During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart ...transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers.
A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide repeat expansion in FMR1 leads to ...the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins that contribute to disease pathogenesis. Here we assessed whether these same repeats might trigger stalling and interfere with translational elongation. We find that depletion of ribosome-associated quality control (RQC) factors NEMF, LTN1 and ANKZF1 markedly boost RAN translation product accumulation from both G4C2 and CGG repeats while overexpression of these factors reduces RAN production in both reporter assays and C9ALS/FTD patient iPSC-derived neurons. We also detected partially made products from both G4C2 and CGG repeats whose abundance increased with RQC factor depletion. Repeat RNA sequence, rather than amino acid content, is central to the impact of RQC factor depletion on RAN translation-suggesting a role for RNA secondary structure in these processes. Together, these findings suggest that ribosomal stalling and RQC pathway activation during RAN translation inhibits the generation of toxic RAN products. We propose augmenting RQC activity as a therapeutic strategy in GC-rich repeat expansion disorders.
The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine ...whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.
Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort,
= 566) and verification (PETACC3 clinical trial,
= 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes
and
), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.
Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of
, the alpha subunit of the heterodimeric IL22 receptor, and
mutation relapse-free survival (RFS): HR = 2.93,
= 0.0006; overall survival (OS): HR = 2.45,
= 0.0023.
mutations showed a similar interaction with
and conferred the worst prognosis in tumors with high expression of both
and
(RFS: HR = 3.81,
= 0.0036; OS: HR = 3.90,
= 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in
mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.
Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.
Coronary heart disease is a major cause of heart failure. Availability of risk-prediction models that include both clinical parameters and biomarkers is limited. We aimed to develop such a model for ...prediction of incident heart failure.
A multivariable risk-factor model was developed for prediction of first occurrence of heart failure death or hospitalization. A simplified risk score was derived that enabled subjects to be grouped into categories of 5-year risk varying from <5% to >20%.
Among 7101 patients from the LIPID study (84% male), with median age 61years (interquartile range 55–67years), 558 (8%) died or were hospitalized because of heart failure. Older age, history of claudication or diabetes mellitus, body mass index>30kg/m2, LDL-cholesterol >2.5mmol/L, heart rate>70 beats/min, white blood cell count, and the nature of the qualifying acute coronary syndrome (myocardial infarction or unstable angina) were associated with an increase in heart failure events. Coronary revascularization was associated with a lower event rate. Incident heart failure increased with higher concentrations of B-type natriuretic peptide >50ng/L, cystatin C>0.93nmol/L, D-dimer >273nmol/L, high-sensitivity C-reactive protein >4.8nmol/L, and sensitive troponin I>0.018μg/L. Addition of biomarkers to the clinical risk model improved the model's C statistic from 0.73 to 0.77. The net reclassification improvement incorporating biomarkers into the clinical model using categories of 5-year risk was 23%.
Adding a multibiomarker panel to conventional parameters markedly improved discrimination and risk classification for future heart failure events.
The diagnosis of intraductal papillary lesions of the breast on core biopsy remains challenging in pathology, with most patients requiring formal surgical excision for a definitive diagnosis. The aim ...of this study was to determine whether a representative panel of proliferative cell cycle immunohistochemical markers (cyclin A2, cyclin B1 and cyclin D1) could improve the specificity of pathological diagnosis of these lesions.
A series of 68 surgically excised intraductal papillary lesion cases were retrospectively selected, and immunohistochemistry for cyclin A2, cyclin B1 and cyclin D1 was performed.
Cyclin B1 (OR 1.80, 95% CI 1.01 to 3.2, p=0.046) and cyclin D1 (OR 1.13, 95% CI 1.05 to 1.22, p=0.002) expression was independently associated with a diagnosis of malignancy in papillary lesions, although expression was frequently heterogeneous and only focal. Cyclin A2 expression (OR 0.76, 95% CI 0.41 to 1.4, p=0.38) was not associated with a malignant diagnosis in multivariable logistic regression models. All three cyclins displayed high sensitivity (80%-95%) for a diagnosis of malignancy, although cyclin B1 showed a superior specificity of 72.7% compared with the low specificity of cyclins A2 and D1.
Our study has identified for the first time that the expression of key cell cycle markers differs between benign and malignant papillary breast lesions and identified changes to the mitotic marker, cyclin B1, as particularly significant. However, given the low level and heterogeneous nature of expression of these markers, there remains a significant risk of undersampling in core biopsies and thus they are unlikely to be useful in routine clinical practice.
Introduction and hypothesis
We evaluated whether the use of estrogen vaginally prior to synthetic midurethral sling insertion mediates the risk of mesh exposure. A secondary aim was to evaluate other ...factors that may be associated with mesh exposure.
Methods
We performed a retrospective cohort study of patients undergoing midurethral sling insertion from January to December 2010 within the Southern California Permanente Medical Group. Women who used estrogen vaginally prior to surgery were classified as those who filled a prescription between 1 and 45 days before surgery or whose medical records indicated its use at the time of preoperative evaluation. Logistic regression analysis was used to calculate odds ratios (OR) and 95 % confidence intervals (CI) for factors associated with mesh exposure while controlling for confounding variables.
