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"Barr, Emily"
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The truth and lies of Ella Black
Ella, seventeen, has a very dark side--Bad Ella, or Bella--but when she is whisked away to Brazil and learns she is adopted, she questions everything she thought she knew about herself.
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Spinal cord high-grade infiltrating gliomas in adults: clinico-pathological and molecular evaluation
Primary high-grade infiltrating gliomas of the spinal cord are rare, with prior series including limited numbers of cases and reporting poor outcomes. Additionally, the molecular profile of high-grade infiltrating gliomas of the spinal cord has not been well characterized. We identified 13 adult patients whose surgery had been performed at our institution over a 26-year-period. Radiologically, nine cases harbored regions of post-contrast enhancement. Existing slides were reviewed, and when sufficient tissue was available, immunohistochemical stains (IDH1-R132H, H3-K27M, H3K27-me3, ATRX, p53 and BRAF-V600E), and a targeted 150-gene neuro-oncology next-generation sequencing panel were performed. The 13 patients included 11 men and 2 women with a median age of 38 years (range = 18–69). Histologically, all were consistent with an infiltrating astrocytoma corresponding to 2016 WHO grades III (
n
= 5) and IV (
n
= 8). By immunohistochemistry, six cases were positive for H3K27M, all showing concomitant loss of H3K27-me3. Next-generation sequencing was successfully performed in ten cases. Next-generation sequencing studies were successfully performed in four of the cases positive for H3K27M by immunohistochemistry, and all were confirmed as
H3F3A
K27M-mutant. Additional recurrent mutations identified included those of
TERT
promoter (
n
= 3),
TP53
(
n
= 5),
PPM1D
(
n
= 3),
NF1
(
n
= 3),
ATRX
(
n
= 2), and
PIK3CA
(
n
= 2). No
HIST1H3B
,
HIST1H3C
,
IDH1
,
IDH2
, or
BRAF
mutations were detected. Ten patients have died since first surgery, with a median survival of 13 months and 1 year of 46%. Median survival was 48.5 months for H3K27M-positive cases, compared to 1 month for those with
TERT
promoter mutation and 77 months for those harboring neither (
p
= 0.019). Median survival for cases with
TP53
mutations was 11.5 months and for those with
PPM1D
mutations was 84 months. Our findings suggest that high-grade infiltrating gliomas of the spinal cord in adults represent a heterogeneous group of tumors, with variable outcomes possibly related to their molecular profiles.
Journal Article
Association between child maltreatment and depressive symptoms in emerging adulthood: The mediating and moderating roles of DNA methylation
Prospective studies suggest that child maltreatment substantially increases the risk for depression in adulthood. However, the mechanisms underlying this association require further elucidation. In recent years, DNA methylation has emerged as a potential mechanism by which maltreatment experiences (a) could partly explain the emergence or aggravation of depressive symptoms (i.e., mediation) and/or (b) could increase (or decrease) the risk for depressive symptoms (i.e., moderation). The present study tested whether the methylation levels of nine candidate genes mediated and/or moderated the association between maltreatment experiences in childhood and depressive symptoms in emerging adulthood. The sample comprised 156 men aged between 18 and 35 years. Maltreatment experiences and depressive symptoms were assessed retrospectively using self-reported questionnaires. Methylation levels of nine candidate genes ( COMT , FKBP5 , IL6 , IL10 , MAOA , NR3C1 , OXTR , SLC6A3 and SLC6A4 ), previously reported to be sensitive to early-life stress, were quantified from saliva samples. Maltreatment experiences in childhood were significantly associated with depressive symptoms in emerging adulthood. Both maltreatment experiences and depressive symptoms were associated with the methylation levels of two genomic sites, which cumulatively, but not individually, explained 16% of the association between maltreatment experiences in childhood and depressive symptoms in emerging adulthood. Moreover, maltreatment experiences in childhood interacted with the methylation levels of fourteen genomic sites, which cumulatively, but not individually, modulated the level of depressive symptoms in young male adults who were maltreated as children. However, none of these effects survived multiple testing correction. These findings bring attention to the cumulative effects of DNA methylation measured in several candidate genes on the risk of reporting depressive symptoms following maltreatment experiences in childhood. Nonetheless, future studies need to clarify the robustness of these putative cumulative effects in larger samples and longitudinal cohorts.
