DAXX promotes centromeric stability independently of ATRX by preventing the accumulation of R-loop-induced DNA double-stranded breaks.

Maintaining chromatin integrity at the repetitive non-coding DNA sequences underlying centromeres is crucial to prevent replicative stress, DNA breaks and genomic instability. The concerted action of transcriptional repressors, chromatin remodelling complexes and epigenetic factors controls transcription and chromatin structure in these regions. The histone chaperone complex ATRX/DAXX is involved in the establishment and maintenance of centromeric chromatin through the deposition of the histone variant H3.3. ATRX and DAXX have also evolved mutually-independent functions in transcription and chromatin dynamics. Here, using paediatric glioma and pancreatic neuroendocrine tumor cell lines, we identify a novel ATRX-independent function for DAXX in promoting genome stability by preventing transcription-associated R-loop accumulation and DNA double-strand break formation at centromeres. This function of DAXX required its interaction with histone H3.3 but was independent of H3.3 deposition and did not reflect a role in the repression of centromeric transcription. DAXX depletion mobilized BRCA1 at centromeres, in line with BRCA1 role in counteracting centromeric R-loop accumulation. Our results provide novel insights into the mechanisms protecting the human genome from chromosomal instability, as well as potential perspectives in the treatment of cancers with DAXX alterations.

Fabrication-robust silicon photonic devices in standard sub-micron silicon-on-insulator processes.

Perturbations to the effective refractive index from nanometer-scale fabrication variations in waveguide geometry plague high index-contrast photonic platforms; this includes the ubiquitous sub-micron silicon-on-insulator (SOI) process. Such variations are particularly troublesome for phase-sensitive devices, such as interferometers and resonators, which exhibit drastic changes in performance as a result of these fabrication-induced phase errors. In this Letter, we propose and experimentally demonstrate a design methodology for dramatically reducing device sensitivity to silicon width variations. We apply this methodology to a highly phase-sensitive device, the ring-assisted Mach-Zehnder interferometer (RAMZI), and show comparable performance and footprint to state-of-the-art devices, while substantially reducing stochastic phase errors from etch variations. This decrease in sensitivity is directly realized as energy savings by significantly reducing the required corrective thermal tuning power, providing a promising path toward ultra-energy-efficient large-scale silicon photonic circuits.

In-situ bypass is associated with superior infection-free survival compared with extra-anatomic bypass for the management of secondary aortic graft infections without enteric involvement.

OBJECTIVE: The optimal revascularization modality following complete resection of aortic graft infection (AGI) without enteric involvement remains unclear. The purpose of this investigation is to determine the revascularization approach associated with the lowest morbidity and mortality using real-world data in patients undergoing complete excision of AGI. METHODS: A retrospective, multi-institutional study of AGI from 2002 to 2014 was performed using a standardized database. Baseline demographics, comorbidities, and perioperative variables were recorded. The primary outcome was infection-free survival. Descriptive statistics, Kaplan-Meier survival analysis, and univariate and multivariable analyses were performed. RESULTS: A total of 241 patients at 34 institutions from seven countries presented with AGI during the study period (median age, 68 years; 75% male). The initial aortic procedures that resulted in AGI were 172 surgical grafts (71%), 66 endografts (27%), and three unknown (2%). Of the patients, 172 (71%) underwent complete excision of infected aortic graft material followed by in situ (in-line) bypass (ISB), including antibiotic-treated prosthetic graft (35%), autogenous femoral vein (neo-aortoiliac surgery) (24%), and cryopreserved allograft (41%). Sixty-nine patients (29%) underwent extra-anatomic bypass (EAB). Overall median Kaplan-Meier estimated survival was 5.8 years. Perioperative mortality was 16%. When stratified by ISB vs EAB, there was a significant difference in Kaplan-Meier estimated infection-free survival (2910 days; interquartile range, 391-3771 days vs 180 days; interquartile range, 27-3750 days; P < .001). There were otherwise no significant differences in presentation, comorbidities, or perioperative variables. Multivariable Cox regression showed lower infection-free survival among patients with EAB (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.6-3.6; P < .001), polymicrobial infection (HR, 2.2; 95% CI, 1.4-3.5; P = .001), methicillin-resistant Staphylococcus aureus infection (HR, 1.7; 95% CI, 1.1-2.7; P = .02), as well as the protective effect of omental/muscle flap coverage (HR, 0.59; 95% CI, 0.37-0.92; P = .02). CONCLUSIONS: After complete resection of AGI, perioperative mortality is 16% and median overall survival is 5.8 years. EAB is associated with nearly a two and one-half-fold higher reinfection/mortality compared with ISB. Omental and/or muscle flap coverage of the repair appear protective.

