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Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds. In contrast, silibinin is composed only of a 1:1 mixture of silybin A and silybin B. With these isomers now isolated in quantities sufficient for biological studies, each pure compound was assessed for antiproliferative activities against LNCaP, DU145, and PC3 human prostate carcinoma cell lines. Isosilybin B was the most consistently potent suppressor of cell growth relative to either the other pure constituents or the commercial extracts. Isosilybin A and isosilybin B were also the most effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIα gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective. These findings are significant in that isosilybin B composes no more than 5% of silymarin and is absent from silibinin. Whereas several other more abundant flavonolignans do ultimately influence the same end points at higher exposure concentrations, these findings are suggestive that extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment.

Supplementary Figure 2 from Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells

Supplementary Figure Legends from Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells

Supplementary Figure 1B from Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells

Cyclopeptide alkaloids are an abundant class of plant cyclopeptides with over 200 analogs described and bioactivities ranging from analgesic to antiviral. While these natural products have been known for decades, their biosynthetic basis remains unclear. Using a transcriptome-mining approach, we link the cyclopeptide alkaloids from Ceanothus americanus to dedicated RiPP precursor peptides and identify new, widely distributed split BURP peptide cyclase containing gene clusters. Guided by our bioinformatic analysis, we identify and isolate new cyclopeptides from Coffea arabica, which we named arabipeptins. Reconstitution of the enzyme activity for the BURP found in the biosynthesis of arabipeptin A validates the activity of the newly discovered split BURP peptide cyclases. These results expand our understanding of the biosynthetic pathways responsible for diverse cyclic plant peptides and suggest that these side chain cross-link modifications are widely distributed in eudicots.

Cyclopeptide alkaloids are an abundant class of plant cyclopeptides with over 200 analogs described and bioactivities ranging from analgesic to antiviral. While these natural products have been known for decades, their biosynthetic basis remains unclear. Using a transcriptome-mining approach, we link the cyclopeptide alkaloids from Ceanothus americanus to dedicated RiPP precursor peptides and identify new, widely distributed split BURP-domain containing gene clusters. Precursor peptides from these biosynthetic cassettes directly map to both cyclopeptide alkaloids from Ziziphus jujuba and the structurally distinct hibispeptins from Hibiscus syriacus. Guided by our bioinformatic analysis, we identify and isolate new cyclopeptides from Coffea arabica, which we named arabipeptins. These results expand our understanding of the biosynthetic pathways responsible for diverse plant side chain cross-linked cyclopeptides and suggest the presence of previously unknown natural products or protein post-translational modifications that are widely distributed in eudicots.

Background Intraarticular corticosteroid (IACS) injections are frequently performed for hip and knee osteoarthritis (OA); however, there are conflicting data about the benefits and complications of IACS injections and a lack of large studies with follow-up. Purpose To determine the number of patients with complications after hip and knee IACS injections in a large study sample with long-term follow-up. Materials and Methods This retrospective single-center case series included patients who received a corticosteroid injection in the hip (

The Beckwith-Wiedemann spectrum (BWSp) as well as the WT1-related syndromes, Denys-Drash syndrome (DDS) and WAGR spectrum (Wilms tumor, Aniridia, genitourinary anomalies and a range of developmental delays) are tumor predisposition syndromes (TPS) of Wilms tumor (WT). Patients with associated TPS are at higher risk of developing chronic kidney disease and bilateral and metachronous tumors as well as nephrogenic rests.Standard imaging diagnostics for WT include renal ultrasound and magnetic resonance imaging (MRI). In the current renal tumor studies Umbrella SIOP-RTSG 2016 and Randomet 2017, thoracic computed tomography (CT) is also recommended as standard. Positron emission tomography (PET)-CT and whole-body MRI, on the other hand, are not part of routine diagnostics.In recent publications, renal ultrasound is recommended every 3 months until the age of 7 years in cases of clinical suspicion or molecularly proven TPS.Patients with TPS and regular renal ultrasounds have smaller tumor volumes and lower tumor stages at WT diagnosis than patients without such a screening. This allows a reduction of therapy intensity and facilitates the performance of nephron sparing surgery, which is prognostically relevant especially in bilateral WT.Early diagnosis of WT in the context of TPS ensures the greatest possible preservation of healthy and functional renal tissue. Standardized screening by regular renal ultrasounds should therefore be firmly established in clinical practice.The initial diagnosis of TPS is clinical and requires a skilled and attentive examiner in the presence of sometimes subtle clinical manifestations, especially in the case of BWSp. Clinical diagnosis should be followed by genetic testing, which should then be followed by sonographic screening.KLINISCHES/METHODISCHES PROBLEM: Das Beckwith-Wiedemann-Spektrum (BWSp) und die WT1-vermittelten Syndrome, Denys-Drash-Syndrom (DDS) und WAGR-Spektrum (Wilms-Tumor, Aniridie, urogenitale Anomalien und eine Reihe an Entwicklungsverzögerungen) zählen zu den Tumorprädispositionssyndromen (TPS) des Wilms-Tumors (WT). Patienten mit TPS haben ein höheres Risiko für eine chronische Nierenerkrankung und weisen eine erhöhte Rate an bilateralen und metachronen Tumoren sowie nephrogenen Resten (NR) auf.Zur bildgebenden Standarddiagnostik des WT zählen die Sonographie und die Magnetresonanztomographie (MRT). In den aktuellen Nierentumorstudien Umbrella SIOP-RTSG 2016 und Randomet 2017 wird zudem standardmäßig eine Thorax-Computertomographie (CT) empfohlen. Positronen-Emissions-Tomographie (PET)/CT und Ganzkörper-MRT sind hingegen nicht Teil der Routinediagnostik.In aktuellen Publikationen wird bei klinischem Verdacht bzw. molekulargenetisch nachgewiesenem TPS eine renale Sonographie in 3‑monatlichen Abständen bis zum Alter von 7 Jahren routinemäßig empfohlen. LEISTUNGSFäHIGKEIT: Patienten mit TPS und regelmäßiger sonographischer Vorsorgeuntersuchung haben bei WT-Diagnose kleinere Tumorvolumina und niedrigere Tumorstadien als Patienten ohne Vorsorgeuntersuchung. Dies ermöglicht eine Reduktion der Therapieintensität sowie die erleichterte Durchführung einer nierenerhaltenden Teilresektion, welche insbesondere bei bilateralen WT prognostisch relevant ist.Die frühzeitige Diagnostik eines WT im Kontext eines TPS gewährleistet den größtmöglichen Erhalt von gesundem Nierengewebe. Einheitliche sonographische Vorsorgeuntersuchungen sollten daher in der klinischen Praxis fest etabliert werden. EMPFEHLUNG FüR DIE PRAXIS: Die initiale Diagnostik eines TPS erfolgt klinisch und erfordert bei zum Teil subtiler klinischer Manifestation, insbesondere im Fall eines BWSp, einen geübten und achtsamen Untersucher. An die klinische Diagnostik sollte sich eine genetische Untersuchung anschließen, gefolgt von einer sonographischen Vorsorge.