Journal Article
Biliary Multifocal Chromosomal Polysomy and Cholangiocarcinoma in Primary Sclerosing Cholangitis
Polysomy detected by fluorescence in situ hybridization (FISH) is associated with cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC). However, a subset of PSC patients with polysomy do not manifest CCA even after long-term follow-up. It is unknown if patients with chromosomal gains detected by FISH in multiple areas of the biliary tree (i.e., multifocal polysomy, MFP) are more likely to be diagnosed with CCA than patients with unifocal polysomy (UFP). Therefore, our aim is to determine whether patients with MFP are more likely to manifest CCA compared with patients with other chromosomal abnormalities including UFP and other FISH subtypes.
We performed a retrospective review of PSC patients without a mass lesion who underwent FISH testing at our institution from 1 January 2005 to 1 July 2013.
Three-hundred and seventy-one PSC patients were included. Compared with patients with UFP, those with MFP were more likely to have weight loss (32 vs. 9%), suspicious cytology (45 vs. 13%) and develop serial polysomy (91 vs. 35%). MFP was associated with CCA (hazard ratio (HR), 82.42; 95% confidence interval (CI), 24.50-277.31) and was the strongest predictor of cancer diagnosis. Suspicious cytology (HR, 26.31; 95% CI, 8.63-80.24) and UFP (HR, 13.27; 95% CI, 3.32-53.08) were also predictive of CCA. MFP, UFP and suspicious cytology remained associated with CCA in the multivariable model.
Compared with other FISH subtypes, MFP is the strongest predictor of CCA. However, patients with UFP and suspicious cytology (regardless of FISH status) are also at an increased risk for CCA.
Journal Article
The Impact of Working from Home on Mental Health: A Cross-Sectional Study of Canadian Worker’s Mental Health during the Third Wave of the COVID-19 Pandemic
The COVID-19 pandemic has seen a considerable expansion in the way work settings are structured, with a continuum emerging between working fully in-person and from home. The pandemic has also exacerbated many risk factors for poor mental health in the workplace, especially in public-facing jobs. Therefore, we sought to test the potential relationship between work setting and self-rated mental health. To do so, we modeled the association of work setting (only working from home, only in-person, hybrid) on self-rated mental health (Excellent/Very Good/Good vs. Fair/Poor) in an online survey of Canadian workers during the third wave of COVID-19. The mediating effects of vaccination, masking, and distancing were explored due to the potential effect of COVID-19-related stress on mental health among those working in-person. Among 1576 workers, most reported hybrid work (77.2%). Most also reported good self-rated mental health (80.7%). Exclusive work from home (aOR: 2.79, 95%CI: 1.90, 4.07) and exclusive in-person work (aOR: 2.79, 95%CI: 1.83, 4.26) were associated with poorer self-rated mental health than hybrid work. Vaccine status mediated only a small proportion of this relationship (7%), while masking and physical distancing were not mediators. We conclude that hybrid work arrangements were associated with positive self-rated mental health. Compliance with vaccination, masking, and distancing recommendations did not meaningfully mediate this relationship.
Journal Article
The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen
Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death.
Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling.
Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n = 3), moderate (n = 10)], resulting in the following CYP2D6 metabolism: extensive (n = 115) and decreased (n = 65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p = 0.034; adj HR = 1.91; 95% CI 1.05-3.45) and worse relapse-free survival (RFS) (p = 0.017; adj HR = 1.74; 1.10-2.74); relative to patients with extensive metabolism. Cox' modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12, p = 0.007).
CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.