Cell division rates decrease with age, providing a potential explanation for the age-dependent deceleration in cancer incidence.

A new evaluation of previously published data suggested to us that the accumulation of mutations might slow, rather than increase, as individuals age. To explain this unexpected finding, we hypothesized that normal stem cell division rates might decrease as we age. To test this hypothesis, we evaluated cell division rates in the epithelium of human colonic, duodenal, esophageal, and posterior ethmoid sinonasal tissues. In all 4 tissues, there was a significant decrease in cell division rates with age. In contrast, cell division rates did not decrease in the colon of aged mice, and only small decreases were observed in their small intestine or esophagus. These results have important implications for understanding the relationship between normal stem cells, aging, and cancer. Moreover, they provide a plausible explanation for the enigmatic age-dependent deceleration in cancer incidence in very old humans but not in mice.

Long-term outcomes of transposed femoral vein arteriovenous fistula for abandoned upper extremity dialysis access.

BACKGROUND: The number and longevity of patients with end-stage renal disease requiring dialysis access have continued to increase, leading to challenging situations, including exhausted upper extremity access and severe central venous stenosis. This has led to an increase in the use of alternative access sites, including the lower extremities. The transposed femoral vein arteriovenous fistula for dialysis access is a previously described alternative, although limited data are available on its long-term patency. METHODS: Patients treated with a transposed femoral vein fistula were retrospectively reviewed. A transposed femoral vein fistula was created by harvesting the femoral vein and transposing it to the distal superficial femoral artery at the level of the adductor canal. The demographic information, perioperative characteristics, complications, and long-term outcomes were recorded and analyzed. RESULTS: A total of 21 patients had undergone transposed femoral vein fistula for dialysis access after an average of 5.3 ± 2.8 failed dialysis access procedures and a duration of 6.1 ± 4.9 years from the initiation of dialysis. The average age at the procedure was 53.5 ± 12.8 years. Ten patients (47.6%) had a history of diabetes mellitus and nine (42.9%) had a history of coronary artery disease. Technical success was achieved in 100% of cases, and 16 patients (76.2%) were discharged with anticoagulation therapy. The primary patency at 1, 3, and 5 years was 93%, 74%, and 74%, respectively. The secondary patency at 1, 3, and 5 years was 100%, 89%, and 89%, respectively. Two patients had compartment syndrome requiring fasciotomy, and six patients experienced wound complications. CONCLUSIONS: Transposed femoral vein fistula for dialysis access is a viable alternative for patients with an exhausted upper extremity access, with good long-term patency.

Push-pull microring-assisted space-and-wavelength selective switch.

We introduce a novel design of a space-and-wavelength selective switch based on microring-assisted Mach-Zehnder interferometers. Multiple pairs of overcoupled microring resonators are incorporated as efficient and narrowband phase shifters and are driven in push-pull scheme. We design and demonstrate a 2×2×2λ elementary switch block with full spatial and spectral switching capabilities. The switching device's cross talk suppression and extinction ratio both exceed 21 dB. We measure over 75 GHz optical bandwidth per channel and less than 1.5 dB power penalty at 10-9 BER when two 32 Gbps on-off keying signals are loaded simultaneously. This new class of switching elements can further enable compact and high-performance space-and-wavelength selective switch fabrics without the need for wavelength (de)multiplexers or parallel switching planes.

TERT promoter mutations in solitary fibrous tumour.

AIMS: TERT promoter mutations have been reported in 22% of solitary fibrous tumours (SFT) and have been associated with poor outcomes. We performed testing for TERT hot-spot mutations in a large series of SFT in order to confirm this finding and explore clinicopathological correlates of mutation status. METHODS AND RESULTS: PCR for TERT hot-spot mutations C250T and C228T was performed on DNA extracted from 216 SFT and mutation status correlated with clinicopathological factors, including predicted risk for metastasis using a previously published model. Testing was successful in 189 tumours from 172 patients, and mutations were present in 29%. The presence of TERT promoter mutation was associated with larger primary tumour size, necrosis and older patient age. TERT promoter mutations were most common in high-risk tumours (nine of 20, 45%), and were present in 11 of 26 (42%) moderate-risk tumours and 14 of 67 (21%) low-risk tumours (P = 0.004). Overall, TERT mutations were associated with shorter time to first metastasis (P = 0.04), but had no impact on overall survival. TERT promoter mutation status was found not to provide additional prognostic information in low- and high-risk SFT, but did identify a group of patients with intermediate risk SFT who had an increased risk of metastasis. CONCLUSIONS: TERT promoter mutations were more frequent in SFT with higher risk of metastasis, but TERT promoter mutation status was not a reliable predictor of clinical outcome by itself. However, mutations in the TERT promoter may be useful in further stratifying patients with intermediate risk tumours.

