Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model.

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.

Diversity strengthens competing teams.

How does the composition of a collection of individuals affect its outcome in competition with other collections of individuals? Assuming that individuals can be different, we develop a model to interpolate between individual-level interactions and collective-level consequences. Rooted in theoretical mathematics, the model is not constrained to any specific context. Potential applications include research, education, sports, politics, ecology, agriculture, algorithms and finance. Our first main contribution is a game theoretic model that interpolates between the internal composition of an ensemble of individuals and the repercussions for the ensemble as a whole in competition with others. The second main contribution is the rigorous identification of all equilibrium points and strategies. These equilibria suggest a mechanistic underpinning for biological and physical systems to tend towards increasing diversity due to the strength it imparts to the system in competition with others.

Genomic and Seasonal Variations among Aquatic Phages Infecting the Baltic Sea Gammaproteobacterium Rheinheimera sp. Strain BAL341.

Knowledge in aquatic virology has been greatly improved by culture-independent methods, yet there is still a critical need for isolating novel phages to identify the large proportion of "unknowns" that dominate metagenomes and for detailed analyses of phage-host interactions. Here, 54 phages infecting Rheinheimera sp. strain BAL341 (Gammaproteobacteria) were isolated from Baltic Sea seawater and characterized through genome content analysis and comparative genomics. The phages showed a myovirus-like morphology and belonged to a novel genus, for which we propose the name Barbavirus All phages had similar genome sizes and numbers of genes (80 to 84 kb; 134 to 145 genes), and based on average nucleotide identity and genome BLAST distance phylogeny, the phages were divided into five species. The phages possessed several genes involved in metabolic processes and host signaling, such as genes encoding ribonucleotide reductase and thymidylate synthase, phoH, and mazG One species had additional metabolic genes involved in pyridine nucleotide salvage, possibly providing a fitness advantage by further increasing the phages' replication efficiency. Recruitment of viral metagenomic reads (25 Baltic Sea viral metagenomes from 2012 to 2015) to the phage genomes showed pronounced seasonal variations, with increased relative abundances of barba phages in August and September synchronized with peaks in host abundances, as shown by 16S rRNA gene amplicon sequencing. Overall, this study provides detailed information regarding genetic diversity, phage-host interactions, and temporal dynamics of an ecologically important aquatic phage-host system.IMPORTANCE Phages are important in aquatic ecosystems as they influence their microbial hosts through lysis, gene transfer, transcriptional regulation, and expression of phage metabolic genes. Still, there is limited knowledge of how phages interact with their hosts, especially at fine scales. Here, a Rheinheimera phage-host system constituting highly similar phages infecting one host strain is presented. This relatively limited diversity has previously been seen only when smaller numbers of phages have been isolated and points toward ecological constraints affecting the Rheinheimera phage diversity. The variation of metabolic genes among the species points toward various fitness advantages, opening up possibilities for future hypothesis testing. Phage-host dynamics monitored over several years point toward recurring "kill-the-winner" oscillations and an ecological niche fulfilled by this system in the Baltic Sea. Identifying and quantifying ecological dynamics of such phage-host model systems in situ allow us to understand and study the influence of phages on aquatic ecosystems.

E-cadherin mediated cell-biomaterial interaction reduces migration of keratinocytes in-vitro.

