Objectives Carotid artery angioplasty and stenting (CAS) is now routinely performed with embolic protection devices, yet little is known about the compositional characteristics of the captured ...embolic debris and whether the type or quantity of debris correlates with patient, lesion, or operator characteristics. This study examined the embolic debris generated during CAS using electron microscopy and energy dispersive spectroscopy (EDS) for symptomatic and asymptomatic patients. Methods Between 2003 and 2005, CAS for carotid stenosis was performed in 175 patients. Cerebral protection devices were used in all but three cases. Sixty-four consecutive unselected microporous filters from procedures performed by a single vascular surgeon were obtained for analysis. Captured particulate debris within the protection devices was quantified (number and mean size of particles) by light microscopy for all filters. Twenty protection devices (9 symptomatic, 11 asymptomatic patients) were processed for electron microscopy and EDS to assess morphology, cellular composition, and calcium content of debris. Results Captured particulate matter was present in 49 filters (77%) and included particles measuring 200 to 500 μm in 72%, 500 to 1000 μm in 53%, and >1000 μm in 33%. The mean number of captured particles was 6.9, and mean size was 248 ± 150 μm. Univariate analysis revealed that sequential patient cohort and filter type were correlated with the number (but not size) of captured particles. The number of particles significantly decreased after the first cohort of 20 patients (11.5 particles) compared with the second (5.0 particles, P = .023) and third (5.2 particles, P = .029) cohorts. The type of captured debris ranged from sheets of damaged red blood cells without other components to clumps of recently activated platelets with early fibrin crosslinking to plaque debris coated with well-organized coalescing areas of platelet thrombus. Platelet activation was more common in symptomatic patients (78%) than asymptomatic patients (27%; P < .05). Despite the presence of calcified lesions in six patients whose filters were analyzed by EDS, <1% of energy emission on EDS of scanned particulate debris fell within the emission range of calcium, indicating the presence of minimal calcium in the embolic particles. Conclusions Particulate embolic debris is released in most patients during CAS and can measure >1000 μm in one third of patients. The number of particles may decrease with increasing operator experience with CAS. Debris captured during CAS with embolic protection exhibits a range of cellular and acellular components on electron microscopy, with a higher prevalence of platelet activation evident in symptomatic patients.
Reviews of Books Hirschler, Konrad; Smith, Jonathan Riley; Israel, Jonathan ...
International history review,
12/2009, Letnik:
31, Številka:
4
Journal Article
Objective
Prospectively characterize changes in serum proteins following sport‐related concussion and determine whether candidate biomarkers discriminate concussed athletes from controls and are ...associated with duration of symptoms following concussion.
Methods
High school and collegiate athletes were enrolled between 2015 and 2018. Blood was collected at preinjury baseline and within 6 hours (early acute) and at 24 to 48 hours (late acute) following concussion in football players (n = 106), matched uninjured football players (n = 84), and non–contact‐sport athletes (n = 50). Glial fibrillary acidic protein, ubiquitin c‐terminal hydrolase‐L1, S100 calcium binding protein B, alpha‐II‐spectrin breakdown product 150, interleukin 6, interleukin 1 receptor antagonist, and c‐reactive protein were measured in serum. Linear models assessed changes in protein concentrations over time. Receiver operating curves quantified the discrimination of concussed athletes from controls. A Cox proportional hazard model determined whether proteins were associated with symptom recovery.
Results
All proteins except glial fibrillary acidic protein and c‐reactive protein were significantly elevated at the early acute phase postinjury relative to baseline and both control groups and discriminated concussed athletes from controls with areas under the curve of 0.68 to 0.84. The candidate biomarkers also significantly improved the discrimination of concussed athletes from noncontact controls compared to symptom severity alone. Glial fibrillary acidic protein was elevated postinjury relative to baseline in concussed athletes with a loss of consciousness or amnesia. Finally, early acute levels of interleukin 1 receptor antagonist were associated with the number of days to symptom recovery.
