Colophonium-related Allergic Contact Dermatitis Caused by Medical Adhesive Tape Used to Prevent Skin Lesions in Soldiers.

Medical adhesive tapes are commonly recommended for the prevention of friction blisters during hiking and military marches. The aim of this paper is to report on the results of investigations into an outbreak of tape-related foot dermatitis in 26 military conscripts following continuous use of medical adhesive tapes for several days during a field exercise. Patch tests were performed using baseline series and aimed testing was performed with colophonium-related substances and different medical adhesive tapes. Contact allergy to the adhesive tapes used was found in 20 (77%) subjects, and contact allergy to colophonium in 16 (61%). Chemical analysis detected colophonium-related substances in the culprit tapes. Compared with consecutive dermatitis patients investigated at our Department of Occupational and Environmental Dermatology in the previous 10 years, conscripts with colophonium allergy had increased odds ratios for concomitant contact allergy to phenol formaldehyde resins and fragrance substances including hydroperoxides of limonene and linalool. The results show that prolonged use of medical adhesive tapes on intact skin carries a high risk for allergic contact dermatitis. Prior to their introduction on the market, medical devices should be assessed for possible side-effects.

Developing and designing an internet-based support and education program for patients awaiting kidney transplantation with deceased donors through: a Delphi study.

AIMS: The aim of this study was to develop and refine the content and design of an internet-based support and education program for patients awaiting kidney transplantation from deceased donors. DESIGN: A Delphi process was used. METHODS: A prototype internet-based intervention was drafted, based on previous research. The intervention included educational and psychological support to manage the uncertain waiting time and specific education enabling preparation for transplantation and adjustment to life after transplantation. In a two-round Delphi process, patients who had received a kidney transplant from a deceased donor within the last 2 years (n = 27), significant others (n = 6), health-care personnel with renal (n = 20) or transplant (n = 14) expertise, rated importance of content and design aspects of the prototype intervention on a 5-point scale using web questionnaires. A median of ≥ 3 was considered as consensus. Quantitative data was analyzed using descriptive statistics. Free text answers were encouraged and analyzed using deductive content analysis. The STROBE-checklist was used. RESULTS: Consensus was reached for all suggested content and design items in round 1, with median ratings of 4 or 5. Qualitative analysis from round 1 suggested four new content and design items which were rated in round 2, on all which consensus was reached; information about life with young children as relatives, expansion of kidney transplantation specific information, program extension by one week and individualization by making information available based on individual needs. CONCLUSION: There was consensus among heterogenous experts regarding suggested educational and psychological support content and design aspects, and additional content and design aspects were identified for an internet-based support and education program for patients awaiting kidney transplantation from deceased donors.

Evaluation of four surface surrogates for modeling lung tumor positions over several fractions in radiotherapy.

Patient breathing during lung cancer radiotherapy reduces the ability to keep a sharp dose gradient between tumor and normal tissues. To mitigate detrimental effects, accurate information about the tumor position is required. In this work, we evaluate the errors in modeled tumor positions over several fractions of a simple tumor motion model driven by a surface surrogate measure and its time derivative. The model is tested with respect to four different surface surrogates and a varying number of surrogate and image acquisitions used for model training. Fourteen patients were imaged 100 times with cine CT, at three sessions mimicking a planning session followed by two treatment fractions. Patient body contours were concurrently detected by a body surface laser scanning system BSLS from which four surface surrogates were extracted; thoracic point TP, abdominal point AP, the radial distance mean RDM, and a surface derived volume SDV. The motion model was trained on session 1 and evaluated on sessions 2 and 3 by comparing modeled tumor positions with measured positions from the cine images. The number of concurrent surrogate and image acquisitions used in the training set was varied, and its impact on the final result was evaluated. The use of AP as a surface surrogate yielded the smallest error in modeled tumor positions. The mean deviation between modeled and measured tumor positions was 1.9 mm. The corresponding deviations for using the other surrogates were 2.0 mm (RDM), 2.8 mm (SDV), and 3.0 mm (TP). To produce a motion model that accurately models the tumor position over several fractions requires at least 10 simultaneous surrogate and image acquisitions over 1-2 minutes.

