Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC(-/-) background. XPC(-/-) cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk

Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

SummarySomatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk

Single-stage forehead flap in nasal reconstruction

The paramedian forehead flap has become the standard of care for major nasal reconstruction. The classic procedure involves a second-stage operation to divide and inset the external pedicle. We present our experience in a clinical series using single-stage forehead flap reconstruction. Our indications include elderly patients, pediatric patients treated during mission trips, and any patient in whom an external pedicle or two-stage procedure is problematic. From 2008 to 2009, 9 patients underwent a single-stage forehead flap. The majority had defects after excision of skin cancer. Our modification involves removal of radix and proximal nasal skin and fat and deepithelialization of the proximal pedicle to allow inset without excess compression or kinking. This modification avoids the sequelae of an external pedicle, which include bleeding, dressings, the inability to wear eyeglasses, and the patient\u27s reluctance to appear in public. It safely provides acceptable results and avoids a mandatory secondary procedure

Use of gauze-based negative pressure wound therapy in a pediatric burn patient

Negative pressure wound therapy (NPWT) is described as it is used in the treatment of an infant burn victim. This case highlights the ability and techniques used to maintain an airtight dressing seal in the perirectal region. Use of this dressing type post-skin grafting allowed for 100% graft adhesion and no bacterial contamination despite close proximity to the rectum. Favorable experience and outcome with this patient are strong indicators that NPWT should be considered as a viable treatment in pediatric populations and that situations where body contour or fluids may make NPWT difficult to administer should not be a deterrent to therapy

The microvenous valvular anatomy of the human dorsal thoracic fascia

The use of free scapular fasciocutaneous flaps for reconstruction of recalcitrant grade 6 venous stasis ulcers has shown excellent early success rates. Venous refilling times measured postoperatively over the flaps by photoplethysmography have noted improvements to normal levels. Preliminary anatomic studies have demonstrated valves in the circumflex scapular veins of flaps used in reconstruction. The purpose of this study was to investigate and document the number, morphology, size, and location of valves in the human dorsal thoracic fascia. Ten scapular flaps were obtained from unembalmed cadavers and injected with methyl methacrylate. Each flap cast was divided into four parts: proximal, right and left, and distal, right and left. We reduced the size of specimens (the largest being 24 x 11 mm) and studied them in a scanning electron microscope. We identified all valves, estimated the diameter of the corresponding vein, calculated the depth of the valvular sinus, and related it to the corresponding venous size. Light microscopy and transmission electron microscopy were used as assisting tools applied to glutaraldehyde-fixed specimens. Analysis of injected specimens showed that valves were most abundant in veins with a luminal diameter of 30 to 120 microns (59.3 percent of 905 valves). The depth of valves became larger with increasing venous diameter. The sizes of valve sinuses were not different for individual valves. Except for veins larger than 1000 microns in diameter, there was no significant difference between the number of valves in different parts of an individual flap, nor were there significant differences between the valve numbers in different flaps. Most valves were bicuspid; only in the vein category of 30 to 120 microns were unicuspid valves encountered. Valves sometimes were located in series in a short segment of a vein; occasionally, they were found at the merging site of two veins. Transmission electron microscopy showed that valve leaflets had collagen fibers that ascended toward the tip of the leaflet and occasionally were accompanied by elastic fibers. Myofibroblasts were regularly present in the valve leaflets. These data show that fasciocutaneous flaps from the scapular region have numerous valves (90 valves on average in each flap) in the venous microcirculation. The microvenous valves in the dorsal thoracic fascia appear to be structurally similar to valves in larger veins. These valves may play a role in the improved hemodynamics and promising clinical outcome of patients with chronic venous insufficiency who have undergone free scapular flap reconstruction