Introduction Complete surgical resection remains the mainstay of the treatment of soft tissue sarcomas. Intraoperative positioning of the patient is dictated by tumor location, whereas preoperative imaging is always performed in the supine position. The effect of changing the patient position on the exact location of the tumor with regard to neurovascular structures and bone is unknown. Material and methods Two fresh frozen cadavers (pelvis and legs) were thawed and warmed. Three standardized tumor models were implanted in the thigh and calf. MR/CT images of the cadavers were obtained sequentially in four different patient positions. The minimal distance of each “tumor” to neurovascular structures was measured on axial MR images and the 3D shift of the center of the tumor to the bone was measured after segmentation of the CT images. Results A significant difference of the minimal distance of the “tumor” to the femoral artery (P = 0.019/0.023) and a significantly greater number of deviations of more than 5mm/10 mm in the thigh between the supine position and the other positions compared to two supine positions (p = 0.027/0.028) were seen. The center of the “tumor” compared to the bone shifted significantly in the thigh (P Conclusion Obtaining images in the same patient position as the planned tumor resection may become particularly relevant if computer assisted surgery, which is based on preoperative imaging, is introduced into soft tissue sarcoma surgery as the patient position significantly influences the spatial position of the tumor.

Objective To prospectively assess the evolution of postoperative MRI findings in asymptomatic patients after total hip arthroplasty (THA) over 24 months (mo). Methods This prospective cohort study included 9 asymptomatic patients (56.7 ± 15.0 years) after THA. Metal artifact–reduced 1.5-T MRI was performed at 3, 6, 12, and 24 mo after surgery. The femoral stem and acetabular cup were assessed by two readers for bone marrow edema (BME), periprosthetic bone resorption, and periosteal edema in addition to periarticular soft tissue edema and joint effusion. Results BME was common around the femoral stem in all Gruen zones after 3 mo (range: 50–100%) and 6 mo (range: 33–100%) and in the acetabulum in DeLee and Charnley zone II after 3 mo (100%) and 6 mo (33%). BME decreased substantially after 12 mo (range: 0–78%) and 24 mo (range: 0–50%), may however persist in particular in Gruen zones 1 + 7. Periosteal edema along the stem was common 3 mo postoperatively (range: 63–75%) and rare after 24 mo: 13% only in Gruen zones 2 and 5. Twelve months and 24 mo postoperatively, periprosthetic bone resorption was occasionally present around the femoral stem (range: 11–33% and 13–38%, respectively). Soft tissue edema occurred exclusively along the surgical access route after 3 mo (100%) and 6 mo (89%) and never at 12 mo or 24 mo (0%). Conclusion Around the femoral stem, BME (33–100%) and periosteal edema (0–75%) are common until 6 mo after THA, decreasing substantially in the following period, may however persist up to 24 mo (BME: 0–50%; periosteal edema: 0–13%) in few non-adjoining Gruen zones. Soft tissue edema along the surgical access route should have disappeared 12 mo after surgery.