Identification of novel GPR81 agonist lead series for target biology evaluation.

GPR81 is a novel drug target that is implicated in the control of glucose and lipid metabolism. The lack of potent GPR81 modulators suitable for in vivo studies has limited the pharmacological characterization of this lactate sensing receptor. We performed a high throughput screen (HTS) and identified a GPR81 agonist chemical series containing a central acyl urea scaffold linker. During SAR exploration two additional new series were evolved, one containing cyclic acyl urea bioisosteres and another a central amide bond. These three series provide different selectivity and physicochemical properties suitable for in-vivo studies.

Reproducibility of heart and thoracic wall position in repeated deep inspiration breath holds for radiotherapy of left-sided breast cancer patients.

BACKGROUND: Deep inspiration breath hold (DIBH) for radiotherapy of left-sided breast cancer patients can effectively move the heart away from the target and reduce the heart dose compared to treatments in free breathing. This study aims to investigate the positional reproducibility of heart edge (HE) and thoracic wall (TW) during repeated DIBHs. MATERIAL AND METHODS: At three occasions, 11 left-sided breast cancer patients were CT imaged during 6 minutes of repeated DIBHs with 60 cine CT series. The series were evenly distributed over three bed positions and for each bed position, the heart edge associated maximum heart distance (MHD) and thoracic wall-associated maximum lung distance (MLD) from a reference line were retrospectively analyzed. The high temporal resolution of the CT series enabled intrinsic heart movements to be resolved from breath hold variations. A body surface laser scanning system continuously extracted the thorax height and displayed it in a pair of goggles for patient feedback. To check for 'fake-breathing' movements, e.g. that the patient lifts its back from the couch to reach DIBH, the couch-to-spine distance was also measured in all CT series. RESULTS: The analysis was done for 1432 cine CTs captured during 292 breath holds. The DIBH moved the heart on average 15 mm in medial direction compared with free breathing. For the three bed positions studied, the mean value of the max range, across all patients, was between 11-13 mm for the MHD and 4-8 mm for the MLD. The MHD variation due to breath hold variation was twice as large as the MHD variation due to intrinsic heart movement. The couch-to-spine distance varied less than 3 mm for all fractions, i.e., no fake-breathing was discovered. CONCLUSIONS: The heart edge and thoracic wall reproducibility was high in relation to the medial heart displacement induced by the DIBH.

Practice Patterns of Stereotactic Radiotherapy in Pediatrics: Results From an International Pediatric Research Consortium.

PURPOSE/OBJECTIVES: There is little consensus regarding the application of stereotactic radiotherapy (SRT) in pediatrics. We evaluated patterns of pediatric SRT practice through an international research consortium. MATERIALS AND METHODS: Eight international institutions with pediatric expertise completed a 124-item survey evaluating patterns of SRT use for patients 21 years old and younger. Frequencies of SRT use and median margins applied with and without SRT were evaluated. RESULTS: Across institutions, 75% reported utilizing SRT in pediatrics. SRT was used in 22% of brain, 18% of spine, 16% of other bone, 16% of head and neck, and <1% of abdomen/pelvis, lung, and liver cases across sites. Of the hypofractionated SRT cases, 42% were delivered with definitive intent. Median gross tumor volume to planning target volume margins for SRT versus non-SRT plans were 0.2 versus 1.4 cm for brain, 0.3 versus 1.5 cm for spine/other bone, 0.3 versus 2.0 cm for abdomen/pelvis, 0.7 versus 1.5 cm for head and neck, 0.5 versus 1.7 cm for lung, and 0.5 versus 2.0 cm for liver sites. CONCLUSIONS: SRT is commonly utilized in pediatrics across a range of treatment sites. Margins used for SRT were substantially smaller than for non-SRT planning, highlighting the utility of this approach in reducing treatment volumes.

Practice patterns of palliative radiation therapy in pediatric oncology patients in an international pediatric research consortium.