Indications and risk factors for midurethral sling revision.

INTRODUCTION AND HYPOTHESIS: To determine the indications and risk factors for needing midurethral sling revision in a cohort of women undergoing midurethral sling placement. METHODS: This was a case-control study of all women undergoing midurethral sling placement for stress urinary incontinence (SUI) between January 2003 and December 2013. Cases were patients who underwent midurethral sling placement followed by sling revision (incision, partial or complete excision). Controls were patients who underwent sling placement only. Once all subjects had been identified, the electronic medical record was queried for demographic and perioperative and postoperative data. RESULTS: Of 3,307 women who underwent sling placement, 89 (2.7%, 95% CI 1.9 - 3.4) underwent sling revision for one or more of the following indications: urinary retention (43.8%), voiding dysfunction (42.7%), recurrent urinary tract infection (20.2%), mesh erosion (21.3%), vaginal pain/dyspareunia (7.9%), and groin pain (3.4%). The median time from the index to the revision surgery was 7.8 months (2.3 - 17.9 months), but was significantly shorter in patients with urinary retention. The type of sling placed (retropubic or transobturator) was not associated with indication for revision. Patients who underwent revision surgery were more likely to have had previous SUI surgery (adjusted odds ratio 4.4, 95% CI 1.7 - 6.5) and to have undergone concomitant vaginal apical suspension (adjusted odds ratio 2.4, 95% CI 1.4 - 4.5). CONCLUSIONS: The rate of sling revision after midurethral sling placement was 2.7%. Urinary retention and voiding dysfunction were the most common indications. Patients with a history of previous SUI surgery and concomitant apical suspension at the time of sling placement may be at higher risk of requiring revision surgery.

Deguelins, Natural Product Modulators of NF1-Defective Astrocytoma Cell Growth Identified by High-Throughput Screening of Partially Purified Natural Product Extracts.

A high-throughput screening assay for modulators of Trp53/NF1 mutant astrocytoma cell growth was adapted for use with natural product extracts and applied to a novel collection of prefractionated/partially purified extracts. Screening 68 427 samples identified active fractions from 95 unique extracts, including the terrestrial plant Millettia ichthyotona. Only three of these extracts showed activity in the crude extract form, thus demonstrating the utility of a partial purification approach for natural product screening. The NF1 screening assay was used to guide purification of active compounds from the M. ichthyotona extract, which yielded the two rotenones deguelin (1) and dehydrodeguelin (2). The deguelins have been reported to affect growth of a number of cancer cell lines. They potently inhibited growth of only one of a panel of NF1/Trp53 mutant murine astrocytoma cell lines, possibly related to epigenetic factors, but had no effect on the growth of normal astrocytes. These results suggest the potential utility of deguelins as tools for further investigating NF1 astrocytoma cell growth. These bioprobes were identified only as a result of screening partially purified natural product extracts.

Outcome of recurrent uterine papillary serous carcinoma treated with platinum-based chemotherapy.