The safety and efficacy of kratom (Mitragyna speciosa) for treatment of pain is highly controversial. Kratom produces more than 40 structurally related alkaloids, but most studies have focused on just two of these, mitragynine and 7-hydroxymitragynine. Here, we profiled 53 commercial kratom products using untargeted LC–MS metabolomics, revealing two distinct chemotypes that contain different levels of the alkaloid speciofoline. Both chemotypes were confirmed with DNA barcoding to be M. speciosa. To evaluate the biological relevance of variable speciofoline levels in kratom, we compared the opioid receptor binding activity of speciofoline, mitragynine, and 7-hydroxymitragynine. Mitragynine and 7-hydroxymitragynine function as partial agonists of the human µ-opioid receptor, while speciofoline does not exhibit measurable binding affinity at the µ-, δ- or ƙ-opioid receptors. Importantly, mitragynine and 7-hydroxymitragynine demonstrate functional selectivity for G-protein signaling, with no measurable recruitment of β-arrestin. Overall, the study demonstrates the unique binding and functional profiles of the kratom alkaloids, suggesting potential utility for managing pain, but further studies are needed to follow up on these in vitro findings. All three kratom alkaloids tested inhibited select cytochrome P450 enzymes, suggesting a potential risk for adverse interactions when kratom is co-consumed with drugs metabolized by these enzymes.

Purpose To evaluate the MRI anatomy of the scapho-trapezial-trapezoidal (STT) ligament complex in asymptomatic and symptomatic individuals. Material and methods In this retrospective study, STT ligament complex of 42 (male 69%, median age 37.5 years) asymptomatic (n = 25) and symptomatic (n = 17) (defined as pain described over the STT joint) individuals was examined using a high-resolution 3D proton density-weighted isovoxel sequence (MR arthrogram) with multiplanar reconstructions. Two musculoskeletal radiologists independently assessed visibility, signal intensity (SI), morphology, and thickness of the radiopalmar scapho-trapezial ligament (rpSTL), palmar scapho-capitate capsular ligament (pSCL), palmar STT capsule (pSTTC), and dorsal STT capsule (dSTTC). Results Interreader agreement ranged from fair to good and intraclass correlations were good. The rpSTL was almost always visible (85.7%/80.1%; reader 1/reader 2). The pSCL and dSTTC were visible in all cases. The pSTTC was visible in only 52.4%/42.9%. Mean thickness of the rpSTL, pSCL, pSTTC, and dSTTC was 1.4 ± 0.5 mm/1.3 ± 0.5 mm, 2.8 ± 0.7 mm/2.7 ± 0.6 mm, 0.5 ± 0.5 mm/0.4 ± 0.4 mm, and 0.5 ± 0.3 mm/0.3 ± 0.3 mm. Both readers rated SI of the rpSTL significantly more often as increased in the symptomatic group (increased SI in asymptomatic group: 20%/15%; symptomatic group: 56%/50%) (p-values p-values ranging between 0.188 and 0.890). For all other ligaments, no significant differences were observed regarding ligament visibility, morphology, and thickness (p-values ranging between 0.274 and 1.000). Conclusion The anatomy of the STT ligament complex can consistently be visualized on high-resolution 3D MRI. Increased signal intensity of rpSTL is significantly more frequent in patients with radial-sided wrist pain.

Objective To investigate the impact of contrast dispersion pattern/location during lumbar CT-guided transforaminal epidural steroid injection (TFESI) and experience of the performing radiologist on therapeutic outcome. Materials and methods In this single-center retrospective cohort study, two observers analyzed contrast dispersion during CT-guided TFESI of 204 patients (age 61.1 ± 14 years) with discogenic unilateral single-level L4 or L5 radiculopathy. The contrast dispersion pattern was classified as “focal,” “linear,” or “tram-track”; the location was divided into “extraforaminal,” “foraminal,” or “recessal.” Pain was assessed before and 4 weeks after treatment using a numerical rating scale (0, no pain; 10, intolerable pain). Additionally, the patient global impression of change (PGIC) was assessed. The TFESI was performed by musculoskeletal radiologists (experience range: first year of musculoskeletal fellowship training to 19 years). Contrast pattern/location and radiologist’s experience were compared between “good responder” (≥ 50% pain reduction) and “poor responder” (p-value Results Overall, CT-guided TFESI resulted in a substantial pain reduction in 46.6% of patients with discogenic radiculopathy. The contrast dispersion pattern and location had no effect on pain relief (p = 0.75 and p = 0.09) and PGIC (p = 0.70 and p = 0.21) 4 weeks after TFESI. Additionally, the experience of the radiologist had no influence on pain reduction (p = 0.92) or PGIC (p = 0.75). Regarding pre-interventional imaging findings, both the location and grading of nerve compression had no effect on pain relief (p = 0.91 and p = 0.85) and PGIC (p = 0.18 and p = 0.31). Conclusion Our results indicate that neither contrast agent dispersion/location nor the experience of the radiologist allows predicting the therapeutic outcome 4 weeks after the procedure.

Neuroblastome gehoren zusammen mit den benignen Ganglioneuromen und den Ganglioneuroblastomen zu der Gruppe der neuroblastischen Tumoren und entstehen aus unreifen Zellen des sympathischen Nervensystems. Dementsprechend konnen Neuroblastome ubiquitar im Bereich des Sympathikus auftreten, die haufigsten Lokalisationen sind jedoch das Nebennierenmark (ca. 1/3), die retroperitonealen sympathischen Ganglien (ca. 20 %) und das Zuckerkandl-Organ (sympathisches Paraganglion am Abgang der A. mesenterica inferior). Die Risikogruppeneinteilung erfolgt heute entsprechend der International Neuroblastoma Risk Group (INRG) und beinhaltet Stadium, Alter, Histologie mit Grad der Tumordifferenzierung, den Status der MYCN-Amplifikation, den Status von Chromosom 11q und die DNA-Aneuploidie.

