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Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to the DNA crosslinking agents, mitomycin C and olaparib, as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA-damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets. The prognostic value of the repair defect prediction profiles was assessed in two retrospective cohorts with a total of 180 patients with advanced HPV-negative HNSCC, who were treated with cisplatin-based chemoradiotherapy. DNA repair defects, as predicted by the profiles, were associated with poor outcome in both patient cohorts. The poor prognosis association was particularly strong in normoxic tumor samples and was linked to an increased risk of distant metastasis. In vitro, only crosslink repair–defective HNSCC cell lines are highly migratory and invasive. This phenotype could also be induced in cells by inhibiting rad51 in repair competent and reduced by DNA-PK inhibition. In conclusion, DNA crosslink repair prediction expression profiles reveal a poor prognosis association in HNSCC. Significance: This study uses innovative machine learning-based approaches to derive models that predict the effect of DNA repair defects on treatment outcome in HNSCC.

PURPOSE: A reduction in the dose, irradiated volume, and sensitivity of, in particular, normal tissue stem cells is needed to advance radiation therapy. This could be obtained with the use of particles for radiation therapy. However, the radiation response of normal tissue stem cells is still an enigma. Therefore, in the present study, we developed a model to investigate the in vitro response of stem cells to particle irradiation.METHODS AND MATERIALS: We used the immortalized human salivary gland (HSG) cell line resembling salivary gland (SG) cells to translate the radiation response in 2-dimensional (2D) to 3-dimensional (3D) conditions. This response was subsequently translated to the response of SG stem cells (SGSCs). Dispersed single cells were irradiated with photons or carbon ions at different linear energy transfers (LETs; 48.76 ± 2.16, 149.9 ± 10.8, and 189 ± 15 keV/μm). Subsequently, 2D or 3D clonogenicity was determined by counting the colonies or secondary stem cell-derived spheres in Matrigel. γH2AX immunostaining was used to assess DNA double strand break repair.RESULTS: The 2D response of HSG cells showed a similar increase in dose response to increasing higher LET irradiation as other cell lines. The 3D response of HSG cells to increasing LET irradiation was reduced compared with the 2D response. Finally, the response of mouse SGSCs to photons was similar to the 3D response of HSG cells. The response to higher LET irradiation was reduced in the stem cells.CONCLUSIONS: Mouse SGSC radiosensitivity seems reduced at higher LET radiation compared with transformed HSG cells. The developed model to assess the radiation response of SGSCs offers novel possibilities to study the radiation response of normal tissue in vitro.

Diseases of the coxofemoral (hip) joint are infrequently diagnosed in horses. Most cases are presented as an unilateral condition and usually are of traumatic origin. This case report describes a Friesian foal with a clinically obvious thoracolumbar kyphosis, combined with a weight-shifting stance and a shortened stride of both hindlimbs. General clinical and lameness examinations, computed tomographic examination of the pelvis, and macroscopic and histopathological examinations of the coxofemoral joints were performed. This revealed a final, phenotypical diagnosis of a primary osteochondral dysplasia of both coxofemoral joints with secondary osteoarthritis. Similar to the occurrence of this condition in other species and considering the small genetic basis of the Friesian horse breed, a genetic predisposing factor is suspected to play a key role in the developing mechanism of dysplastic coxofemoral joint disease in horses as illustrated with this case. Computed tomography scanning appears to be a useful imaging technique in the detection of coxofemoral joint disease in small horses and foals.

Reasons for performing study: In horses, aortic sinus of Valsalva aneurysms or tears in the aortic root are well-recognised conditions in breeding stallions, often leading to sudden death. A more uncommon form of aortic rupture, located proximal to the ligamentum arteriosum has been reported in 3 Friesian horses. Objectives: The purpose of this study was to phenotypically characterise aortic rupture and aorto-pulmonary fistulation in Friesian horses in terms of clinical and post mortem data based on 24 cases. Methods: Friesian horses that were diagnosed with aortic rupture and aorto-pulmonary fistulation over a period of 13 years (19972010) at the Department of Equine Sciences of Utrecht University (n = 15) and Wolvega Equine Hospital (n = 9), were included in this study. Case history, results of clinical examination and gross post mortem findings were screened and analysed. Results: Some cases were found dead without prior symptoms, but in several cases signs such as recurrent colic, peripheral oedema and sustained tachycardia were present for several weeks prior to cardiac failure. Clinical examination during hospitalisation revealed increased rectal temperature, peripheral oedema and increased jugular pulse with a bounding arterial pulse. In the majority of horses an aortic rupture of the aortic arch near the ligamentum arteriosum, concurrent with a circumferential cuff of perivascular haemorrhage and aorto-pulmonary fistulation, was found at post mortem examination. Conclusions: Aorto-pulmonary fistulation in conjunction with aortic rupture is more common in Friesians than previously estimated. In some cases findings demonstrate a progressive pathology rather than acute cardiac failure and sudden death. An appropriate approach is necessary during post mortem examination of the heart in order not to overlook the diagnosis. Potential relevance: Equine practitioners should realise that in Friesian horses presented with a history of recurrent false colic, coughing, sustained tachycardia and/or peripheral oedema, aortic rupture and aorto-pulmonary fistulation should be included in the differential diagnosis.