Percutaneous devices suffer from imperfect sealing of the epidermis-implant interphase, the so-called three-phase junction, allowing invading pathogens access to colonize the implant at the tissue interface and potentially cause an infection. In skin, one of the key components of the epidermal barrier is the E-cadherin mediated adherens junctions. We investigated the response of a human keratinocyte cell line (HaCaT) to a titanium substrate functionalized with the extracellular domain of E-cadherin fused to an Fc domain. Polydopamine was used as a binding layer to attach the E-cadherin to the titanium surface in two ways: 1) by attaching protein A to the polydopamine followed by E-cadherin (aligned orientation) or 2) by direct attachment of the E-cadherin to the polydopamine (random orientation). The E-cadherin surface functionalization was stable for up to two months as determined by ELISA. HaCaTs did attach to the surface irrespective of E-cadherin orientation. However, decreased cell proliferation and increased cell size was observed for cells on aligned E-cadherin surfaces as compared to a positive control coated with fibronectin. The adhesion of the HaCaTs to the surface with aligned E-cadherin was more sensitive to cell media Ca2+ depletion. A confluent layer of HaCaTs was almost immobile on the aligned E-cadherin surface, as compared to a surface coated with fibronectin, whereas cell migration was also observed on randomly oriented E-cadherin. The E-cadherin coated surfaces were non-adhesive for primary human dermal fibroblasts, a cell type not expressing E-cadherin. These results show the potential of using E-cadherin as a functional surface at the three-phase junction of percutaneous implants to ensure epidermal attachment, limit epidermal downgrowth and prevent fibroblast adhesion.

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159-0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.

Extended physical education in children aged 6-15 years was associated with improved academic achievement in boys.

AIM: Physical activity (PA) has been associated with enhanced cognition, brain development and concentration. This study evaluated whether increased physical education (PE) improved academic achievement. METHODS: We recruited 304 children (55% boys) from a Swedish school in Skane County in 1998-2002 when they were six to seven years of age and followed them through all nine mandatory school years. Their PE level was increased from 60 to 200 minutes per week, and their results were compared with 73 885 control children (51% boys) in the county who graduated in the same years and did the standard 60 minutes of PE per week. Their academic achievements were measured as their final grade scores and the proportion of students eligible for upper secondary school. RESULTS: The eligibility for further education increased in the intervention boys by 6.8 percentage points and the mean grade score by 12.1 points, while in the control group as a whole, the eligibility rate decreased by 0.7 percentage points and the mean grade score increased by 1.7 points. No changes in eligibility rates or mean grade scores were seen in the intervention girls. CONCLUSION: Increasing weekly PE over nine years was associated with improved academic achievement in boys.

Selective Lesioning of Nuclear Factor-κB Activated Cells in the Nucleus Accumbens Shell Attenuates Alcohol Place Preference.

Nuclear factor κ-light chain enhancer of activated B cells (NF-κB) is a transcription factor commonly associated with innate immunity and is activated by infection and inflammation. NF-κB has recently gained attention as a mediator of complex psychiatric phenomena such as stress and addiction. In regards to alcohol, most research on NF-κB has focused on neurotoxicity and few studies have explored the role of NF-κB in alcohol reward, reinforcement, or consumption. In these studies, we used conditioned place preference to assess the activity of NF-κB in response to rewarding doses of alcohol. To measure NF-κB activity we used a line of transgenic mice that express the LacZ gene under the control of an NF-κB-regulated promoter. In these animals, staining for ß-galactosidase (ß-gal) identifies cells in which NF-κB has been activated. We then used the Daun02 inactivation method to specifically silence NF-κB-expressing cells during place preference conditioning. Daun02 is an inactive prodrug that is converted to the inhibitory molecule daunorubicin by ß-gal. After alcohol place conditioning, we observed increased ß-gal staining in the nucleus accumbens (NAC) shell and dorsal raphe nucleus, and found that disruption of NF-κB-expressing cells using Daun02 attenuated the development of alcohol place preference when infused into the NAC shell following conditioning sessions. We found this effect to be regionally and temporally specific. These results suggest that, in addition to its role in alcohol-induced neurotoxicity, NF-κB mediates the development of alcohol place preference via its actions in the NAC shell.

Re-treatment with radium-223: first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: Six radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections. PATIENTS AND METHODS: Patients had castration-resistant prostate cancer and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase and prostate-specific antigen progression, radiographic progression-free survival, overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival, and time to pain progression. RESULTS: Among 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event. No grade 4-5 hematologic treatment-emergent adverse events occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node and five visceral metastases). Median times to total alkaline phosphatase and prostate-specific antigen progression were not reached and 2.2 months, respectively. Median radiographic progression-free survival was 9.9 months (12.8-month maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-free survival were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months. CONCLUSIONS: Re-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

Low physical activity is related to clustering of risk factors for fracture-a 2-year prospective study in children.