Two separate commercial products of kratom [Mitragyna speciosa (Korth.) Havil. Rubiaceae] were used to generate reference standards of its indole and oxindole alkaloids. While kratom has been studied for over a century, the characterization data in the literature for many of the alkaloids are either incomplete or inconsistent with modern standards. As such, full (1)H and (13)C NMR spectra, along with HRESIMS and ECD data, are reported for alkaloids 1-19. Of these, four new alkaloids (7, 11, 17, and 18) were characterized using 2D NMR data, and the absolute configurations of 7, 17, and 18 were established by comparison of experimental and calculated ECD spectra. The absolute configuration for the N(4)-oxide (11) was established by comparison of NMR and ECD spectra of its reduced product with those for compound 7. In total, 19 alkaloids were characterized, including: the indole alkaloid mitragynine (1) and its diastereoisomers speciociliatine (2), speciogynine (3) and mitraciliatine (4); the indole alkaloid paynantheine (5) and its diastereoisomers isopaynantheine (6) and epiallo-isopaynantheine (7); the N(4)-oxides mitragynine-N(4)-oxide (8), speciociliatine-N(4)-oxide (9), isopaynantheine-N(4)-oxide (10), and epiallo-isopaynantheine-N(4)-oxide (11); the 9-hydroxylated oxindole alkaloids speciofoline (12), isorotundifoleine (13) and isospeciofoleine (14); and the 9-unsubstituted oxindoles corynoxine A (15), corynoxine B (16), 3-epirhynchophylline (17), 3-epicorynoxine B (18), and corynoxeine (19). With the ability to analyze the spectroscopic data of all of these compounds concomitantly, a decision tree was developed to differentiate these kratom alkaloids based on a few key chemical shifts in the (1)H and/or (13)C NMR spectra.

Recently, the isolation and elucidation of a series of polyhydroxyanthraquinones were reported from an organic extract of a solid phase culture of an endophytic fungus, Penicillium restrictum (strain G85). One of these compounds, ω-hydroxyemodin (1), showed promising quorum-sensing inhibition against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) in both in vitro and in vivo models. The initial supply of 1 was 19 mg, and this amount needed to be scaled by a factor of 30 to 50 times, in order to generate material for further in vivo studies. To do so, improvements were implemented to enhance both the fermentation of the fungal culture and the isolation of this compound, with the target of generating > 800 mg of study materials in a period of 13 wk. Valuable insights, both regarding chemistry and mycology, were gained during the targeted production of 1 on the laboratory-scale. In addition, methods were modified to make the process more environmentally friendly by judicious choice of solvents, implementing procedures for solvent recycling, and minimizing the use of halogenated solvents.

Objective This study aims to evaluate the image quality of virtual non-contrast (VNC) images calculated from dual-energy CT shoulder arthrography (DECT-A) and their ability to detect periosteal calcifications and intraarticular loose bodies. Materials and methods In 129 shoulders of 123 patients, DECT arthrography (80 kV/140 kV) was performed with diluted iodinated contrast material (80 mg/ml). VNC images were calculated with image postprocessing. VNC image quality (1 = worst, 5 = best), dose parameters, and CT numbers (intraarticular iodine, muscle, VNC joint fluid density) were assessed. Image contrast (iodine/muscle) and percentage of iodine removal were calculated. Two independent readers evaluated VNC and DECT-A images for periosteal calcifications and intraarticular loose bodies, and diagnostic confidence (1 = low, 4 = very high) was assessed. Results VNC images (129/129) were of good quality (median 4 (3–4)), and the mean effective dose of DECT-A scans was 2.21 mSv (± 1.0 mSv). CT numbers of iodine, muscle, and VNC joint fluid density were mean 1017.6 HU (± 251.6 HU), 64.6 HU (± 8.2 HU), and 85.3 HU (± 39.5 HU), respectively. Image contrast was mean 953.1 HU (± 251 HU) on DECT-A and 31.3 HU (± 32.3 HU) on VNC images. Iodine removal on VNC images was 91% on average. No difference was observed in the detection of periosteal calcifications between VNC (n = 25) and DECT-A images (n = 21) (p = 0.29), while the detection of intraarticular loose bodies was superior on VNC images (14 vs. 7; p = 0.02). Diagnostic confidence was higher on VNC images for both periosteal calcifications (median 3 (3–3) vs. 3 (3–3); p = 0.009) and intraarticular loose bodies (median 3 (3–4) vs. 3 (3–3); p Conclusion VNC images from DECT shoulder arthrography are superior to DECT-A images for the detection of intraarticular loose bodies and increase the confidence in detecting periosteal calcifications.

