[Safety of patient care on an interprofessional training ward in visceral surgery]. / Sicherheit der Patientenversorgung auf einer viszeralchirurgischen interprofessionellen Ausbildungsstation.

BACKGROUND: Interprofessional training wards (ITW) are increasingly being integrated into teaching and training concepts in visceral surgery clinics. OBJECTIVE: How safe is patient care on an ITW in visceral surgery? MATERIAL AND METHODS: Data collection took place from November 2021 to December 2022. In this nonrandomized prospective evaluation study the frequency and severity of adverse events (AE) in 3 groups of 100 patients each in a tertiary referral center hospital for visceral surgery were investigated. The groups consisted of patients on the ITW and on the conventional ward before and after implementation of the ITW. The Global Trigger Tool (GTT) was used to search for AE. Simultaneously, a survey of the treatment was conducted according to the Picker method to measure patient reported outcome. RESULTS: Baseline characteristics and clinical outcome parameters of the patients in the three groups were comparable. The GTT analysis found 74 nonpreventable and 5 preventable AE in 63 (21%) of the patients and 12 AE occurred before the hospital stay. During the hospital stay 50 AE occurred in the operating theater and 17 on the conventional ward. None of the five preventable AE (in 1.7% of the patients) was caused by the treatment on the ITW. Patients rated the safety on the ITW better than in 90% of the hospitals included in the Picker benchmark cohort and as good as on the normal ward. CONCLUSION: The GTT-based data as well as from the patients' point of view show that patient care on a carefully implemented ITW in visceral surgery is safe.

Impact of individualized treatment on recovery from fatigue and return to work in survivors of advanced-stage Hodgkin's lymphoma: results from the randomized international GHSG HD18 trial.

BACKGROUND: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W). PATIENTS AND METHODS: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables. RESULTS: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL. CONCLUSIONS: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL.

Polymer-nucleobase composites for chemotherapy drug capture.

Intravenous chemotherapy (e.g., doxorubicin (DOX)) is standard treatment for many cancers but also leads to side effects due to off-target toxicity. To address this challenge, devices for removing off-target chemotherapy agents from the bloodstream have been developed, but the efficacy of such devices relies on the ability of the underlying materials to specifically sequester small-molecule drugs. Anion-exchange materials, genomic DNA, and DNA-functionalized iron oxide particles have all been explored as drug-capture materials, but cost, specificity, batch-to-batch variation, and immunogenicity concerns persist as challenges. Here, we report a new class of fully synthetic drug-capture materials. We copolymerized methacrylic acid and ethylene glycol dimethacrylate in the presence of several nucleobases and derivatives (adenine, cytosine, xanthine, and thymine) to yield a crosslinked resin with nucleobases integrated into the material. These materials demonstrated effective DOX capture: up to 27 mg of DOX per g of material over 20 minutes from a phosphate-buffered saline solution with an initial concentration of 0.05 mg mL-1 of DOX. These materials use only the individual nucleobases for DOX capture and exhibit competitive capture efficacy compared to previous materials that used genomic DNA, making this approach more cost-effective and reducing potential immunological concerns.

Src42A is required for E-cadherin dynamics at cell junctions during Drosophila axis elongation.

Src kinases are important regulators of cell adhesion. Here, we have explored the function of Src42A in junction remodelling during Drosophila gastrulation. Src42A is required for tyrosine phosphorylation at bicellular (bAJ) and tricellular (tAJ) junctions in germband cells, and localizes to hotspots of mechanical tension. The role of Src42A was investigated using maternal RNAi and CRISPR-Cas9-induced germline mosaics. We find that, during cell intercalations, Src42A is required for the contraction of junctions at anterior-posterior cell interfaces. The planar polarity of E-cadherin is compromised and E-cadherin accumulates at tricellular junctions after Src42A knockdown. Furthermore, we show that Src42A acts in concert with Abl kinase, which has also been implicated in cell intercalations. Our data suggest that Src42A is involved in two related processes: in addition to establishing tension generated by the planar polarity of MyoII, it may also act as a signalling factor at tAJs to control E-cadherin residence time.

Sex Differences in the Immune System Become Evident in the Perinatal Period in the Four Core Genotypes Mouse.