The study investigates the effect of physical activity (PA) on a composite score for fracture risk in pre-pubertal children. Low PA in children is related to the composite score for fracture risk and the pre-pubertal years seem to be a period when PA positively affects the score. INTRODUCTION: This study evaluates if PA in children is related to clustering of risk factors for fracture. Research questions are the following: (i) What is the effect of physical activity (PA) on single traits and a composite score for fracture risk? (ii) Could this score be used to identify the level of PA needed to reach beneficial effects? METHODS: This prospective population-based study included 269 children, aged 7-9 years at baseline while 246 attended the 2-year follow-up. We estimated duration of PA by questionnaires and measured traits that independently predict fractures. We then calculated gender specific Z-scores for each variable. The mean Z-score of all traits was used as a composite score for fracture risk. We tested correlation between duration of PA, each trait, and the composite score and group differences between children in different quartiles of PA. RESULTS: At baseline, we found no correlation between duration of PA and any of the traits or the composite score. At follow-up, we found a correlation between PA and the composite score. Physical activity had an effect on composite score, and children in the lowest quartiles of PA had unbeneficial composite score compared to children in the other quartiles. CONCLUSION: Low PA in children is related to clustering of risk factors for fracture, and the pre-pubertal years seem to be a period when PA positively affects the composite score.

Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF.

KRAS and BRAF are among the most commonly mutated oncogenes in human cancer that contribute to tumorigenesis in both distinct and overlapping tissues. However, KRAS and BRAF mutations are mutually exclusive; they never occur in the same tumor cell. The reason for the mutual exclusivity is unknown, but there are several possibilities. The two mutations could be functionally redundant and not create a selective advantage to tumor cells. Alternatively, they could be deleterious for the tumor cell and induce apoptosis or senescence. To distinguish between these possibilities, we activated the expression of BRAF(V600E) and KRAS(G12D) from their endogenous promoters in mouse lungs. Although the tumor-forming ability of BRAF(V600E) was higher than KRAS(G12D), KRAS(G12D) tumors were larger and more advanced. Coactivation of BRAF(V600E) and KRAS(G12D) markedly reduced lung tumor numbers and overall tumor burden compared with activation of BRAF(V600E) alone. Moreover, several tumors expressed only one oncogene, suggesting negative selection against expression of both. Similarly, expression of both oncogenes in mouse embryonic fibroblasts essentially stopped proliferation. The expression of both oncogenes hyperactivated the MEK-ERK-cyclin D pathway but reduced proliferation by increasing the production of p15, p16 and p19 proteins encoded by the Ink4/Arf locus and thereby increased senescence-associated ß-galactosidase-positive cells. The data suggest that coexpression of BRAF(V600E) and KRAS(G12D) in early tumorigenesis leads to negative selection due to oncogene-induced senescence.

Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice.

The role of hyperactive RAS signaling is well established in myeloid malignancies but less clear in T-cell malignancies. The Kras2(LSL)Mx1-Cre (KM) mouse model expresses endogenous KRAS(G12D) in hematopoietic cells and is widely used to study mechanisms and treatment of myeloproliferative neoplasms (MPN). The model displays an intriguing shift from MPN to acute T-cell leukemia (T-ALL) after transplantation to wild-type mice, but the mechanisms underlying this lineage shift is unknown. Here, we show that KRAS(G12D) increases proliferation of both myeloid and T-cell progenitors, but whereas myeloid cells differentiate, T-cell differentiation is inhibited at early stages. Secondary mutations in the expanded pool of T-cell progenitors accompany T-ALL development, and our results indicate that the shift from myeloid to T-lymphoid malignancy after transplantation is explained by the increased likelihood for secondary mutations when the tumor lifespan is increased. We demonstrate that tumor lifespan increases after transplantation because primary KM mice die rapidly, not from MPN, but from KRAS(G12D) expression in nonhematopoietic cells, which causes intestinal bleeding and severe anemia. We also identify loss of the wild-type KRAS allele as a secondary mutation in all T-ALL cells and provide evidence that wild-type KRAS acts as a tumor suppressor in the T-cell lineage in mice.