Nierentumoren im Kindesalter werden nach Vorgaben der Renal Tumor Study Group der Internationalen Gesellschaft fur padiatrische Onkologie (RTSG-SIOP) behandelt. Der haufigste renale Tumor im Kindesalter ist das Nephroblastom. Die Magnetresonanztomographie (MRT) ist nach der Sonographie die bevorzugte bildgebende Methode. Die Aufgabe der Bildgebung umfasst die Differenzialdiagnose renaler Tumoren im Kindesalter anhand epidemiologischer und morphologischer Kriterien. Neu ist die Einfuhrung der Thorax-Computertomographie (CT) in der initialen Diagnostik. Neue Studien zu Nephroblastomsubtypen mit Diffusionsbildgebung (DWI) zeigen, dass durch Auswertungen des ADC(„apparent diffusion coefficient“)-Histogramms blastemreiche und anaplastische High-risk-Tumoren zu differenzieren sind. Bildgebende Kriterien zur nierenerhaltenden chirurgischen Therapie sind aktuell festgelegt und erlauben eine individuelle Therapie bei unilateralen, aber insbesondere bei bilateralen Tumoren. Differenzialdiagnosen sind neben dem kongenitalen mesoblastischen Nephrom, der Rhabdoidtumor, das Klarzellsarkom und das Nierenzellkarzinom. Herausfordernd ist die Diagnose nephrogener Reste und der Nephroblastomatose. Durch standardisierte Bildgebung verbessert sich Diagnostik und Therapie renaler Tumoren im Kindesalter, und neue prognostische Marker konnen zukunftig in der Bildgebung etabliert werden.

Renal tumors in children are treated according to the guidelines of the Renal Tumor Study Group of the International Society of Pediatric Oncology (SIOP-RTSG). Nephroblastoma is the most frequent renal tumor in children.After sonography, magnetic resonance imaging (MRI) is the preferred imaging modality. The task of imaging includes differential diagnosis with the help of morphological and epidemiological criteria. Thorax computed tomography (CT) is introduced for initial staging.Current studies of diffusion-weighted imaging (DWI)-MRI with analysis of the apparent diffusion coefficient (ADC) histogram indicate the potential to differentiate blastemal or anaplastic high-risk histology nephroblatoma subtypes. Imaging criteria for nephron-sparing surgery are defined and allow an individual therapy option in unilateral and especially in bilateral renal nephroblastoma.In addition to nephroblastoma, the differential diagnosis includes congenital mesoblastic nephroma, malignant rhabdoid tumor of the kidney, clear cell sarcoma and renal cell carcinoma. The diagnosis of nephrogenic rests and nephroblastomatosis is challenging.Diagnostic standardization improves diagnosis and therapy of renal childhood tumors, and new prognostic markers may be introduced in the near future.KLINISCHES/METHODISCHES PROBLEM: Nierentumoren im Kindesalter werden nach Vorgaben der Renal Tumor Study Group der Internationalen Gesellschaft für pädiatrische Onkologie (RTSG-SIOP) behandelt. Der häufigste renale Tumor im Kindesalter ist das Nephroblastom.Die Magnetresonanztomographie (MRT) ist nach der Sonographie die bevorzugte bildgebende Methode. Die Aufgabe der Bildgebung umfasst die Differenzialdiagnose renaler Tumoren im Kindesalter anhand epidemiologischer und morphologischer Kriterien. Neu ist die Einführung der Thorax-Computertomographie (CT) in der initialen Diagnostik.Neue Studien zu Nephroblastomsubtypen mit Diffusionsbildgebung (DWI) zeigen, dass durch Auswertungen des ADC(„apparent diffusion coefficient“)-Histogramms blastemreiche und anaplastische High-risk-Tumoren zu differenzieren sind. Bildgebende Kriterien zur nierenerhaltenden chirurgischen Therapie sind aktuell festgelegt und erlauben eine individuelle Therapie bei unilateralen, aber insbesondere bei bilateralen Tumoren. LEISTUNGSFäHIGKEIT: Differenzialdiagnosen sind neben dem kongenitalen mesoblastischen Nephrom, der Rhabdoidtumor, das Klarzellsarkom und das Nierenzellkarzinom. Herausfordernd ist die Diagnose nephrogener Reste und der Nephroblastomatose.Durch standardisierte Bildgebung verbessert sich Diagnostik und Therapie renaler Tumoren im Kindesalter, und neue prognostische Marker können zukünftig in der Bildgebung etabliert werden.

Postoperative shoulder: Normal postoperative MRI findings after rotator cuff repair in sportive patients include increased signal of the rotator cuff tendons and peribursal soft tissues on fluid-sensitive sequences as well as small dehiscences of the rotator cuff tendons. The postoperative glenoid labrum may be rounded or even slightly frayed after Bankart repair; however, the labrum should be closely attached to the underlying glenoid without undercutting joint fluid or contrast medium (so-called watertight labrum).