BACKGROUND/OBJECTIVES: The practice of palliative radiation therapy (RT) is based on extrapolation from adult literature. We evaluated patterns of pediatric palliative RT to describe regimens used to identify opportunity for future pediatric-specific clinical trials. DESIGN/METHODS: Six international institutions with pediatric expertise completed a 122-item survey evaluating patterns of palliative RT for patients ≤21 years old from 2010 to 2015. Two institutions use proton RT. Palliative RT was defined as treatment with the goal of symptom control or prevention of immediate life-threatening progression. RESULTS: Of 3,225 pediatric patients, 365 (11%) were treated with palliative intent to a total of 427 disease sites. Anesthesia was required in 10% of patients. Treatment was delivered to metastatic disease in 54% of patients. Histologies included neuroblastoma (30%), osteosarcoma (18%), leukemia/lymphoma (12%), rhabdomyosarcoma (12%), medulloblastoma/ependymoma (12%), Ewing sarcoma (8%), and other (8%). Indications included pain (43%), intracranial symptoms (23%), respiratory compromise (14%), cord compression (8%), and abdominal distention (6%). Sites included nonspine bone (35%), brain (16% primary tumors, 6% metastases), abdomen/pelvis (15%), spine (12%), head/neck (9%), and lung/mediastinum (5%). Re-irradiation comprised 16% of cases. Techniques employed three-dimensional conformal RT (41%), intensity-modulated RT (23%), conventional RT (26%), stereotactic body RT (6%), protons (1%), electrons (1%), and other (2%). The most common physician-reported barrier to consideration of palliative RT was the concern about treatment toxicity (83%). CONCLUSION: There is significant diversity of practice in pediatric palliative RT. Combined with ongoing research characterizing treatment response and toxicity, these data will inform the design of forthcoming clinical trials to establish effective regimens and minimize treatment toxicity for this patient population.

Hypofractionated high-energy proton-beam irradiation is an alternative treatment for WHO grade I meningiomas.

BACKGROUND: Radiation treatment is commonly employed in the treatment of meningiomas. The aim of this study was to evaluate the effectiveness and safety of hypofractionated high-energy proton therapy as adjuvant or primary treatment for WHO grade I meningiomas. METHOD: A total of 170 patients who received irradiation with protons for grade I meningiomas between 1994 and 2007 were included in the study. The majority of the tumours were located at the skull base (n = 155). Eighty-four patients were treated post subtotal resection, 42 at tumour relapse and 44 with upfront radiotherapy after diagnosis based on the typical radiological image. Irradiation was given in a hypofractionated fashion (3-8 fractions, usually 5 or 6 Gy) with a mean dose of 21.9 Gy (range, 14-46 Gy). All patients were planned for follow-up with clinical controls and magnetic resonance imaging scans at 6 months and 1, 2, 3, 5, 7 and 10 years after treatment. The median follow-up time was 84 months. Age, gender, tumour location, Simpson resection grade and target volume were assessed as possible prognostic factors for post-irradiation tumour progression and radiation related complications. RESULTS: The actuarial 5- and 10-year progression-free survival rates were 93% and 85% respectively. Overall mortality rate was 13.5%, while disease-specific mortality was 1.7% (3/170 patients). Older patients and patients with tumours located in the middle cranial fossa had a lower risk for tumour progression. Radiation-related complications were seen in 16 patients (9.4%), with pituitary insufficiency being the most common. Tumour location in the anterior cranial fossa was the only factor that significantly increased the risk of complications. CONCLUSIONS: Hypofractionated proton-beam radiation therapy may be used particularly in the treatment of larger World Health Organisation grade I meningiomas not amenable to total surgical resection. Treatment is associated with high rates of long-term tumour growth control and acceptable risk for complications.

Positive correlation between occlusion rate and nidus size of proton beam treated brain arteriovenous malformations (AVMs).

