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Cancer cells exploit CD47 overexpression to inhibit phagocytic elimination and neoantigen processing via the myeloid CD47-SIRP alpha axis and thereby indirectly evade adaptive T cell immunity. Here, we report on a hitherto unrecognized direct immunoinhibitory feature of cancer cell-expressed CD47. We uncovered that in response to IFN gamma released during cognate T cell immune attack, cancer cells dynamically enhance CD47 cell surface expression, which coincides with acquiring adaptive immune resistance toward pro-apoptotic effector T cell mechanisms. Indeed, CRISPR/Cas9-mediated CD47-knockout rendered cancer cells more sensitive to cognate T cell immune attack. Subsequently, we developed a cancer-directed strategy to selectively overcome CD47-mediated adaptive immune resistance using bispecific antibody (bsAb) CD47xEGFR-IgG2s that was engineered to induce rapid and prolonged cancer cell surface displacement of CD47 by internalization. Treatment of CD47(pos) cancer cells with bsAb CD47xEGFR-IgG2s potently enhanced susceptibility to cognate CD8(pos) T cells. Targeting CD47-mediated adaptive immune resistance may open up new avenues in cancer immunotherapy.

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.

Megaesophagus appears to be more common in Friesian horses than in other breeds. A prevalence of approximately 2% was observed among Friesian horses presented to the Wolvega Equine Clinic and the Utrecht University Equine Clinic. In this study, morphologic changes in the esophagi of Friesian horses with megaesophagus were compared with those of 6 control horses. Of 18 horses with clinically observed megaesophagus, only 12 animals had esophageal dilation at necropsy, usually involving the thoracic portion. Muscular hypertrophy of the distal esophagus was present in only one-third of the affected horses, indicating that this change is not the most relevant cause of megaesophagus in Friesians. Increased deposition of clumped and disorganized collagen was present in these clinically affected horses mainly in the non-dilated portion of the esophagus. At necropsy, a decrease in neural elements and elastin was present principally in horses with megaesophagus. Mild degeneration and necrosis of the tunica muscularis along the entire length of the esophagus were present in clinically affected horses and encountered only rarely in control animals. There were no significant differences among affected and control horses with respect to inflammation, mineralization, or the number of cells of Cajal. The increased occurrence of megaesophagus in the Friesian breed compared with other horse breeds, together with the presence of abnormal collagen in very young foals, supports the hypothesis that megaesophagus is hereditary in Friesians.

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.

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.

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