Immunological alteration and changes of gut microbiota after dextran sulfate sodium (DSS) administration in mice.

Ulcerative colitis (UC) is characterized by chronic inflammation of the colonic mucosa. Administration of dextran sulfate sodium (DSS) to animals is a frequently used model to mimic human colitis. Deregulation of the immune response to the enteric microflora or pathogens as well as increased intestinal permeability have been proposed as disease-driving mechanisms. To enlarge the understanding of the pathogenesis, we have studied the effect of DSS on the immune system and gut microbiota in mice. Intestinal inflammation was verified through histological evaluation and myeloperoxidase activity. Immunological changes were assessed by flow cytometry in spleen, Peyer's patches and mesenteric lymph nodes and through multiplex cytokine profiling. In addition, quantification of the total amount of bacteria on colonic mucosa as well as the total amount of lactobacilli, Akkermansia, Desulfovibrio and Enterobacteriaceae was performed by the use of quantitative PCR. Diversity and community structure were analysed by terminal restriction fragment length polymorphism (T-RFLP) patterns, and principal component analysis was utilized on immunological and T-RFLP patterns. DSS-induced colitis show clinical and histological similarities to UC. The composition of the colonic microflora was profoundly changed and correlated with several alterations of the immune system. The results demonstrate a relationship between multiple immunological changes and alterations of the gut microbiota after DSS administration. These data highlight and improve the definition of the immunological basis of the disease and suggest a role for dysregulation of the gut microbiota in the pathogenesis of colitis.

Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34(+) cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML.

Alemtuzumab (anti-CD52 monoclonal antibody) as single-agent therapy in patients with relapsed/refractory chronic lymphocytic leukaemia (CLL)-a single region experience on consecutive patients.

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is used in patients with refractory chronic lymphocytic leukaemia (CLL). We report results in health care with alemtuzumab on consecutive, advanced-stage patients from a well-defined geographical region. Records from 1,301 patients (Stockholm-Cancer-Registry 1991-2010) identified 56 relapsed/refractory patients treated with alemtuzumab. Median age was 69 years, 88 % had advanced Rai-stage with median 3 prior therapies. One fourth had bulky lymphadenopathy and 73 % were refractory to purine analogues. Median treatment length was 11.6 weeks. Median cumulative dose was 930 mg, significantly higher (p = 0.0277) for responders. Overall response-rate (ORR) was 43 %; 32.5 %, 50 % and 87.5 % in the Refractory, Purine analogue relapsed and Relapsed/Other subgroup, respectively. Response rate was significantly associated with subgroup (p = 0.0104). Good performance status (PS) was associated with better response rate (p = 0.0227). Median time-to-treatment-failure (TTF) (months) was 7.8 months, significantly (p < 0.0001) longer for responders (13.4) Major infections occurred in 36 %. Median overall survival was 22.5 months (range 0.4-74.3). Positive predictive factors were good PS (p < 0.0001) and fewer previous therapies (p = 0.0038). Twenty percent were retreated with alemtuzumab with an ORR of 54.5 %, and a TTF of 7.1 months. A high cumulative dose/longer duration of therapy and a relatively high response rate was observed compared to previous reports. Optimal patient identification and management may result in avoidance of early discontinuation and possibly better outcomes.

Bone mass and anthropometry in patients with osteoarthritis of the foot and ankle.