BACKGROUND: Proton beam radiotherapy of arteriovenous malformations (AVM) in the brain has been performed in Uppsala since 1991. An earlier study based on the first 26 patients concluded that proton beam can be used for treating large and medium sized AVMs that were considered difficult to treat with photons due to the risk of side effects. In the present study we analyzed the result from treating the subsequent 65 patients. MATERIAL AND METHODS: A retrospective review of the patients' medical records, treatment protocols and radiological results was done. Information about gender, age, presenting symptoms, clinical course, the size of AVM nidus and rate of occlusion was collected. Outcome parameters were the occlusion of the AVM, clinical outcome and side effects. RESULTS: The rate of total occlusion was overall 68%. For target volume 0-2 cm(3) it was 77%, for 3-10 cm(3) 80%, for 11-15 cm(3) 50% and for 16-51 cm(3) 20%. Those with total regress of the AVM had significantly smaller target volumes (p < 0.009) higher fraction dose (p < 0.001) as well as total dose (p < 0.004) compared to the rest. The target volume was an independent predictor of total occlusion (p = 0.03). There was no difference between those with and without total occlusion regarding mean age, gender distribution or symptoms at diagnosis. Forty-one patients developed a mild radiation-induced brain edema and this was more common in those that had total occlusion of the AVM. Two patients had brain hemorrhages after treatment. One of these had no effect and the other only partial occlusion from proton beams. Two thirds of those presenting with seizures reported an improved seizure situation after treatment. CONCLUSION: Our observations agree with earlier results and show that proton beam irradiation is a treatment alternative for brain AVMs since it has a high occlusion rate even in larger AVMs.

A comparison of patient position displacements from body surface laser scanning and cone beam CT bone registrations for radiotherapy of pelvic targets.

BACKGROUND AND PURPOSE: Optical surface detection has attractive features as a mean in radiotherapy for patient positioning tasks such as set-up, monitoring and gating. To aid in hitting radiotherapy targets the correlation between detected surface displacements and internal structure displacements is crucial. In this study, we compare set-up displacements derived from a body surface laser scanning (BSLS) system to displacements derived from bone registrations with a cone beam computed tomography (CBCT) system in order to quantify the accuracy and applicability of BSLS for fractionated treatments in the pelvic region. MATERIAL AND METHODS: Displacements from concurrent BSLS and CBCT registrations were compared for 40 patients treated in the pelvic region for a total of 170 set-ups. Surface data captured by BSLS at the first treatment fraction (BSLSref) was used as main reference for the BSLS system, while bony structures from the planning CT were used as a reference for the CBCT method. As comparison, the patient outline extracted from the planning CT was used as BSLS reference (CTref). The displacements detected by the CBCT system (skin-marks-only) was also used for comparison. RESULTS: The mean differences (± 1 SD) between the BSLS and CBCT displacements were -0.01 (± 0.17) cm, 0.00 (± 0.21) cm and 0.01 (± 0.17) cm in the lateral, longitudinal and vertical directions, respectively. The median length of the difference was 0.26 cm (0.24-0.29 cm, 95% CI). The median of the difference between CBCT and BSLS displacements based on CTref was 0.37 cm (0.30-0.39 cm) and the median for skin-marks-only was 0.38 cm (0.34-0.42 cm). CONCLUSIONS: The BSLS system is a good supplement to the CBCT system for accurate set-up for fractions when no CBCT is deemed necessary for pelvic targets. Inter-fractional skin movement in relation to bone was estimated to be 0.2 cm in the lateral (X), longitudinal (Y) and vertical direction (Z), respectively.

Assessment of volume segmentation in radiotherapy of adolescents; a treatment planning study by the Swedish Workgroup for Paediatric Radiotherapy.

