or deferred initiation of antiretroviral therapy in HIV-1-infected patients, presenting late with pneumocystis pneumonia (PCP) or toxoplasma encephalitis (TE).
Methods: Phase IV, multicenter, prospective, randomized open-label clinical trial. Patients were randomized into an immediate therapy arm (starting antiretroviral therapy (ART) within 7 days after initiation of OI treatment) versus a deferred arm (starting ART after completing the OI-therapy). All patients were followed for 24 weeks. The rates of clinical progression (death, new or relapsing opportunistic infections (OI) and other grade 4 clinical endpoints) were compared, using a combined primary endpoint. Secondary endpoints were hospitalization rates after completion of OI treatment, incidence of immune reconstitution inflammatory syndrome (IRIS), virologic and immunological outcome, adherence to proteinase-inhibitor based antiretroviral therapy (ART) protocol and quality of life.
Results: 61 patients (11 patients suffering TE, 50 with PCP) were enrolled. No differences between the two therapy groups in all examined primary and secondary endpoints could be identified: immunological and virologic outcome was similar in both groups, there was no significant difference in the incidence of IRIS (11 and 10 cases), furthermore 9 events (combined endpoint of death, new/relapsing OI and grade 4 events) occurred in each group.
Conclusions: In summary, this study supports the notion that immediate initiation of ART with a ritonavir-boosted proteinase-inhibitor and two nucleoside reverse transcriptase inhibitors is safe and has no negative effects on incidence of disease progression or IRIS, nor on immunological and virologic outcomes or on quality of life.
Background. Spontaneous reports of herb induced liver injury (HILI) represent a major regulatory issue, and it is in the interest of pharmacovigilance to identify and quantify previously unrecognized adverse reactions and to confirm or refute false positive signals of safety concerns. In a total of 13 spontaneous cases, liver disease has initially been attributed to the use of Pelargonium sidoides (PS), a plant from the South African region. Water/ethanol extracts derived from its roots are available as registered herbal drugs for the treatment of upper respiratory tract infections including acute bronchitis. Objectives. The present study examines whether and to what extent treatment by PS was associated with the risk of liver injury in these spontaneous cases. Study design: Overall, 13 spontaneous cases with primarily suspected PS hepatotoxicity were included in the study. Their data were submitted to a thorough clinical evaluation that included the use of the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences) to assess causality levels. These scales are liver specific, validated for liver toxicity, structured and quantitative.
Results. None of the 13 spontaneous cases of liver disease generated a positive signal of safety concern, since causality for PS could not be established on the basis of the applied CIOMS scales in any of the assessed patients. Confounding variables included comedication with synthetic drugs, major comorbidities, low data quality, lack of appropriate consideration of differential diagnoses, and multiple alternative diagnoses. Among these were liver injury due to comedication, acute pancreatitis and cholangitis, acute cholecystitis, hepatic involvement following lung contusion, hepatitis in the course of virus and bacterial infections, ANA positive autoimmune hepatitis, and other preexisting liver diseases. In the course of the case assessments and under pharmacovigilance aspects, data and interpretation deficits became evident. Possible improvements include appropriate data quality of cases in spontaneous reports, case assessment by skilled specialists, use of a validated liver specific causality assessment method, and inclusion only of confirmed cases into the final regulatory case database.
Conclusions. This study shows lack of hepatotoxicity by PS in all 13 spontaneous cases as opposed to initial judgment that suggested a toxic potential of PS. Major shortcomings emerged in the pharmacovigilance section that require urgent improvements.
Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.
Abstract: Neurophysiological measures of preparation and attention are often atypical in ADHD. Still, replicated findings that these measures predict which patients improve after Neurofeedback (NF), reveal neurophysiological specificity, and reflect ADHD-severity are limited. Methods: We analyzed children’s preparatory (CNV) and attentional (Cue-P3) brain activity and behavioral performance during a cued Continuous Performance Task (CPT) before and after slow cortical potential (SCP)-NF or semi-active control treatment (electromyogram biofeedback). Mixed-effects models were performed with 103 participants at baseline and 77 were assessed for pre-post comparisons focusing on clinical outcome prediction, specific neurophysiological effects of NF, and associations with ADHD-severity. Results: Attentional and preparatory brain activity and performance were non-specifically reduced after treatment. Preparatory activity in the SCP-NF group increased with clinical improvement. Several performance and brain activity measures predicted non-specific treatment outcome. Conclusion: Specific neurophysiological effects after SCP-NF were limited to increased neural preparation associated with improvement on ADHD-subscales, but several performance and neurophysiological measures of attention predicted treatment outcome and reflected symptom severity in ADHD. The results may help to optimize treatment.