BACKGROUND: Patients with hip and knee osteoarthritis (OA) have high bone mineral density (BMD) and high BMI. If the same accounts for patients with foot or ankle OA is unknown. METHODS: We measured BMD and femoral neck (FN) width by dual-energy X-ray absorptiometry in 42 women and 19 men with idiopathic OA in the foot or ankle, and in 99 women and 82 men as controls. RESULTS: Women with OA had significant higher BMI than controls. Women with OA had higher BMI-adjusted BMD (p<0.01) and smaller BMI-adjusted FN width (p<0.01) than controls. Men with OA had higher BMI adjusted-BMD (p<0.05) and smaller BMI-adjusted FN width (p<0.01) than controls. CONCLUSION: Patients with OA in the foot or ankle have higher BMD and smaller bone size than being expected by their BMI. This phenotype may provide unfavourable forces across the joint and is hypothetically important for development of OA.

Oral biopharmaceutics tools - time for a new initiative - an introduction to the IMI project OrBiTo.

OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.

Human progenitor cells for bone engineering applications.

In this report, the authors review the human skeleton and the increasing burden of bone deficiencies, the limitations encountered with the current treatments and the opportunities provided by the emerging field of cell-based bone engineering. Special emphasis is placed on different sources of human progenitor cells, as well as their pros and cons in relation to their utilization for the large-scale construction of functional bone-engineered substitutes for clinical applications. It is concluded that, human pluripotent stem cells represent a valuable source for the derivation of progenitor cells, which combine the advantages of both embryonic and adult stem cells, and indeed display high potential for the construction of functional substitutes for bone replacement therapies.

Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study.

AIMS: Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyses the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction. This first-time-in-human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687. METHODS: Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1-60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% (SMM 60%; five cohorts, 1-20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity. RESULTS: AZD7687 markedly reduced postprandial TAG excursion with a steep concentration-effect relationship. Incremental TAG AUC (area under the serum concentration vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhoea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687. CONCLUSIONS: The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet-related gastrointestinal side effects may impact further development of DGAT1 inhibitors.

Toxicity in patients receiving adjuvant docetaxel + hormonal treatment after radical radiotherapy for intermediate or high-risk prostate cancer: a preplanned safety report of the SPCG-13 trial.

BACKGROUND: Radical radiotherapy (RT) combined with androgen deprivation therapy is currently the standard treatment for elderly patients with localized intermediate- or high-risk prostate cancer (PC). To increase the recurrence-free and overall survival, we conducted an adjuvant, randomized trial using docetaxel (T) in PC patients (Scandinavian Prostate Cancer Group trial 13). METHODS: The inclusion criteria are the following: men >18 and ≤75 years of age, WHO/ECOG performance status 0--1, histologically proven PC within 12 months before randomization and one of the following: T2, Gleason 7 (4+3), PSA >10; T2, Gleason 8--10, any PSA; or any T3 tumors. Neoadjuvant/adjuvant hormone therapy is mandatory for all patients. The patients were randomized to receive six cycles of T (75 mgm(-2) d 1. cycle 21 d) or no docetaxel after radical RT (with a minimum tumor dose of 74 Gy). This study identifier number is NTC 006653848 (http://www.clinicaltrials.org). RESULTS: In this preplanned safety analysis of 100 patients, T treatment induced grade (G) 3 adverse events (AEs) in 15 patients (30%) and G4 AEs in 30 patients (60%), mainly due to bone marrow toxicity. Neutropenia G3--4 was observed in 72% of the patients, febrile neutropenia was found in 24% of patients, neutropenic infection in 10% of patients and G3 infection without neutropenia in 4% of patients. Nonhematological G3 AEs were rare: anorexia, diarrhea, mucositis, nausea, pain (1 patient each) and fatigue (5). Other severe serious AEs related to T were pulmonary embolism and renal failure. However, only three patients discontinued T before completing the planned six cycles. No deaths had occurred. No patients in the control arm experienced G3--4 toxicities at 12 weeks after the randomization. CONCLUSIONS: Adjuvant docetaxel chemotherapy after radiotherapy has a higher frequency of neutropenia than previous studies on patients with metastatic disease. Otherwise, the treatment was quite well tolerated.