We have used the four core genotypes (FCG) mouse model, which allows a distinction between effects of gonadal secretions and chromosomal complement, to determine when sex differences in the immune system first appear and what influences their development. Using splenic T cell number as a measure that could be applied to neonates with as yet immature immune responses, we found no differences among the four genotypes at postnatal day 1, but by day 7, clear sex differences were observed. These sex differences were unexpectedly independent of chromosomal complement and similar in degree to gonadectomized FCG adults: both neonatal and gonadectomized adult females (XX and XY) showed 2-fold the number of CD4+ and 7-fold the number of CD8+ T cells versus their male (XX and XY) counterparts. Appearance of this long-lived sex difference between days 1 and 7 suggested a role for the male-specific perinatal surge of testicular testosterone. Interference with the testosterone surge significantly de-masculinized the male CD4+, but not CD8+ splenic profile. Treatment of neonates demonstrated elevated testosterone limited mature cell egress from the thymus, whereas estradiol reduced splenic T cell seeding in females. Neonatal male splenic epithelium/stroma expressed aromatase mRNA, suggesting capacity for splenic conversion of perinatal testosterone into estradiol in males, which, similar to administration of estradiol in females, would result in reduced splenic T cell seeding. These sex steroid effects affected both CD4+ and CD8+ cells and yet interference with the testosterone surge only significantly de-masculinized the splenic content of CD4+ cells. For CD8+ cells, male cells in the thymus were also found to express one third the density of sphingosine-1-phosphate thymic egress receptors per cell compared to female, a male characteristic most likely an indirect result of Sry expression. Interestingly, the data also support a previously unrecognized role for non-gonadal estradiol in the promotion of intra-thymic cell proliferation in neonates of both sexes. Microarray analysis suggested the thymic epithelium/stroma as the source of this hormone. We conclude that some immune sex differences appear long before puberty and more than one mechanism contributes to differential numbers and distribution of T cells.

[Thermographic monitoring of skin surface temperature associated with hot-iron disbudding in calves]. / Einsatz der Thermographie zum Monitoring der operationsbedingten Hitzeentwicklung während der thermischen Enthornung von Kälbern.

INTRODUCTION: The goal of this study was to determine the skin surface temperatures of the head using thermography in 28 German Holstein heifer calves at the time of hot iron disbudding. Calves were divided into group 1 (hot-iron disbudding, n = 14) and 2 (sham disbudding, n = 14). Thermographic measurements were made at eight locations of the head (area surrounding both horn buds, both horn buds, muzzle, mucous membranes of the muzzle, both eyes) at nine time points (- 60 min (basal value), time of disbudding, 5, 30, 60, 90, 120, 240 and 480 min after disbudding) using a high-end thermographic camera (ThermoPro TP8, Firma DIAS Infrared GmbH). The rectal temperature was measured 60 min before and 5, 240 and 480 min after disbudding. The statistical software SAS version 9.4 was used for analysis. Skin surface temperatures and rectal temperature correlated at several locations (rp ≥ 0.45; p ≤ 0.05). The maximum temperature (approx. 67 ºC) was measured at the horn buds immediately after the hot-iron procedure. By five and 30 min after hot-iron disbudding, the temperature of the horn buds had decreased by up to 50%, whereas the temperatures at the other locations had increased significantly (p.