BACKGROUND AND PURPOSE: The variability in target delineation for similar cases between centres treating paediatric and adolescent patients, and the apparent differences in interpretation of radiotherapy guidelines in the treatment protocols encouraged us to perform a dummy-run study as a part of our quality assurance work. The aim was to identify and quantify differences in the segmentation of target volumes and organs at risk (OARs) and to analyse the treatment plans and dose distributions. MATERIALS AND METHODS: Four patient cases were selected: Wilm's tumour, Hodgkin's disease, rhabdomyosarcoma of the prostate and chordoma of the skull base. The five participating centres received the same patient-related material. They introduced the cases in their treatment planning system, delineated target volumes and OARs and created treatment plans. Dose-volume histograms were retrieved for relevant structures and volumes and dose metrics were derived and compared, e.g. target volumes and their concordance, dose homogeneity index (HI), treated and irradiated volumes, remaining volume at risk and relevant Vx and Dx values. RESULTS: We found significant differences in target segmentation in the majority of the cases. The planning target volumes (PTVs) varied two- to four-fold and conformity indices were in the range of 0.3-0.6. This resulted in large variations in dose distributions to OARs as well as in treated and irradiated volumes even though the treatment plans showed good conformity to the PTVs. Potential reasons for the differences in target delineation were analysed. CONCLUSION: Considerations of the growing child and difficulties in interpretation of the radiotherapy information in the treatment protocols were identified as reasons for the variation. As a result, clarified translated detailed radiotherapy guidelines for paediatric/adolescent patients have been recognised as a way to reduce this variation.

Procalcitonin levels in community-acquired pneumonia - correlation with aetiology and severity.

We studied procalcitonin (PCT) levels at hospital admittance and their association with aetiology and severity in patients with community-acquired pneumonia (CAP). Median PCT concentrations were higher in bacteraemic patients than in those without bacteraemia (6.11 µg/L vs 0.34 µg/L, p = 0.0002), in patients with non-bacteraemic pneumococcal aetiology than in those infected with other classic bacteria (1.18 vs 0.18, p = 0.038), and in patients with pneumococcal as compared with viral aetiology (2.43 vs 0.24, p = 0.017). When aetiology, bacteraemia and severity according to the pneumonia severity index (PSI) were included in logistic regression analyses with PCT > 0.5 as a dependent variable, the odds ratio (OR) for non-bacteraemic pneumococcal aetiology was 5.7 (p = 0.008) and 3.0 ( p = 0.1) for PSI 4-5. A separate analysis for bacteraemia and PSI 4-5 showed an OR of 17.5 (p = 0.008) and 2.7 (p = 0.092), respectively. In CAP patients, high PCT seems to be a good marker for invasive disease and pneumococcal aetiology. As a predictor of severity it appears to be less important.

Role of YopK in Yersinia pseudotuberculosis resistance against polymorphonuclear leukocyte defense.

The enteropathogen Yersinia pseudotuberculosis can survive in the harsh environment of lymphoid compartments that abounds in immune cells. This capacity is dependent on the plasmid-encoded Yersinia outer proteins (Yops) that are delivered into the host cell via a mechanism involving the Yersinia type III secretion system. We show that the virulence protein YopK has a role in the mechanism by which Y. pseudotuberculosis avoids the polymorphonuclear leukocyte or neutrophil (PMN) defense. A yopK mutant, which is attenuated in the mouse infection model, where it fails to cause systemic infection, was found to colonize Peyer's patches and mesenteric lymph nodes more rapidly than the wild-type strain. Further, in mice lacking PMNs, the yopK mutant caused full disease with systemic spread and typical symptoms. Analyses of effects on PMNs revealed that both the wild-type strain and the yopK mutant inhibited internalization and reactive oxygen species production, as well as neutrophil extracellular trap formation by PMNs. However, the wild-type strain effectively avoided induction of PMN death, whereas the mutant caused a necrosis-like PMN death. Taken together, our results indicate that YopK is required for the ability of Yersinia to resist the PMN defense, which is critical for the virulence of the pathogen. We suggest a mechanism whereby YopK functions to prevent unintended Yop delivery and thereby PMN disruption, resulting in necrosis-like cell death, which would enhance the inflammatory response favoring the host.

Isolation and characterization of progenitor-like cells from human renal proximal tubules.