Interpretation
Brain injury and inflammatory proteins show promise as objective diagnostic biomarkers for sport‐related concussion, and inflammatory markers may provide prognostic value. ANN NEUROL 2020;87:907–920
Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we used a genome-wide RNA interference screen to search ...for Myc-synthetic lethal genes and uncovered a role for the SUMO-activating enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death upon Myc hyperactivation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human breast cancers suggest that low SAE1 and SAE2 abundance in the tumors correlates with longer metastasis-free survival of the patients. Thus, inhibition of SUMOylation may merit investigation as a possible therapy for Myc-driven human cancers.
Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the ...association between arsenic and CVD.
Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE
) mouse model of atherosclerosis.
A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic.
Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.
Introduction
International Study Group of Pancreatic Fistula (ISGPF) grade C postoperative pancreatic fistulas (POPF) are the greatest contributor to major morbidity and mortality following ...pancreatoduodenectomy (PD); however, their infrequent occurrence has hindered deeper analysis. This study sought to develop a predictive algorithm, which could facilitate effective management of this challenging complication.
Methods
Data were accrued from 4301 PDs worldwide. Demographics, postoperative management, and microbiological characteristics of grade C POPFs were evaluated. American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) preoperative and intraoperative variables were compared between grade C POPFs and a 639-case sample of non-grade C POPFs. Risk factors for grade C POPF formation were identified using regression analysis.
Results
Grade C POPFs developed in 79 patients (1.8 %). Deaths (90 days) occurred in 2.0 % (
N
= 88) of the overall series, with 35 % (
N
= 25) occurring in the presence of a grade C POPF. Reoperations occurred 72.2 % of the time. The rates of single- and multi-system organ failure were 28.2 and 39.7 %, respectively. Mortality rates escalated with pulmonary, renal, and neurologic organ failure, but they were unaffected by reoperation(s). The median number of complications incurred was four (IQR: 2–5), and the median duration of hospital stay was 32 (IQR: 21–54) days. Warning signs for impending grade C POPFs most often presented on postoperative day (POD) 6. Adjuvant chemotherapy might have benefited 55.7 % of grade C POPF patients, yet it was delayed in 25.6 % and never delivered in 67.4 % of these patients. Predictive models for grade C POPF occurrence based on preoperative factors alone and preoperative and intraoperative factors yielded areas under the receiver operating characteristic curve of 0.73 and 0.84 (both
P
< 0.000001), respectively.
Conclusion
This global study represents the largest analysis of grade C POPFs following PD. It describes the severe burden that grade C POPFs incur on patients, with high rates of reoperation and infection, while also potentially worsening overall survival by causing death and delay/omission of adjuvant therapy. Additionally, aggressive clinical management for these POPFs did not improve or worsen 90-day mortality. Predictive tools developed through these data may provide value in managing this difficult complication.
Among breast cancers, triple-negative breast cancer (TNBC) is the most poorly understood and is refractory to current targeted therapies. Using a genetic screen, we identify the PTPN12 tyrosine ...phosphatase as a tumor suppressor in TNBC. PTPN12 potently suppresses mammary epithelial cell proliferation and transformation. PTPN12 is frequently compromised in human TNBCs, and we identify an upstream tumor-suppressor network that posttranscriptionally controls PTPN12. PTPN12 suppresses transformation by interacting with and inhibiting multiple oncogenic tyrosine kinases, including HER2 and EGFR. The tumorigenic and metastatic potential of PTPN12-deficient TNBC cells is severely impaired upon restoration of PTPN12 function or combined inhibition of PTPN12-regulated tyrosine kinases, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting proto-oncogenic tyrosine kinases in TNBC and other cancers based on their profile of tyrosine-phosphatase activity.
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► Tyrosine phosphatase PTPN12 suppresses transformation, tumorigenesis, and metastasis ► PTPN12 inhibits multiple oncogenic tyrosine kinases including HER2, EGFR, and PDGFR-β ► PTPN12 is frequently inactivated in human triple negative breast cancer (TNBC) ► PTPN12-deficient TNBCs can be treated with combinatorial tyrosine kinase inhibitors
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