INTRODUCTION: Le but de cette étude était de montrer les températures de surface dans la zone de tête chez 28 veaux femelles Holstein allemandes autour de la période d'écornage en utilisant la thermographie. À cette fin, les animaux étudiés ont été divisés en deux groupes (1: écornage thermique (thermE), N = 14; 2: pseudo-écornage (ScheinE), N = 14). À neuf reprises (- 60 [valeur au repos], 0, 5, 30, 60, 90, 120, 240, 480 min) des mesures thermographiques ont été effectuées à huit endroits dans la zone de la tête (environs du bourgeon de corne gauche (UliHa), bourgeon de corne gauche (liHa), œil gauche (liAu), mufle (FM), muqueuse nasale (SHFM), œil droit (reAu), bourgeon de corne droite (reHa), environs du bourgeon de corne droit (UreHa)). Ces mesures ont été réalisés à l'aide d'une caméra d'imagerie thermique haut de gamme (ThermoPro TP8, société DIAS Infrared GmbH). De plus, la température interne du corps (ICT) a été enregistrée par voie rectale aux minutes - 60, 5, 240 et 480. L'évaluation statistique de chaque caractéristique a été effectuée avec SAS, version 9.4. À plusieurs endroits (reAu, liAu, SHFM, liHa), une relation entre les ICT mesurées par voie rectale et les températures de surface déterminées par thermographie a pu être démontrée (rp ≥ 0,45; p ≤ 0,05). La température maximale (env. 67 °C) a pu être constatée au niveau des bourgeons de corne directement après l'écornage thermique. Cinq et 30 minutes après l'intervention, la température au niveau des bourgeons de corne avait diminué jusqu'à 50%, tandis que les températures de surface des autres emplacements chez les veaux des deux groupes avaient augmenté par rapport à la valeur au repos (p.

Densely Populated Water Droplets in Heavy-Oil Seeps.

Most of the microbial degradation in oil reservoirs is believed to take place at the oil-water transition zone (OWTZ). However, a recent study indicates that there is microbial life enclosed in microliter-sized water droplets dispersed in heavy oil of Pitch Lake in Trinidad and Tobago. This life in oil suggests that microbial degradation of oil also takes place in water pockets in the oil-bearing rock of an oil leg independent of the OWTZ. However, it is unknown whether microbial life in water droplets dispersed in oil is a generic property of oil reservoirs rather than an exotic exception. Hence, we took samples from three heavy-oil seeps, Pitch Lake (Trinidad and Tobago), the La Brea Tar Pits (California, USA), and an oil seep on the McKittrick oil field (California, USA). All three tested oil seeps contained dispersed water droplets. Larger droplets between 1 and 10 µl revealed high cell densities of up to 109 cells ml-1 Testing for ATP content and LIVE/DEAD staining showed that these populations consist of active and viable microbial cells with an average of 60% membrane-intact cells and ATP concentrations comparable to those of other subsurface ecosystems. Microbial community analyses based on 16S rRNA gene amplicon sequencing revealed the presence of known anaerobic oil-degrading microorganisms. Surprisingly, the community analyses showed similarities between all three oil seeps, revealing common OTUs, although the sampling sites were thousands of kilometers apart. Our results indicate that small water inclusions are densely populated microhabitats in heavy oil and possibly a generic trait of degraded-oil reservoirs.IMPORTANCE Our results confirmed that small water droplets in oil are densely populated microhabitats containing active microbial communities. Since these microhabitats occurred in three tested oil seeps which are located thousands of kilometers away from each other, such populated water droplets might be a generic trait of biodegraded oil reservoirs and might be involved in the overall oil degradation process. Microbial degradation might thus also take place in water pockets in the oil-bearing oil legs of the reservoir rock rather than only at the oil-water transition zone.

Anesthesia for Open Radical Retropubic Prostatectomy: A Comparison between Combined Spinal Epidural Anesthesia and Combined General Epidural Anesthesia.

BACKGROUND: Several anesthesiologic regimens can be used for open radical retropubic prostatectomy. The aim of this retrospective analysis was to compare the combined general epidural anesthesia and the combined spinal epidural anesthesia with regard to availability, efficacy, side effects, and perioperative time consumption in a high-volume center. METHODS: A retrospective analysis was performed by querying the electronic medical records of 1207 consecutive patients from the database of our online documentation software. All patients underwent open radical retropubic prostatectomy from 01/2008 to 08/2011 and met the study criteria. Linear and multivariate regression analyses were performed to identify differences in parameters such as time consumption in the operating unit, hemodynamic parameters, volume replacement, and catecholamine therapy. RESULTS: 698 (57.8%) patients have been undergoing open radical retropubic prostatectomy under combined spinal epidural anesthesia and 509 (42.2%) patients by combined general epidural anesthesia. Operating unit (p <0.0001) and post-anesthesia care unit stay (p <0.0001) as well as total hospital stay (p <0.0001) were significantly shorter in the combined spinal epidural anesthesia group. In addition, this group had reduced intraoperative volume need (p <0.0001) as well as lower need of catecholamines (p <0.0001). CONCLUSIONS: This retrospective study suggests that the combined spinal epidural anesthesia seems to be a suitable and efficient anesthesia technique for patients undergoing open radical retropubic prostatectomy. This specific approach reduces time in the operation unit and length of hospital stay.