OBJECTIVE: The aim of this study was to estimate the outcome and response to platinum-based chemotherapy (CT) in patients with recurrent uterine papillary serous carcinoma (UPSC). METHODS: Patients with recurrent UPSC from 2000 to 2012 were included retrospectively. All patients received platinum-based CT for recurrent disease. Platinum-free interval was divided into less than 6 months (platinum resistant) and 6 months or longer (platinum sensitive). RESULTS: Twenty-two patients with recurrent UPSC were included. The median age was 66.5 years. The majority of the patients initially presented with advanced-stage disease (68%). A total of 84% (18/22) received adjuvant CT; all regimens were platinum based.The overall response rate (RR) and stable disease were 50% and 36.4%. The mean duration of response and stable disease were 9.4 and 5.6 months. Among the platinum-sensitive group, the overall RR was 64.7% compared with 0% in the platinum-resistant group. Among the patients who received prior adjuvant platinum-based CT, the RR was 38.8% compared with 100% among those who did not receive adjuvant CT. When stratified by platinum-based regimen, those who received the platinum-taxane regimen had a higher RR compared with those who received the platinum-gemcitabine regimen (62.5% vs 20%) among those who received prior adjuvant platinum therapy. The median progression-free survival and overall survival for the entire cohort were 8.4 and 24.9 months, respectively. The median progression-free survival was significantly longer for platinum-sensitive disease compared with platinum-resistant disease (10.2 vs 3.3 months, respectively; P = 0.002). Similarly, the median overall survival was longer for platinum-sensitive disease compared with platinum-resistant disease (27.1 vs 13.7 months, respectively). However, this difference was not statistically significant (P = 0.15). CONCLUSIONS: Platinum-based CT is an active regimen in recurrent UPSC even if patients received prior adjuvant platinum CT. Platinum-free interval predicts response and outcome of platinum-based CT in recurrent setting such as in ovarian cancer. Plantinum-taxane is more active than platinum-gemcitabine in recurrent UPSC.

Radiation therapy for glioma stem cells.

Radiation therapy is the most effective adjuvant treatment modality for virtually all patients with high-grade glioma. Its ability to improve patient survival has been recognized for decades. Cancer stem cells provide new insights into how tumor biology is affected by radiation and the role that this cell population can play in disease recurrence. Glioma stem cells possess a variety of intracellular mechanisms to resist and even flourish in spite of radiation, and their proliferation and maintenance appear tied to supportive stimuli from the tumor microenvironment. This chapter reviews the basis for our current use of radiation to treat high-grade gliomas, and addresses this model in the context of therapeutically resistant stem cells. We discuss the available evidence highlighting current clinical efforts to improve radiosensitivity, and newer targets worthy of further development.

Celiac artery occlusion from median arcuate ligament compression complicating a hemorrhagic duodenal ulcer repair.

We present a case of a hemorrhagic duodenal ulcer complicated by occlusion of the celiac artery (CA) by acute median arcuate ligament (MAL) compression. Angiography revealed retrograde flow through the gastroduodenal artery (GDA) to the hepatic artery, with occlusion at the CA origin. This unique presentation required coordinated release of the MAL to reestablish antegrade CA flow before pyloroplasty and GDA ligation. The presence of preexisting MAL compression of the CA should be considered during the repair of bleeding duodenal ulcers through embolization or ligation of the GDA, because impaired CA perfusion could result in foregut ischemia.

Suture fixation of traumatic rib fracture flail segment with Klebsiella osteomyelitis.

We report the case of a 71-year-old male who initially presented with urosepsis and was found to have a rib fracture of his right 6th rib with a flail segment and an associated abscess. Given the concern for infection, surgical rib fixation with titanium plating was not pursued during the washout of his abscess and instead, he successfully underwent rib fracture stabilization with bilateral suture transfixation. He was continued on a prolonged course of antibiotics for Klebsiella pneumonia osteomyelitis and was discharged uneventfully with optimal pain control and adequate respiratory effort.

Endovascular covered stent graft repair by through-and-through snaring of an acute traumatic femoral-femoral arteriovenous fistula following a gunshot wound.

Arteriovenous fistula (AVF) formation after penetrating injury underscores a rare and challenging complication of vascular trauma. Traumatic AVFs have various clinical presentations and reported methods of repair. Although open surgical repair is the most frequently used method of repair, the advancement of endovascular techniques has been increasingly used during the past 3 decades. We report a case of an acute traumatic AVF of the superficial femoral artery and superficial femoral vein from a gunshot wound repaired with a unique endovascular technique involving snaring to establish through-and-through access to allow deployment of a covered stent graft.

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.

Epigenetic control of cellular transcription and phenotype is influenced by changes in the cellular microenvironment, yet how mechanical cues from these microenvironments precisely influence epigenetic state to regulate transcription remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a new class of genomic enhancers that responds to the mechanical microenvironment. These 'mechanoenhancers' could be active on either soft or stiff extracellular matrix contexts, and regulated transcription to influence critical cell functions including apoptosis, mechanotransduction, proliferation, and migration. Epigenetic editing of mechanoenhancers on rigid materials tuned gene expression to levels observed on softer materials, thereby reprogramming the cellular response to the mechanical microenvironment. These editing approaches may enable the precise alteration of mechanically-driven disease states.

