SNM1A is crucial for efficient repair of complex DNA breaks in human cells.

DNA double-strand breaks (DSBs), such as those produced by radiation and radiomimetics, are amongst the most toxic forms of cellular damage, in part because they involve extensive oxidative modifications at the break termini. Prior to completion of DSB repair, the chemically modified termini must be removed. Various DNA processing enzymes have been implicated in the processing of these dirty ends, but molecular knowledge of this process is limited. Here, we demonstrate a role for the metallo-ß-lactamase fold 5'-3' exonuclease SNM1A in this vital process. Cells disrupted for SNM1A manifest increased sensitivity to radiation and radiomimetic agents and show defects in DSB damage repair. SNM1A is recruited and is retained at the sites of DSB damage via the concerted action of its three highly conserved PBZ, PIP box and UBZ interaction domains, which mediate interactions with poly-ADP-ribose chains, PCNA and the ubiquitinated form of PCNA, respectively. SNM1A can resect DNA containing oxidative lesions induced by radiation damage at break termini. The combined results reveal a crucial role for SNM1A to digest chemically modified DNA during the repair of DSBs and imply that the catalytic domain of SNM1A is an attractive target for potentiation of radiotherapy.

Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target.

The three human SNM1 metallo-ß-lactamase fold nucleases (SNM1A-C) play key roles in DNA damage repair and in maintaining telomere integrity. Genetic studies indicate that they are attractive targets for cancer treatment and to potentiate chemo- and radiation-therapy. A high-throughput screen for SNM1A inhibitors identified diverse pharmacophores, some of which were shown by crystallography to coordinate to the di-metal ion centre at the SNM1A active site. Structure and turnover assay-guided optimization enabled the identification of potent quinazoline-hydroxamic acid containing inhibitors, which bind in a manner where the hydroxamic acid displaces the hydrolytic water and the quinazoline ring occupies a substrate nucleobase binding site. Cellular assays reveal that SNM1A inhibitors cause sensitisation to, and defects in the resolution of, cisplatin-induced DNA damage, validating the tractability of MBL fold nucleases as cancer drug targets.

Functional outcomes, quality of life, sexual function, and fertility of adult patients undergoing ileo-anal pouch anastomosis in childhood.

BACKGROUND: We conducted a questionnaire-based study of pouch function, quality of life, sexual function, and fertility among patients who had undergone ileal pouch anal anastomosis (IPAA) in childhood and who are now more than 18 years old. METHODS: A consecutive series of patients were asked to complete the following questionnaires: Pouch function score (PFS), short form 36 (SF-36), International index of erectile function (IIEF) (males), and Female sexual function index (FSFI) (females). Fertility in females was also assessed. Data are quoted as a median (SD). RESULTS: Of 144 patients who had IPAA, 101 were eligible, and 70 responded. Mean age at surgery was 14 years, and mean current age is 26 years. Most patients had either ulcerative colitis or familial adenomatous polyposis. The questionnaire was completed by 38/70 (54%). Median PFS score was 6 (5). SF-36 were lower than previous reports. Median FSFI was 30 (7.6), 84% of possible maximum. Median IIEF was 69, 92% of possible maximum. Successful conception was reported in 5/7 women who had tried. However, there were several miscarriages and two surgical emergencies during pregnancies. CONCLUSIONS: IPAA can be performed in childhood with similar pouch function to reported adult series. Quality of life appears poorer, but sexual function is maintained. There may be an association with adverse events in pregnancy. LEVEL OF EVIDENCE: IV.

Outcomes During a Transition Period from Open to Laparoscopic Pyloromyotomy.

BACKGROUND: Previous studies suggest that laparosopic pyloromyotomy may have some benefits over an open approach. We examined our results during a transition period from open to laparoscopic pyloromyotomy to see whether these benefits are sustained during the learning curve. METHODS: This is a retrospective case note review of all patients undergoing pyloromyotomy at a tertiary institution for a 5-year period (2010-2015). Data are presented as median (range). Statistical analysis was performed with Fisher's exact and Student's t-test. RESULTS: A total of 185 pyloromyotomies were performed, with data available for 90 open and 60 laparoscopic procedures. Duration of surgery was 42 (16-102) minutes for open and 28 (14-97) minutes for laparoscopic procedures (P = .0001). Total paracetamol requirements were 23.5 (0-169.4) mg/kg for open and 13.9 (0-95.3) mg/kg for laparoscopic cases (P = .008). No postoperative analgesia was required for 23 open and 29 laparoscopic patients (P = .005). Complications in the open group included incomplete pyloromyotomy (n = 1) and wound infection (n = 4); complications in the laparoscopic group included incisional hernia (n = 1), omental port-site herniation (n = 2), and suspected perforation with conversion to open procedure, although no perforation was found (n = 1; P = 1.000). CONCLUSION: Our results suggest that when the laparoscopic technique is first introduced, overall complication rates are not statistically higher, and operative times and analgesia requirements are significantly shorter, despite the learning curve.

Novel use of an osmotic self-inflating tissue expander for hypospadias revision surgery.

We describe the successful use of an osmotic self-inflating tissue expander for complex pediatric hypospadias repair. A 5-year-old boy, who had undergone previous hypospadias repair and subsequent fistula repair, presented with significant rotation of the penile shaft, with extensive scar tissue but insufficient native penile shaft skin for redo surgery. A 15 × 6 mm Osmed self-inflating cylindrical expander was used to allow excision of scar tissue and cover with expanded native skin. An excellent cosmetic and functional outcome was achieved at clinic review, 18 months postoperatively. The use of self-inflating tissue expanders offers a novel technique to achieve adequate native skin in the management of complex pediatric hypospadias.

Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience.

BACKGROUND: Neuroendocrine tumours (NET) of the appendix are rare histopathological neoplasms detected following operation for appendicitis in childhood. The role (if any) for radical surgery notably right hemicolectomy (RHC) has often reflected the 'expert opinion' of adult general surgeons with wider experience of managing NET lesions of the gastrointestinal tract. Critical decisions have focused on (a) tumour size, (b) histology, (c) tumour location/invasion and (d) positive lymph nodes. Against this background we report the clinical outcome of children with 'incidental' appendix carcinoid tumours managed at two regional UK paediatric surgery centres. A critical review of the literature is additionally provided in an effort to define contemporary patterns of care in paediatric surgical practice. METHODS: Hospital records and pathology database(s) identified 27 patients at two UK centres with a confirmed histological diagnosis of appendix NET lesions during January 1997-January 2013. A PUBMED and EMBASE search strategy-(English language publications only), 1975-present, was performed to gather information on all patients younger than 20years at primary diagnosis with NET appendix tumours to review their management and outcomes. RESULTS: All 27 patients treated at the two institutions had acute appendicitis including 3 cases presenting with an appendix mass. Twenty-five underwent appendicectomy with two having interval operations. Tumours had a maximum diameter of 2-18mm (median 9mm) with 73% of lesions located at the appendix tip. Fourteen (52%) had tumour invading the mesoappendix. All patients underwent appendicectomy only with no single case having RHC or additional surgery. Surveillance studies (5HIAA, chromogranin-A) and imaging including ultrasound or CT were deployed in a minority of patients revealing no abnormality. All 27 cases are alive and well-(mean follow up 5years; range: 9months-16years). The literature highlights varied management strategies and no recorded fatalities with radical surgery in children largely evolving from adult surgical practice. CONCLUSIONS: This study confirms that paediatric patients with 'incidental' NET tumours of the appendix have an excellent prognosis. Consensus guidelines should ideally be developed by paediatric oncology surgeons to avoid unnecessary radical surgery in many otherwise healthy children.

Is spinal stenosis assessment dependent on slice orientation? A magnetic resonance imaging study.

INTRODUCTION: Lumbar spinal stenosis (LSS) treatment is based primarily on the clinical criteria providing that imaging confirms radiological stenosis. The radiological measurement more commonly used is the dural sac cross-sectional area (DSCA). It has been recently shown that grading stenosis based on the morphology of the dural sac as seen on axial T2 MRI images, better reflects severity of stenosis than DSCA and is of prognostic value. This radiological prospective study investigates the variability of surface measurements and morphological grading of stenosis for varying degrees of angulation of the T2 axial images relative to the disc space as observed in clinical practice. MATERIALS AND METHODS: Lumbar spine TSE T2 three-dimensional (3D) MRI sequences were obtained from 32 consecutive patients presenting with either suspected spinal stenosis or low back pain. Axial reconstructions using the OsiriX software at 0°, 10°, 20° and 30° relative to the disc space orientation were obtained for a total of 97 levels. For each level, DSCA was digitally measured and stenosis was graded according to the 4-point (A-D) morphological grading by two observers. RESULTS: A good interobserver agreement was found in grade evaluation of stenosis (k = 0.71). DSCA varied significantly as the slice orientation increased from 0° to +10°, +20° and +30° at each level examined (P < 0.0001) (-15 to +32% at 10°, -24 to +143% at 20° and -29 to +231% at 30° of slice orientation). Stenosis definition based on the surface measurements changed in 39 out of the 97 levels studied, whereas the morphology grade was modified only in two levels (P < 0.01). DISCUSSION: The need to obtain continuous slices using the classical 2D MRI acquisition technique entails often at least a 10° slice inclination relative to one of the studied discs. Even at this low angulation, we found a significantly statistical difference between surface changes and morphological grading change. In clinical practice, given the above findings, it might therefore not be necessary to align the axial cuts to each individual disc level which could be more time-consuming than obtaining a single series of axial cuts perpendicular to the middle of the lumbar spine or to the most stenotic level. In conclusion, morphological grading seems to offer an alternative means of assessing severity of spinal stenosis that is little affected by image acquisition technique.

Patients' experiences of appearance changes following allogeneic bone marrow transplantation.

BACKGROUND: No previous research has explored the impact of the many appearance changes that can occur in patients following bone marrow transplantation (BMT). OBJECTIVE: This research aimed to explore in depth patients' experiences of appearance changes following allogeneic BMT to address the lack of knowledge in this area. METHODS: Semistructured interviews were conducted with 6 men and women who had received an allogeneic BMT within the previous 6 months to 2 years. Interviews were analyzed using interpretative phenomenological analysis. RESULTS: The findings illustrated that appearance changes had an impact on participants' confidence. It was also found that participants appeared to prioritize and view their appearance changes in the context of having a life-threatening treatment and experiencing many adverse effects. Appearance changes were a low priority until the immediate dangers of treatment had subsided and participants were returning to their former roles. In addition, it was also found that the isolation that participants experienced while recovering from transplant seemed to lessen the effects of appearance changes by limiting their exposure to the reactions and perceptions of others. CONCLUSIONS: The effects of appearance changes on confidence may become problematic if individuals are still experiencing an altered appearance when returning to former roles. IMPLICATIONS FOR PRACTICE: This study highlights the need to identify and support those with long-term appearance changes.