Thrombosis as a treatment complication in Hodgkin lymphoma patients: a comprehensive analysis of three prospective randomized German Hodgkin Study Group (GHSG) trials.

BACKGROUND: The prognosis of Hodgkin lymphoma (HL) is excellent rendering research into treatment complications highly important. An important complication of cancer and its treatment is thrombosis. Thrombotic events are regularly observed in HL patients but precise information on incidence and risk factors is lacking and the value of prophylactic anticoagulation unclear. PATIENTS AND METHODS: Thus, we comprehensively studied thrombotic events in 5773 patients from the German Hodgkin Study Group (GHSG) HD13-15 trials in early-favorable, intermediate and advanced HL. We estimated the incidence of and identified risk factors for thrombotic events. Additionally, we provide detailed data on the time course and characteristics of thrombotic events. RESULTS: A total of 193 thrombotic events occurred for an incidence of 3.3%. Out of these, 175 (90.7%) were venous thromboses, 3 (1.5%) newly emerging post-thrombotic syndromes and 15 (7.8%) arterial thromboses. There were 11 (0.7%) events in early-favorable, 27 (1.3%) in early-unfavorable and 155 (7.3%) in advanced patients, the latter incidence being significantly higher (P < 0.001). The most common locations were deep vein thrombosis of the arm (46.3%) and leg (24.6%). Most venous thrombotic events occurred during chemotherapy (78.9%). We observed 59 (30.6%) catheter-associated events and a descriptively increased risk of venous thrombotic events in patients with oral contraception use during treatment (6.8% versus 3.9%). In advanced HL, the incidence of venous thrombotic events was increased upon treatment with BEACOPP-14 (9.4%, P = 0.0079) compared with 5.1% with 6×BEACOPPesc and 5.7% with 8×BEACOPPesc. Among commonly applied risk factors, including the Khorana score, only age and smoking were prognostic. CONCLUSIONS: The incidence of thrombotic events in advanced stage HL is comparable to other high-risk cancer patients, especially if treated with dose-dense regimens. Additional risk factors are higher age and smoking. Selected HL patients could benefit from prophylactic anticoagulation, however, further interventional studies are needed before general recommendations can be made.

Periostin concentrations in childhood-onset craniopharyngioma patients.

PURPOSE: Periostin is highly expressed in craniopharyngioma (CP)-associated fibroblasts and has been identified as a marker for non-alcoholic fatty liver disease (NAFLD). Half of CP patients with hypothalamic syndrome develop NAFLD. We hypothesized that periostin concentration is elevated in biological fluids of CP and associated with pathological hepatic parameters, indicating increased risk for NAFLD. METHODS: A cross-sectional study on 35 patients with sellar masses (SMP) recruited in the German Childhood Craniopharyngioma Registry (32 CP, 2 xanthogranuloma, 1 pilocytic astrocytoma), three short-statured patients with isolated growth hormone deficiency, five short-statured patients with normal findings in GH-stimulating tests and decreased insulin-like growth factor (IGF)-1 and seven healthy controls. Periostin was measured by Elisa in serum, urine and saliva. RESULTS: Periostin serum, urine and saliva concentrations in CP were similar to concentrations of the other groups. Hypothalamic involvement/hypothalamic lesions, degree of obesity as well as hepatic enzymes were not associated with elevated periostin concentrations. Due to low patient numbers with pathological hepatic parameters, missing imaging data on the degree of steatosis hepatis and the lack of histological proof of NAFLD, no definitive conclusions can be drawn from measured periostin concentrations in serum. Interestingly, the subgroup of patients with decreased IGF-1 levels showed elevated concentrations of serum periostin when compared with other groups. CONCLUSIONS: In CP, periostin concentrations are not associated with known risk factors for NAFLD such as hepatic and metabolic parameters, obesity and hypothalamic lesions. Accordingly, periostin does not seem to be a suitable marker for NAFLD in CP.