Nine-month results of the REFORM study: a prospective, single-arm, multicenter clinical study of the safety and effectiveness of the Formula™ balloon-expandable stent for treatment of renal artery stenosis.

OBJECTIVES: To evaluate the 9-month safety and effectiveness outcomes of the Formula™ balloon-expandable renal stent (Cook Medical, Bloomington, IN) for the treatment of atherosclerotic renal artery stenosis (RAS) following suboptimal angioplasty. BACKGROUND: Atherosclerotic RAS can cause hypertension and ischemic nephropathy. When clinically indicated, an interventional approach with renal angioplasty and stent implantation is the preferred method for revascularization of atherosclerotic renal artery stenoses. METHODS: The REFORM study is a prospective, multicenter, single-arm study of stent implantation following suboptimal PTRA using the Formula stent. One hundred patients with atherosclerotic ostial renal artery lesions =18 mm in length with a >50% residual stenosis following PTA were enrolled. The primary endpoint was 9-month primary patency. RESULTS: The 9-month primary patency rate was 91.7%. The 9-month major adverse event rate was 2.2%. Mean systolic blood pressure was significantly decreased at follow-up (from 150 ± 21 mm Hg at baseline to 141 ± 21 mm Hg at 9 months; P = 0.003). Mean serum creatinine (SCr) level and mean estimated glomerular filtration rate (eGFR) were not significantly different at 9 months. A clinically meaningful improvement in renal function (i.e., =25% increase in eGFR or =0.5 mg/dl decrease in SCr) was observed in 9% of patients at 1 month and 12% of patients at 9 months. A clinically meaningful decline in renal function (i.e., =25% decrease in eGFR or =0.5 mg/dl increase in SCr) was observed in only 3% of patients at 1 month and 7% of patients at 9 months. CONCLUSIONS: The Formula stent was safe and effective in treating atherosclerotic RAS following suboptimal angioplasty.

Gunshot Wound to the Right Superior Pulmonary Vein With Bullet Embolization to the Aortic Bifurcation: Emergent Surgical Repair.

Bullet embolization is a rare complication of gunshot wound injuries with most of the literature consisting of case reports. We report a case regarding bullet embolization to the distal aorta following entry into the right superior pulmonary vein as a result of a gunshot wound to the posterior chest. The patient presented with signs of lower extremity ischemia. Imaging revealed an intrabdominal bullet at the level of L4 and laparatomy identified the bullet to be within the aorta at the bifurcation. Successful repair of the cardiac injury and removal of the intra-aortic bullet were achieved by sternotomy and laparatomy.

A paradoxical internal hernia at Brolin's anti-obstruction stitch following Roux-en-Y gastric bypass: a case report.

Internal hernias are a rare but morbid complication following Roux-en-Y gastric bypass surgery. The incorporation of Brolin's anti-obstruction stitch has historically demonstrated a significant reduction in the incidence of internal hernias following Roux-en-Y gastric bypass. We present an ironic and unique case of a patient with small bowel herniation into a defect between Brolin's stitch and the stapled closed common enterotomy of the jejunojejunostomy and technical considerations to decrease internal hernias at this site in the future.

Operative technique for a successful laparoscopic en-bloc resection of gastrogastric fistula following roux-en-Y gastric bypass.

Gastrogastric fistulas are rare complications following Roux-en-Y gastric bypass surgery and are characterized by a fistulous connection between the gastric pouch and the remnant stomach. The presentation is often variable and a high-index of suspicion must be maintained for accurate and timely diagnosis. In this case report, we provide a detailed review of the technical steps taken to successfully resect a gastrogastric fistula en-bloc laparoscopically with an unremarkable post-operative course.

The Female Reproductive Tract Microbiome-Implications for Gynecologic Cancers and Personalized Medicine.

The microbial colonization of the lower female reproductive tract has been extensively studied over the past few decades. In contrast, the upper female reproductive tract including the uterine cavity and peritoneum where the ovaries and fallopian tubes reside were traditionally assumed to be sterile under non-pathologic conditions. However, recent studies applying next-generation sequencing of the bacterial 16S ribosomal RNA gene have provided convincing evidence for the existence of an upper female reproductive tract microbiome. While the vaginal microbiome and its importance for reproductive health outcomes has been extensively studied, the microbiome of the upper female reproductive tract and its relevance for gynecologic cancers has been less studied and will be the focus of this article. This targeted review summarizes the pertinent literature on the female reproductive tract microbiome in gynecologic malignancies and its anticipated role in future research and clinical applications in personalized medicine.