Silybum marianum (L.) Gaertn. (Asteraceae), commonly known as milk thistle, is a botanical natural product used to self-treat multiple diseases such as type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH). An extract from milk thistle seeds (achenes), termed silymarin, is comprised primarily of several flavonolignans. Systemic concentrations of these flavonolignans can influence the potential biologic effects of silymarin and the risk for pharmacokinetic silymarin-drug interactions. The aims of this research were to determine the roles of organic anion transporting polypeptides (OATPs/Oatps) in silymarin flavonolignan disposition and in pharmacokinetic silymarin-drug interactions. The seven major flavonolignans from silymarin were determined to be substrates for OATP1B1, OATP1B3, and OATP2B1. Sprague Dawley rats were fed either a control diet or a NASH-inducing diet and administered pitavastatin (OATP/Oatp probe substrate), followed by silymarin via oral gavage. Decreased protein expression of Oatp1b2 and Oatp1a4 in NASH animals increased flavonolignan area under the plasma concentration-time curve (AUC) and maximum plasma concentration. The combination of silymarin inhibition of OATPs/Oatps and NASH-associated decrease in Oatp expression caused an additive increase in plasma pitavastatin AUC in the animals. These data indicate that OATPs/Oatps contribute to flavonolignan cellular uptake and mediate the interaction between silymarin and NASH on pitavastatin systemic exposure.

Activity-guided fractionation was used to isolate and identify two components of the Brazilian açaí berry (Euterpe oleracea Mart.) with the ability to induce antioxidant response element (ARE)-dependent gene transcription in human hepatoma (HepG2) cells. Using an ARE-Luciferase reporter construct in cultured HepG2 cells, a suite of fractions from dried and powdered açaí berries were evaluated for transcriptional up-regulation of the luciferase gene. Active fractions were further refined until several pure compounds were isolated and identified. These compounds belong to the pheophorbide class of molecules, and are composed of the methyl and ethyl esters of the parent pheophorbide A, all of which are classified as photosensitizers. Using standard pheophorbides, dose response studies were carried out, and ARE-activation could be observed at concentrations as low as 8.2 μM and 16.9 μM for pheophorbide A methyl ester and pheophorbide A, respectively. These studies not only suggest a possible source of antioxidant properties for the açaí berry, but may also explain the recently identified photosensitizing abilities of açaí products as well.

Lung cancer is the leading cause of cancer deaths worldwide. Unfortunately, high recurrence rates and poor survival remain despite surgical resection and conventional chemotherapy. Local drug delivery systems are a promising intervention for lung cancer treatment with the potential for improved efficacy with reduced systemic toxicity. Here, we describe the development of a chemotherapy-loaded polymer buttress, to be implanted along the surgical margin at the time of tumor resection, for achieving local and prolonged release of a new anticancer agent, eupenifeldin. We prepared five different formulations of buttresses with varying amounts of eupenifeldin, and additional external empty polymer coating layers (or thicknesses) to modulate drug release. The in vitro eupenifeldin release profile depends on the number of external coating layers with the formulation of the greatest thickness demonstrating a prolonged release approaching 90 days. Similarly, the long-term cytotoxicity of eupenifeldin-loaded buttress formulations against murine Lewis lung carcinoma (LLC) and human lung carcinoma (A549) cell lines mirrors the eupenifeldin release profiles and shows a prolonged cytotoxic effect. Eupenifeldin-loaded buttresses significantly decrease local tumor recurrence in vivo and increase disease-free survival in a lung cancer resection model.

Searches for electron antineutrino, muon neutrino, and muon antineutrino disappearance driven by sterile neutrino mixing have been carried out by the Daya Bay and MINOS+ collaborations. This Letter presents the combined results of these searches, along with exclusion results from the Bugey-3 reactor experiment, framed in a minimally extended four-neutrino scenario. Significantly improved constraints on the θ_{μe} mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting Δm_{41}^{2}, excluding the 90% C.L. sterile-neutrino parameter space allowed by the LSND and MiniBooNE observations at 90% CL_{s} for Δm_{41}^{2}

We report the final measurement of the neutrino oscillation parameters $\Delta m^2_{32}$ and $\sin^2\theta_{23}$ using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of $23.76 \times 10^{20}$ protons on target producing $\nu_{mu}$ and $\overline{\nu_\mu}$ beams and 60.75 kt$\cdot$yr exposure to atmospheric neutrinos. The measurement of the disappearance of $\nu_{\mu}$ and the appearance of $\nu_e$ events between the Near and Far detectors yields $|\Delta m^2_{32}|=2.40^{+0.08}_{-0.09}~(2.45^{+0.07}_{-0.08}) \times 10^{-3}$ eV$^2$ and $\sin^2\theta_{23} = 0.43^{+0.20}_{-0.04} ~(0.42^{+0.07}_{-0.03})$ at 68% C.L. for Normal (Inverted) Hierarchy., Comment: 6 pages, 4 figures, 3 tables

Background Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. Methods Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009–2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors. Results Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age Conclusions Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.

Post-traumatic stress disorder (PTSD) is a debilitating psychopathological disease that is triggered by exposure to traumatic events. It is usually associated with substantial comorbidities, such as cognitive impairment, anxiety, and depression. Silymarin has been recently reported to exert neuroprotective activities against neurodegenerative diseases such as Alzheimerʼs and Parkinsonʼs diseases. Herein, the beneficial effects of silymarin in ameliorating PTSD-like symptoms such as memory impairments, anxiety, and depression were evaluated using a single-prolonged stress (SPS) rat model of PTSD. Male Wistar rats were randomly assigned into four groups: control, silymarin, SPS, or SPS + silymarin. Rats were administrated silymarin, 100 mg/kg i. p. for 4 wk. Rats in all groups were tested for short- and long-term memory in the radial arm water maze (RAWM), for anxiety-like behaviors using the open field test (OFT) and elevated plus maze (EPM) test, and for depression-like symptoms using the tail suspension test (TST). Conventional analyses of the RAWM, EPM, OFT, and TST were conducted using analysis of variance. Additionally, the anxiety-related behavior parameters of the EPM and OFT were entered to principal component analysis. Regression scores based on the first two extracted components, which accounted for 61% of the variance, were indicative of the anxiolytic activity of silymarin. Collectively, the results suggest that silymarin treatment prevents SPS-induced long-term memory impairments, anxiety, and depressive-like symptoms in rat models.