Journal Article
Stroke in the Young: A Case of CNS Vasculitis Secondary to Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an enigmatic autoimmune disease with a varied presentation that carries with it an increased risk for many potentially life‐threatening problems. When compared with the general population, the relative risk of ischemic stroke in SLE is more than doubled. Our case report highlights a rare complication of SLE, vasculitis as the cause of stroke. CNS vasculitis secondary to SLE most commonly affects the endothelium of small and medium vessel arteries through perivascular inflammation in a concentric pattern. We present a case of a 46‐year‐old female with a history of hypertension, hyperlipidemia, hypothyroidism, multiple ischemic strokes (residual left sided weakness), and elevated cardiolipin IgM levels (not on anticoagulation) who presented with left facial numbness, dysarthria, and word finding difficulty. The initial CT head revealed chronic appearing hypodensities in the right parietal and occipital lobes without hemorrhage. CT angiogram of the head and neck demonstrated multifocal stenosis in the right MCA and right PCA. She received IV tenecteplase and MRI brain revealed an infarct in the left MCA distribution along with infarcts in the right thalamus, hippocampus, and cerebellum. Transesophageal echocardiogram was negative for Libman‐Sacks endocarditis. Given concerns for an underlying vasculitis process, an MRA vessel wall imaging was obtained which demonstrated concentric enhancement and persistent vessel narrowing in the left MCA M2 along with symmetric concentric enhancement of vaso vasorum of intracranial vertebral arteries. Lumbar puncture revealed CSF protein 60, culture negative, glucose 61, white blood cells 3, IgG index 0.5, ACE negative, and no oligoclonal bands. Her ESR was 43 and CRP < 0.5. Hypercoagulability workup demonstrated RNP > 8, SSA 6.4, Smith 1.6, +ANA 1:1280, C4 11, cardiolipin IgM 60. Given serum ANA titers and anti‐cardiolipin IgM labs in the setting of intracranial vessel wall enhancement concerning for an inflammatory process, it was believed that this stroke was actually a result of lupus vasculitis. The paucity of literature on the association between SLE vasculitis and cerebrovascular disease presents an important opportunity for more research, and it may be prudent to further investigate the relative risk of stroke in patients with known SLE vasculitis. This is also important because young individuals with SLE are at a higher relative risk of stroke.
Journal Article
Primary Sclerosing Cholangitis Patients With Serial Polysomy Fluorescence In Situ Hybridization Results Are at Increased Risk of Cholangiocarcinoma
A polysomy fluorescence in situ hybridization (FISH) result in a pancreatobiliary brushing from a patient with primary sclerosing cholangitis (PSC) is very worrisome for carcinoma. However, treatment is not recommended unless verified by corroborative evidence of malignancy because of less than perfect test specificity in this population. The aim of this study was to evaluate the clinical outcome of PSC patients with serial polysomy FISH results.
Patients with PSC underwent endoscopic retrograde cholangiopancreatography with brushings when clinically indicated per standard practice. Brushings were evaluated by routine cytology and FISH. Retrospective review identified patients with a polysomy FISH result without definitive imaging or pathological evidence of malignancy at the time of the first polysomy, who underwent follow-up examinations including subsequent FISH testing (n=30). Patient records were reviewed to determine clinical outcome.
In all, 9 of 13 patients (69%) with a subsequent polysomy result (i.e., serial polysomy) were diagnosed with cholangiocarcinoma (CCA) compared with 3 of 17 patients (18%) with subsequent non-polysomy results (P=0.008). There was a significant difference in time to a diagnosis of CCA between PSC patients with serial polysomy compared with those with subsequent non-polysomy (P=0.01). In four patients with serial polysomy results, imaging/pathological evidence of CCA was not found until 1-2.7 years after the initial polysomy FISH result.
FISH may detect polysomic cells in pancreatobiliary brushings before other pathological or imaging techniques identify CCA. Patients with serial polysomy FISH results are at higher risk for having CCA than those with subsequent non-polysomy FISH results.
Journal Article
Sellar Region Atypical Teratoid/Rhabdoid Tumors in Adults: Clinicopathological Characterization of Five Cases and Review of the Literature
Abstract
Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant CNS neoplasms that typically occur in children <2 years of age. These are characterized by high-grade histologic features and mutations of the INI1/SMARCB1 gene readily detected by loss of expression by immunohistochemistry. Among adults, the majority of AT/RTs occurs in the cerebral hemispheres. A small number of adult AT/RTs involving the sellar and suprasellar region reported in the literature suggest a distinct clinical course for this group. Here, we describe detailed clinical and genetic characterization of 5 adult patients with AT/RTs involving the sellar and suprasellar region, and provide a review of the available clinical and genetic features of 22 previously reported cases in order to help increase our understanding of this unusual entity.
Journal Article