Background Thoracic aortic rupture and aortopulmonary fistulation are rare conditions in horses. It mainly affects Friesian horses. Intrinsic differences in biomechanical properties of the aortic wall might predispose this breed. The biomechanical and biochemical properties of the thoracic aorta were characterized in warmblood horses, unaffected Friesian horses and Friesians with aortic rupture in an attempt to unravel the underlying pathogenesis of aortic rupture in Friesian horses. Samples of the thoracic aorta at the ligamentum arteriosum (LA), mid thoracic aorta (T1) and distal thoracic aorta (T2) were obtained from Friesian horses with aortic rupture (A), nonaffected Friesian (NA) and warmblood horses (WB). The biomechanical properties of these samples were determined using uniaxial tensile and rupture assays. The percentages of collagen and elastin (mg/mg dry weight) were quantified. Results Data revealed no significant biomechanical nor biochemical differences among the different groups of horses. The distal thoracic aorta displayed an increased stiffness associated with a higher collagen percentage in this area and a higher load-bearing capacity compared to the more proximal segments. Conclusions Our findings match reported findings in other animal species. Study results did not provide evidence that the predisposition of the Friesian horse breed for aortic rupture can be attributed to altered biomechanical properties of the aortic wall. Electronic supplementary material The online version of this article (doi:10.1186/s12917-015-0597-0) contains supplementary material, which is available to authorized users.

Four questionnaire surveys were conducted over a period of 20 years to evaluate long-term effects of haemophilia treatment in the Netherlands. The response to the prestructured questionnaires in 1972, 1978, 1985 and 1992 varied between 70% and 84%. Data concerned treatment modalities, bleeding episodes, hospitalization, absenteeism, joint impairment and employment. Results over the period 1972-92 for patients with severe and moderately severe haemophilia showed that the use of prophylaxis had sharply increased (from 21% to 45%), as was the case for home treatment (from 4% to 62%). Consequently, the annual mean number of bleeds diminished from 19 to 13. Absence from school was markedly reduced (from 32 to 5 days), and sick leave in employed patients had also diminished (from 26 to 22 days). Furthermore, the use of inpatient hospital facilities, as well as employment in haemophilia patients, had nearly equalled that of the general Dutch male population. The self-reported degree of joint impairment showed no overall improvement, but in patients aged under 35 years there seemed to be a slight reduction in severe impairment. Patients aged under 15 years finally had no severe impairment at all. Social participation can only be further improved if arthropathy is prevented from an early age. Therefore adequate prophylactic regimens and close monitoring of joint impairment in young adults are needed.

The cornerstones in the detection of urinary bladder cancer is the combination of urinary cytology and urethrocystoscopy (UCS). Limitations concerning these tests are a low sensitivity of cytology and a problem in detection of small papillary lesions and flat carcinoma in situ (CIS) with standard UCS. These limitations have led to newer techniques, like photodynamic diagnosis (PDD) and narrow band imaging (NBI) to improve the visibility by UCS. Once a bladder tumor has been detected it should be resected by transurethral resection (TURBT) to obtain adequate tissue for pathological assessment. PDD-assisted resection is a promising technique with better tumor detection, more complete resection and a better recurrence free survival. Imaging techniques like CT and (enhanced-)MRI play an important role in accurate staging of UBC and in the detection of recurrences of MIBC during follow-up.