Background Clinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone “set the stage” for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL). Methods We have established a rat model for these stage-setting effects of stress. In this model, neither a stressor (electric footshock) nor stress-level corticosterone treatment alone reinstates cocaine seeking following self-administration and extinction, but each treatment potentiates reinstatement in response to an otherwise subthreshold cocaine priming dose (2.5 mg/kg, intraperitoneal). The contributions of endocannabinoid signaling in the PL to the effects of stress-level corticosterone on PL neurotransmission and cocaine seeking were determined using intra-PL microinfusions. Endocannabinoid-dependent effects of corticosterone on inhibitory synaptic transmission in the rat PL were determined using whole-cell recordings in layer V pyramidal neurons. Results Corticosterone application attenuated inhibitory synaptic transmission in the PL via cannabinoid receptor type 1 (CB 1 R)– and 2-arachidonoylglycerol–dependent inhibition of gamma-aminobutyric acid release without altering postsynaptic responses. The ability of systemic stress-level corticosterone treatment to potentiate cocaine-primed reinstatement was recapitulated by intra-PL injection of corticosterone, the CB 1 R agonist WIN 55,212-2, or the monoacylglycerol lipase inhibitor URB602. Corticosterone effects on reinstatement were attenuated by intra-PL injections of either the CB 1 R antagonist, AM251, or the diacylglycerol lipase inhibitor, DO34. Conclusions These findings suggest that stress-induced increases in corticosterone promote cocaine seeking by mobilizing 2-arachidonoylglycerol in the PL, resulting in CB 1 R-mediated attenuation of inhibitory transmission in this brain region.

In the field of natural products chemistry, a common question pertains to the authenticity of an isolated compound, i.e. are the interesting side chains biosynthesized naturally or an artefact of the isolation/purification processes? The droplet-liquid microjunction-surface sampling probe (droplet-LMJ-SSP) coupled to a hyphenated system (UPLC-UV-HRESIMS) empowers the analysis of natural product sources in situ, providing data on the biosynthetic timing and spatial distribution of secondary metabolites. In this study the droplet-LMJ-SSP was utilized to validate the authenticity of two new peptaibols (2 and 3) as biosynthesized secondary metabolites, even though both of them had structural features that could be perceived as artefacts. Compounds 2 and 3 were isolated from the scaled up fermentation of Trichoderma arundinaceum (strain MSX70741), along with a new member of the trichobrevin BIII complex (1), and four known compounds (4–7). The structures of the isolates were established using a set of spectroscopic and spectrometric methods, and their absolute configurations were determined by Marfey's analysis. The cytotoxic activity of compounds 1, 3, 4 and 6 was evaluated against a panel of cancer cell lines, where cytotoxic activity in the single digit μM range was observed.

Current chemotherapeutic dosing strategies are limited by the toxicity of anticancer agents and therefore rely on multiple low-dose administrations. As an alternative, we describe a novel sustained-release, biodegradable polymeric nanocarrier as a single administration replacement of multi-dose paclitaxel (PTX) treatment regimens. The first synthesis of poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX) is described, and its use enables high, controlled PTX loadings of up to 74 wt%. Moreover, the polymer backbone is composed of biocompatible building blocks-glycerol and carbon dioxide. When formulated as nanoparticles (NPs), PGC-PTX NPs exhibit PTX concentrations >15 mg mL-1, sub-100 nm diameters, narrow dispersity, storage stability for up to 6 months, and sustained and controlled PTX release kinetics over an extended period of 70 days. A safely administered single dose of PGC-PTX NPs contains more PTX than the median lethal dose of standard PTX. In murine models of peritoneal carcinomatosis, in which the clinical implementation of multi-dose intraperitoneal (IP) treatment regimens is limited by catheter-related complications, PGC-PTX NPs exhibit improved safety at high doses, tumor localization, and efficacy even after a single IP injection, with comparable curative effect to PTX administered as a multi-dose IP treatment regimen.