Results
A total of 1544 patients met inclusion criteria, of whom 248 (16.1 %) used estrogen vaginally prior to surgery. Mean age was 53.7 years (range 27–89). Thirty-seven (2.4 %) women were diagnosed with mesh exposure, of whom 19 underwent surgical reoperation. In multivariate logistic regression analysis, preoperative use of estrogen vaginally was not associated with the risk of mesh exposure (OR 0.79, CI 0.26–2.38,
p
= 0.67). Age, body mass index, menopausal status, use of hormone replacement therapy, smoking status, and diabetes were not associated with risk of mesh exposure.
Conclusions
Preoperative use of estrogen vaginally did not appear to mediate the risk of mesh exposure following midurethral sling placement in this cohort.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with coronary heart disease (CHD) in healthy individuals and in patients who have had ischemic events.
The Long-term ...Intervention with Pravastatin in Ischemic Disease (LIPID) study randomized 9014 patients with cholesterol levels of 4.0 to 7.0 mmol/L to placebo or pravastatin 3 to 36 months after myocardial infarction or unstable angina and showed a reduction in CHD and total mortality. We assessed the value of baseline and change in Lp-PLA2 activity to predict outcomes over a 6-year follow-up, the effect of pravastatin on Lp-PLA2 levels, and whether pravastatin treatment effect was related to Lp-PLA2 activity change. Lp-PLA2 was measured at randomization and 1 year, and levels were grouped as quartiles. The prespecified end point was CHD death or nonfatal myocardial infarction. Baseline Lp-PLA2 activity was positively associated with CHD events (P < 0.001) but not after adjustment for 23 baseline factors (P = 0.66). In 6518 patients who were event free at 1 year, change in Lp-PLA2 was a significant independent predictor of subsequent CHD events after adjustment for these risk factors, including LDL cholesterol and LDL cholesterol changes (P < 0.001). Pravastatin reduced Lp-PLA2 by 16% compared with placebo (P < 0.001). After adjustment for Lp-PLA2 change, the pravastatin treatment effect was reduced from 23% to 10% (P = 0.26), with 59% of the treatment effect accounted for by changes in Lp-PLA2. Similar reductions in treatment effect were seen after adjustment for LDL cholesterol change.
Reduction in Lp-PLA2 activity during the first year was a highly significant predictor of CHD events, independent of change in LDL cholesterol, and may account for over half of the benefits of pravastatin in the LIPID study.
The material properties of heart valves depend on the subject’s age, the state of the disease and the complex valvular microarchitecture. Furthermore, valvular interstitial cells (VICs) are ...mechanosensitive, and their synthesis of extracellular matrix not only determines the valve’s material properties but also provides an adhesive substrate for VICs. However, the interrelationship between substrate stiffness and VIC phenotype and synthetic properties is poorly understood. Given that the local mechanical environment (substrate stiffness) surrounding VICs differs among different age groups and different anatomic regions of the valve, it was hypothesized that there may be an age- and valve-region-specific response of VICs to substrate stiffness. Therefore, 6-week-, 6-month- and 6-year-old porcine VICs from the center of the mitral valve anterior leaflet (MVAC) and posterior leaflet (PML) were seeded onto poly(ethylene) glycol hydrogels of different stiffnesses and stained for markers of VIC activation (smooth muscle alpha-actin (SMaA)) and collagen synthesis (heat shock protein-47 (HSP47), prolyl 4-hydroxylase (P4H)). Six-week-old MVAC demonstrated decreased SMaA, P4H and HSP47 on stiffer gels, while 6-week-old PML only demonstrated decreased HSP47. Six-month-old MVAC demonstrated no difference between substrates, while 6-month-old PML demonstrated decreased SMaA, P4H and HSP47. Six-year-old MVAC demonstrated decreased P4H and HSP47, while 6-year-old PML demonstrated decreased P4H and increased HSP47. In conclusion, the age-specific and valve-region-specific responses of VICs to substrate stiffness link VIC phenotype to the leaflet regional matrix in which the VICs reside. These data provide further rationale for investigating the role of substrate stiffness in VIC remodeling within diseased and tissue engineered valves.
This study evaluated the effects of localized delivery of nitric oxide (NO) from hydrogels covalently modified with S-nitrosocysteine (Cys-NO) on neoinitma formation, a key component of restenosis, ...in a rat balloon-injury model. Soluble Cys-NO was used in preliminary studies to identify
dosage ranges that were able to simultaneously inhibit smooth muscle cell proliferation, enhance endothelial cell proliferation, and reduce platelet adhesion. Photo-cross-linked PEG-based hydrogels were formed with covalently immobilized Cys-NO. These materials release NO for approximately
24 h and can be applied to tissues and photo-cross-linked in situ to form local drug-delivery systems. Localized delivery of NO from hydrogels containing Cys-NO inhibited neointima formation in a rat balloon-injury model by approximately 75% at 14 days.
This program sought to increase retention rates through the use of a structured, progressive orientation program. Twenty new graduate nurses participated in the 13-week program. Tools used to ...evaluate success were Performance Based Development System, American Society for Training and Development Evaluation Tool, the Professional Judgment Rating Form-Novice/Internship Level, and Retention Rates. Results of the program suggest that an orientation program focused on development of critical thinking skills, patient care management, and enhancement of self-esteem directly influenced retention.
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