More diversity in epithelial cell polarity: A fruit flies' gut feeling.

Multicellular animals face the principle challenge to deal with two distinct compartments: the internal organismal compartment and the external environment. This challenge is met by the differentiation of cell sheets into epithelia, which provide a dynamic barrier in tissues, organs, and organisms. Cell polarity is key to all functions of epithelia, and compromising polarity causes many severe diseases. Within the past 20 years, research on Drosophila melanogaster discovered a conserved molecular machinery that controls epithelial polarity. Recent findings suggest that the textbook Drosophila-based paradigm of the control of epithelial polarity may not be as universal as previously assumed.

[Lutetium-177-PSMA radioligand therapy : Consensus within the framework of GKV-funded care between the university hospitals in Aachen, Bonn, Düsseldorf, Essen, and Cologne and the MDK Nordrhein]. / Lutetium-177-PSMA-Radioligandentherapie : Konsensus im Rahmen der GKV-finanzierten Versorgung zwischen den Hochschulkliniken in Aachen, Bonn, Düsseldorf, Essen und Köln und dem MDK Nordrhein.

In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.

Proton Therapy for Craniopharyngioma - An Early Report from a Single European Centre.

AIMS: Proton beam therapy (PBT) is being increasingly used for craniopharyngioma. We describe our early outcome of patients treated with PBT. MATERIALS AND METHODS: Between August 2013 and July 2016, 18 patients with craniopharyngiomas were treated with 54 Cobalt Gray Equivalent (CGE) in 30 fractions over 6 weeks at our centre. The early outcome of 16 patients included in a registry study was analysed. Radiological response was assessed by RECIST criteria and the disease- and treatment-related toxicities were scored according to the CTCAE 4.0. RESULTS: All patients are alive at a median follow-up of 32.6 months (range 9.2-70.6 months) from initial diagnosis. The median age at PBT was 10.2 years (range 5.4-46.9 years). One patient progressed 8.7 months after PBT and subsequently had complete resection of the tumour. At a median follow-up of 18.4 months after PBT, five patients remained in complete remission, four in partial remission and seven with stable disease. The most common adverse effects during PBT were grade 1 (cutaneous in seven patients and fatigue in six patients). There were no treatment-related grade 3 toxicities. CONCLUSIONS: Our early results are encouraging and comparable with the limited literature on PBT for craniopharyngioma.

Risk factors and a prognostic score for survival after autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma.

BACKGROUND: Novel agents are changing the treatment of relapsed or refractory Hodgkin lymphoma (HL). Nevertheless, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care in eligible patients. To identify patients who could benefit most from novel therapeutic approaches, we investigated a comprehensive set of risk factors (RFs) for survival after ASCT. METHODS: In this multinational prognostic multivariable modeling study, 23 potential RFs were retrospectively evaluated in HL patients from nine prospective trials with multivariable Cox proportional hazards regression analyses (part I). The resulting prognostic score was then validated in an independent clinical sample (part II). RESULTS: In part I, we identified 656 patients treated for relapsed/refractory HL between 1993 and 2013 with a median follow-up of 60 months after ASCT. The majority of potential RFs had significant impact on progression-free survival (PFS) with hazard ratios (HR) ranging from 1.39 to 2.22. The multivariable analysis identified stage IV disease, time to relapse ≤3 months, ECOG performance status ≥1, bulk ≥5 cm and inadequate response to salvage chemotherapy [

Melanocyte transformation requires complete loss of all pocket protein function via a mechanism that mitigates the need for MAPK pathway activation.