A search for mixing between active neutrinos and light sterile neutrinos has been performed by looking for muon neutrino disappearance in two detectors at baselines of 1.04 km and 735 km, using a combined MINOS and MINOS+ exposure of $16.36\times10^{20}$ protons-on-target. A simultaneous fit to the charged-current muon neutrino and neutral-current neutrino energy spectra in the two detectors yields no evidence for sterile neutrino mixing using a 3+1 model. The most stringent limit to date is set on the mixing parameter $\sin^2\theta_{24}$ for most values of the sterile neutrino mass-splitting $\Delta m^2_{41} > 10^{-4}$ eV$^2$., Comment: 7 pages, 4 figures, additional analysis details and a data release in the ancillary materials

The neurodevelopmental fetal alcohol spectrum disorder (FASD) is characterized by cognitive and behavioral deficits in the offspring. Conferring the deficits to the next generation would increase overall FASD disease burden and prevention of this transmission could be highly significant. Prior studies showed the reversal of these behavioral deficits by low dose thyroxine (T4) supplementation to the ethanol-consuming mothers. Here we aim to identify whether prenatal ethanol (PE) exposure impairs hippocampus-dependent learning and memory in the second-generation (F2) progeny, and whether T4 administration to the ethanol-consuming dam can prevent it. Sprague-Dawley (S) dams received control diets (ad libitum and nutritional control) or ethanol containing liquid diet with and without simultaneous T4 (0.3mg/L diet) administration. Their offspring (SS F1) were mated with naive Brown Norway (B) males and females generating the SB F2 and BS F2 progeny. Hippocampus-dependent contextual fear memory and hippocampal expression of the thyroid hormone-regulated type 3 deiodinase, (Dio3) and neurogranin (Nrgn) were assessed. SS F1 PE-exposed females and their SB F2 progeny exhibited fear memory deficits. T4 administration to the mothers of F1 females reversed these deficits. Although SS F1 PE-exposed males also experienced fear memory deficit, this was neither transmitted to their BS F2 offspring nor reversed by prenatal T4 treatment. Hippocampal Dio3 and Nrgn expression showed similar pattern of changes. Grandmaternal ethanol consumption during pregnancy affects fear memory of the matrilineal second-generation progeny. Low dose T4 supplementation prevents this process likely via altering allele-specific and total expression of Dio3 in the hippocampus.

In research focused on the discovery of new chemical diversity from freshwater fungi, a peak library was built and evaluated against a prostate cancer cell line, E006AA-hT, which was derived from an African American, as this population is disproportionately affected by prostate cancer. The chemical study of the bioactive sample accessioned as G858 (Delitschia sp.) led to the isolation of eight new α-pyrone derivatives (1 – 7, and 11), as well as the new 3S*,4S*-7-ethyl-4,8-dihydroxy-3,6-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (15). In addition, the known compounds 5-(3-S-hydroxybutyl)-4-methoxy-6-methyl-2H-pyran-2-one (8), 5-(3-oxobutyl)-4-methoxy-6-methyl-2H-pyran-2-one (9), pyrenocine I (10), 5-butyl-6-(hydroxymethyl)-4-methoxy-2H-pyran-2-one (12), sporidesmin A (13), 6-ethyl-2,7-dimethoxyjuglone (14), artrichitin (16), and lipopeptide 15G256ε (17) were also obtained. The structures of the new compounds were elucidated using a set of spectroscopic (NMR) and spectrometric (HRMS) methods. The absolute configuration of the most abundant member of each subclass of compounds was assigned through a modified Mosherʼs ester method. For 15, the relative configuration was assigned based on analysis of 3 J values. Compounds 1, 2, 5 – 14, 16, and 17 were evaluated against the cancer cell line E006AA-hT under hypoxic conditions, where compound 13 inhibited cell proliferation at a concentration of 2.5 µM.

In the field of natural products chemistry, a common question pertains to the authenticity of an isolated compound, i.e. are the interesting side chains biosynthesized naturally or an artefact of the isolation/purification processes? The droplet-liquid microjunction-surface sampling probe (droplet-LMJ-SSP) coupled to a hyphenated system (UPLC-UV-HRESIMS) empowers the analysis of natural product sources in situ, providing data on the biosynthetic timing and spatial distribution of secondary metabolites. In this study the droplet-LMJ-SSP was utilized to validate the authenticity of two new peptaibols (2 and 3) as biosynthesized secondary metabolites, even though both them had structural features that could be perceived as artefacts. Compounds 2 and 3 were isolated from the scaled up fermentation of Trichoderma arundinaceum (strain MSX70741), along with a new member of the trichobrevin BIII complex (1), and four known compounds (4–7). The structures of the isolates were established using a set of spectroscopic and spectrometric methods, and their absolute configurations were determined by Marfey’s analysis. The cytotoxic activity of compounds 1, 3, 4 and 6 was evaluated against a panel of cancer cell lines, where cytotoxic activity in the single digit μM range was observed.

The development and operation of liquid-argon time-projection chambers for neutrino physics has created a need for new approaches to pattern recognition in order to fully exploit the imaging capabilities offered by this technology. Whereas the human brain can excel at identifying features in the recorded events, it is a significant challenge to develop an automated, algorithmic solution. The Pandora Software Development Kit provides functionality to aid the design and implementation of pattern-recognition algorithms. It promotes the use of a multi-algorithm approach to pattern recognition, in which individual algorithms each address a specific task in a particular topology. Many tens of algorithms then carefully build up a picture of the event and, together, provide a robust automated pattern-recognition solution. This paper describes details of the chain of over one hundred Pandora algorithms and tools used to reconstruct cosmic-ray muon and neutrino events in the MicroBooNE detector. Metrics that assess the current pattern-recognition performance are presented for simulated MicroBooNE events, using a selection of final-state event topologies.