Aims Aortic rupture and aortopulmonary fistulation are reported with increased incidence in the Friesian breed. In contrast to Warmblood horses, the aorta in Friesian horses typically ruptures at the level of the ligamentum arteriosum (Ploeg et al. 2013). This remote location often creates difficulties in identifying the rupture with transthoracic ultrasound. The aim of this study was to evaluate the usefulness of transoesophageal visualisation of the aortopulmonary region with a linear probe in both standing unsedated horses and horses suffering from aortic rupture. Methods Five Friesian horses, 2 healthy and 3 affected, were subjected to transthoracic ultrasound (2.5 MHz sectorial probe GE) followed by transoesophageal ultrasound (7.5 or 10 MHz linear probe). Correct oesophageal introduction of the probe was guided by means of endoscopy. After visualisation of the aortopulmonary region, horses were anaesthetised, and the transoesophageal ultrasound was repeated. In 4 horses, simultaneous carotid artery catheterisation was performed, to visualise the catheter at the zone of interest. After obtaining a diagnosis, all affected horses were subjected to euthanasia and autopsies were performed. Results The aortopulmonary region could be visualised in all horses. In the affected horses presence or absence of a periaortic blood cuff, aortic rupture and or aortopulmonary fistulation could be clearly identified. In one horse during carotid catheterisation, the catheter could be guided into the fistulation site, which was clearly visualised by means of transoesophageal ultrasound. Conclusions and practical significance Transoesophageal ultrasound by means of a 7.5 or 10 MHz linear probe allows for good visualisation of the aortopulmonary region and for diagnosing aortic rupture in Friesian horses. The technique will be further developed as an elegant noninvasive way to screen Friesian horses for this pathology, even in the standing nonsedated horse. Ethical animal research Owner informed consent was obtained for all horses. Sources of funding: This study was funded by the Dutch Royal Friesian Studbook and Scil Animal Care. Competing interests: None.

later expanded the populationthat could benefit from this by introducing a two-stage vari-ant comprising initial pulmonary artery banding to conditionthe left ventricle. The first early survivors of this arterialswitch procedure are now reaching child- bearing age andwe report the first patient undergoing a successful (live birth)pregnancy.The patient, born in 1974, had complete TGA and aventricular septal defect. After atrial balloon septostomy andpulmonary artery banding in 1975, she underwent an arterialswitch procedure according to Jatene in 1978. During theoperation, the coronary arteries and part of their surround-ing sinus Valsalva (aortic) wall tissue were excised and re-implanted in the proximal part of the pulmonary artery.The proximal pulmonary artery was then connected to thedistal part of the transected ascending aorta. The ventricularseptal defect was closed with a Dacron graft and the atrialseptostomy with a direct suture. Sinus Valsalva tissue utilisedfor coronary artery re-implantation was replaced by twopatches of pericardium. A 16-mm Dacron conduit was placedbetween the distal pulmonary artery and proximal aorta tocomplete the anatomical repair. The pulmonary artery con-duit was replaced due to stenosis in 1985 and 1990, on thelatter occasion with a pulmonary homograft.In 1995, she conceived. Assessment before this had shownthat her exercise tolerance was good (NYHA functionalclass I) even though she smoked more than 20 cigarettesper day and continued to do so throughout the pregnancy.Pre-conceptional physical examination showed an averageheart rate of 75 bpm, blood pressure of 115/70 mmHg. Therewere no signs of (congestive) heart failure. Her last recordedelectrocardiogram prior to pregnancy demonstrated a normalsinus rhythm with a complete right bundle branch block(QRS 160), but without signs of myocardial ischaemia. Dur-ing the first and second trimester, she experienced no com-plaints and exercise tolerance was comparable to otherpregnant women. She used no medication. Physical examina-tions [e.g. blood pressure (105/65 mmHg) and heart rate (77bpm)] stayed well within acceptable limits. No changes in theperformed 12 lead electrocardiograms were reportedthroughout the pregnancy. All three transthoracic echocar-diograms (before, at 28 weeks and after pregnancy) showedminor regurgitation of the pulmonary homograft and a minoraortic valve stenosis (25 mmHg). No changes in ventricularand valvular function were detected. During pregnancy, theaortic sinus diameter, however, increased by 5–33 mm at 28weeks of gestation, which returned back to the baseline valueof 27 mm within 1.5 years after delivery. No cardiac compli-cations occurred during the patient’s gestation.At 30 weeks of gestation, the patient was admitted to hos-pital to assess mild vaginal bleeding for which no cause wasdetected. Fetal ultrasound revealed intrauterine growthrestriction but no structural fetal defects. Close monitoringof fetal growth was performed and at 38 + 5 weeks labour wasinduced to guarantee fetal wellbeing. Fetal distress developedduring labour and she was delivered by caesarean sectionunder general anaesthesia with endocarditis prophylaxis. Thebaby was male, small for his gestational age (1930 g