Deregulation of p16INK4A is a critical event in melanoma susceptibility and progression. It is generally assumed that the major effect of loss of p16 function is mediated through the CDK-cyclin pathway via its influence on the pocket protein (PP) pRb. However, there are also two other PPs, p107 and p130, which, when phosphorylated by CDK-cyclin complexes, play a role in permitting cell progression. Cohorts of mice carrying melanocyte-specific knockouts (KOs) of various combinations of the three PPs were generated. Mice null for pRb, p107, p130 or any combination of double mutants did not develop melanoma. Surprisingly, melanocyte-specific loss of all three PPs facilitated melanoma development (median age of onset 308 days, penetrance 40% at 1 year). Tumorigenesis was exacerbated by Trp53 co-deletion (median age of onset 275 days, penetrance 82% at 1 year), with cell culture studies indicating that this difference may result from the apoptotic role of Trp53. Melanomas in PP;Trp53-deficient mice lacked either Ras or Braf mutations, and hence developed in the absence of constitutive MAPK pathway activation. The lag period between induction of total PP or PP/Trp53 KO and melanoma development indicates that additional genetic or epigenetic alterations may account for neoplastic progression. However, exome sequencing of PP;Trp53 KO melanomas failed to reveal any additional recurrent driver mutations. Analysis of the putative mutation signature of the PP;Trp53 KO melanomas suggests that melanocytes are primed for transformation via a mutagenic mechanism involving an excess of T>G substitutions, but not involving a preponderance of C>T substitutions at CpG sites, which is the case for most spontaneous cancers not driven by a specific carcinogen. In sum, deregulation of all three PPs appears central to neoplastic progression for melanoma, and the customary reference to the p16INKA/CDK4/pRB pathway may no longer be accurate; all PPs are potentially critical targets of CDK-cyclins in melanoma.

Compensatory RNA polymerase 2 loading determines the efficacy and transcriptional selectivity of JQ1 in Myc-driven tumors.

Inhibition of bromodomain and extraterminal motif (BET) proteins such as BRD4 bears great promise for cancer treatment and its efficacy has been frequently attributed to Myc downregulation. Here, we use B-cell tumors as a model to address the mechanism of action of JQ1, a widely used BET inhibitor. Although JQ1 led to widespread eviction of BRD4 from chromatin, its effect on gene transcription was limited to a restricted set of genes. This was unlinked to Myc downregulation or its chromatin association. Yet, JQ1-sensitive genes were enriched for Myc and E2F targets, were expressed at high levels, and showed high promoter occupancy by RNAPol2, BRD4, Myc and E2F. Their marked decrease in transcriptional elongation upon JQ1 treatment, indicated that BRD4-dependent promoter clearance was rate limiting for transcription. At JQ1-insensitive genes the drop in transcriptional elongation still occurred, but was compensated by enhanced RNAPol2 recruitment. Similar results were obtained with other inhibitors of transcriptional elongation. Thus, the selective transcriptional effects following JQ1 treatment are linked to the inability of JQ1-sensitive genes to sustain compensatory RNAPol2 recruitment to promoters. These observations highlight the role of BET proteins in supporting transcriptional elongation and rationalize how a general suppression of elongation may selectively affects transcription.

Inhaled corticosteroid normalizes some but not all airway vascular remodeling in COPD.

BACKGROUND: This study assessed the effects of inhaled corticosteroid (ICS) on airway vascular remodeling in chronic obstructive pulmonary disease (COPD). METHODS: Thirty-four subjects with mild-to-moderate COPD were randomly allocated 2:1 to ICS or placebo treatment in a double-blinded clinical trial over 6 months. Available tissue was compared before and after treatment for vessel density, and expression of VEGF, TGF-ß1, and TGF-ß1-related phosphorylated transcription factors p-SMAD 2/3. This clinical trial has been registered and allocated with the Australian New Zealand Clinical Trials Registry (ANZCTR) on 17/10/2012 with reference number ACTRN12612001111864. RESULTS: There were no significant baseline differences between treatment groups. With ICS, vessels and angiogenic factors did not change in hypervascular reticular basement membrane, but in the hypovascular lamina propria (LP), vessels increased and this had a proportionate effect on lung air trapping. There was modest evidence for a reduction in LP vessels staining for VEGF with ICS treatment, but a marked and significant reduction in p-SMAD 2/3 expression. CONCLUSION: Six-month high-dose ICS treatment had little effect on hypervascularity or angiogenic growth factors in the reticular basement membrane in COPD, but normalized hypovascularity in the LP, and this was physiologically relevant, though accompanied by a paradoxical reduction in growth factor expression.