The tubules of the kidney display a remarkable capacity for self-renewal on damage. Whether this regeneration is mediated by dedifferentiating surviving cells or, as recently suggested, by stem cells has not been unequivocally settled. Herein, we demonstrate that aldehyde dehydrogenase (ALDH) activity may be used for isolation of cells with progenitor characteristics from adult human renal cortical tissue. Gene expression profiling of the isolated ALDH(high) and ALDH(low) cell fractions followed by immunohistochemical interrogation of renal tissues enabled us to delineate a tentative progenitor cell population scattered through the proximal tubules (PTs). These cells expressed CD24 and CD133, previously described markers for renal progenitors of Bowman's capsule. Furthermore, we show that the PT cells, and the glomerular progenitors, are positive for KRT7, KRT19, BCL2, and vimentin. In addition, tubular epithelium regenerating on acute tubular necrosis displayed long stretches of CD133(+)/VIM(+) cells, further substantiating that these cells may represent a progenitor cell population. Furthermore, a potential association of these progenitor cells with papillary renal cell carcinoma was discovered. Taken together, our data demonstrate the presence of a previously unappreciated subset of the PT cells that may be endowed with a more robust phenotype, allowing increased resistance to acute renal injury, enabling rapid repopulation of the tubules.

Waiting for kidney transplantation from deceased donors: Experiences and support needs during the waiting time -A qualitative study.

OBJECTIVES: The study aimed to explore and describe patients' experiences of the transplantation process and the support they had received during the waiting time. METHOD: Semi-structured interviews were conducted with 14 patients currently waiting for kidney transplantation from deceased donors (n = 7) or recently having received kidney transplantation (n = 7). Interviews were transcribed, anonymized and analysed inductively using thematic analysis. RESULTS: Two themes and seven sub-themes were identified. The first theme, "Swaying between hope and despair" describes patients' perceptions of waiting for transplantation as a struggle, their expectations for life after the upcoming transplantation and experienced disappointments. The second theme, "Making your way through the waiting time", describes support, strategies and behaviours used to manage the waiting time. CONCLUSION: Patients described life while waiting for kidney transplantation as challenging, involving unexpected events, not understanding the transplantation process and having unrealistic expectations on life after transplantation. They also described support, strategies and behaviours used, some of which led to unwanted consequences. PRACTICE IMPLICATIONS: Patients waiting for kidney transplantation from deceased donors need continuous and easily available education, practical and emotional support to manage the waiting time. Transplantation specific education is also needed to facilitate preparation for transplantation and adjustment to life after transplantation.

Down-regulation of the oncogene cyclin D1 increases migratory capacity in breast cancer and is linked to unfavorable prognostic features.

The oncogene cyclin D1 is highly expressed in many breast cancers and, despite its proliferation-activating properties, it has been linked to a less malignant phenotype. To clarify this observation, we focused on two key components of malignant behavior, migration and proliferation, and observed that quiescent G(0)/G(1) cells display an increased migratory capacity compared to cycling cells. We also found that the down-regulation of cyclin D1 in actively cycling cells significantly increased migration while also decreasing proliferation. When analyzing a large set of premenopausal breast cancers, we observed an inverse proliferation-independent link between cyclin D1 and tumor size and recurrence, suggesting that this protein might abrogate infiltrative malignant behavior in vivo. Finally, gene expression analysis after cyclin D1 down-regulation by siRNA confirmed changes in processes associated with migration and enrichment of our gene set in a metastatic poor prognosis signature. This novel function of cyclin D1 illustrates the interplay between tumor proliferation and migration and may explain the attenuation of malignant behavior in breast cancers with high cyclin D1 levels.

Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors.

Chemical evolution of a HTS-based fragment hit resulted in the identification of N-(1-adamantyl)-2-[4-(2-tetrahydropyran-4-ylethyl)piperazin-1-yl]acetamide, a novel, selective T-type calcium channel (Ca(v)3.2) inhibitor with in vivo antihypertensive effect in rats.

NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction.

BACKGROUND: In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. MATERIAL AND METHODS: Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/ß = 3 Gy was used and the USC parameters used were: α/ß = 3 Gy, D(0) = 1.0 Gy, [Formula: see text] = 10, α = 0.206 Gy(-1) and d(T) = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether "high doses to small volumes" or "low doses to large volumes" are most important for lung toxicity. RESULTS AND DISCUSSION: NTCP analysis with the LKB-model using parameters m = 0.4, D(50) = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D(50) = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats.

Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.