After fertilization, maternal factors direct development and trigger zygotic genome activation (ZGA) at the maternal-to-zygotic transition (MZT). In zebrafish, ZGA is required for gastrulation and ...clearance of maternal messenger RNAs, which is in part regulated by the conserved microRNA miR-430. However, the factors that activate the zygotic program in vertebrates are unknown. Here we show that Nanog, Pou5f1 (also called Oct4) and SoxB1 regulate zygotic gene activation in zebrafish. We identified several hundred genes directly activated by maternal factors, constituting the first wave of zygotic transcription. Ribosome profiling revealed that nanog, sox19b and pou5f1 are the most highly translated transcription factors pre-MZT. Combined loss of these factors resulted in developmental arrest before gastrulation and a failure to activate >75% of zygotic genes, including miR-430. Our results demonstrate that maternal Nanog, Pou5f1 and SoxB1 are required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR-430 expression.
The public health imperative to reduce the burden of lung cancer has seen unprecedented progress in recent years. Fully realizing the advances in lung cancer treatment and control requires attention ...to potential barriers in their momentum and implementation. In this analysis, we present and evaluate the argument that stigma is a highly significant barrier to fulfilling the clinical promise of advanced care and reduced lung cancer burden. This evaluation of the stigma of lung cancer is based on a multilevel perspective that incorporates the individual, persons in the individual's immediate environment, the health care system, and the larger societal structure that shapes perceptions and decisions. We also consider current interventions and interventional needs within and across aspects of the lung cancer continuum, including prevention, screening, diagnosis, treatment, and survivorship. Current evidence suggests that stigma detrimentally affects psychosocial, communication, and behavioral outcomes over the entire lung cancer control continuum and across multiple levels. Interventional efforts to alleviate stigma in the context of lung cancer show promise, yet more work is needed to evaluate their impact. Understanding and addressing the multilevel role of stigma is a crucial area for future study to realize the full benefits offered by lung cancer prevention, control, and treatment. Coordinated, interdisciplinary, and well-conceptualized efforts have the potential to reduce the barrier of stigma in the context of lung cancer and facilitate demonstrable improvements in clinical care and quality of life.
Purpose
Significant controversy exists regarding the expression patterns of estrogen receptor beta (ERβ) in normal and diseased breast tissue. To address this issue, we have validated two ERβ ...antibodies, optimized the IHC protocols for both antibodies and now report the expression patterns of ERβ in normal and malignant breast tissues.
Methods
ERβ antibody specificity was determined using western blot and IHC analysis. ERβ protein expression patterns were assessed via IHC in normal breast tissue and invasive breast carcinoma. Further, we report the detailed protocol of the ERβ IHC assay developed in our CAP/CLIA certified laboratory to provide a standardized method for future studies.
Results
We have confirmed the specificity of two independent ERβ monoclonal antibodies, one that detects total (i.e., full length plus splice variants 2–5, which do not include the ligand binding domain) ERβ protein (PPZ0506) and one that detects only the full-length form, which includes the ligand binding domain, of ERβ (PPG5/10). Using these two antibodies, we demonstrate that ERβ is highly expressed in normal human breast tissue as well as in 20–30% of invasive breast cancers. Further, these two antibodies exhibited similar staining patterns across multiple different tissues and were highly concordant with regard to determining ERβ positivity in breast cancers.
Conclusions
ERβ protein was shown to be abundant in the majority of normal breast epithelial cells and is present in 20–30% of breast cancers. Use of these two antibodies, along with their standardized IHC protocols, provide a reference for future studies aimed at determining the utility of ERβ as a prognostic and/or predictive biomarker in various tissues of benign or malignant states.
While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of
promoter ...hypermethylation (m
) as a prognostic and predictive marker in colon cancer. We examined the association of m
with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients.
promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of m
in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. m
was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with m
compared to unmethylated
(unm
). There was no significant difference in disease-free or overall survival between patients with m
versus unm
colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by
methylation status. While
promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of m
as a prognostic and predictive marker.
Numerous theoretical models suggest that inhibition difficulties-the inability to moderate automatic responses-contribute to the onset and/or maintenance of internalizing symptoms. Inhibition ...deficits and internalizing disorders run in families and share overlapping genetic risk factors, suggesting that inhibition deficits may be particularly prognostic of internalizing symptoms in those with high familial risk. This study tested this hypothesis in a longitudinal sample during the transition from adolescence to early adulthood. As hypothesized, prospective associations between inhibition and anxiety and depressive symptoms 8 years later were moderated by familial risk for depression. Specifically, poorer inhibition prospectively predicted greater anxiety and depressive symptoms in those at high (but not low) familial risk for major depressive disorder. These findings provide preliminary support for impaired inhibition as an indicator of risk for later internalizing symptoms in those at high familial risk.
Background
Previous studies have suggested that elevated neutrophils, monocytes, and neutrophil-to-lymphocyte ratio (NLR) may be associated with poor outcomes in intracerebral hemorrhage (ICH). We ...sought to determine whether white blood cell (WBC) types were independently associated with poor outcome in ICH in a large cohort.
Methods
We performed a retrospective study of primary ICH at two academic centers. Cases were identified via ICD-9 code and verified via physician review. We included only those patients with WBC types obtained within 24 h of ICH onset.
Results
We identified 593 patients with primary ICH and WBC differentials in the first 24 h. Independent factors (OR, 95% CI) associated with 30-day case fatality were age > 80 (2.4 (1.4, 4.2)),
p
= 0.0023; NIHSS greater than median (3.9 (2.4, 6.3)),
p
< 0.0001; ICH volume quartiles (Q1: ref, Q2: 1.5 (0.7, 3.0), Q3: 3.2 (1.6, 6.6), Q4: 11.9 (5.3, 26.4)),
p
< 0.0001; non-lobar location (3.3 (1.9, 5.9)),
p
≤ 0.0001; IVH (2.3 (1.4, 3.6)),
p
= 0.0005, monocytes greater than median (1.6 (1.0, 2.4)),
p
= 0.0457, and anticoagulant use (3.2 (1.8, 5.6)),
p
< 0.0001. Elevated NLR was not associated with higher case fatality.
Conclusions
We found that elevated monocytes were independently associated with 30-day case fatality. Future studies will investigate whether there are subgroups of ICH patients, including those with particular blood or imaging biomarkers, in which WBC types might help predict poor outcome and provide targets for intervention.
Purpose of Review
This review summarizes recent evidence published since a previous review in 2018 on the association between egg consumption and risk of cardiovascular disease (CVD) mortality, CVD ...incidence, and CVD risk factors.
Recent Findings
No recent randomized controlled trials were identified. Evidence from observational studies is mixed, with studies reporting either an increased risk or no association of highest egg consumption with CVD mortality, and a similar spread of increased risk, decreased risk, or no association between egg intake and total CVD incidence. Most studies reported a reduced risk or no association between egg consumption and CVD risk factors. Included studies reported low and high egg intake as between 0 and 1.9 eggs/week and 2 and ≥14 eggs/week, respectively. Ethnicity may influence the risk of CVD with egg consumption, likely due to differences in how eggs are consumed in the diet rather than eggs themselves.
Summary
Recent findings are inconsistent regarding the possible relationship between egg consumption and CVD mortality and morbidity. Dietary guidance should focus on improving the overall quality of the diet to promote cardiovascular health.
URLi is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This meta-analysis compared and assessed the ...consistency of the pharmacokinetics and glucodynamics between URLi and Humalog® in healthy subjects and patients with T1D or T2D. The analysis included 4 randomized, double-blind, crossover, single dose studies healthy subjects (n=74), patients with T1D (n=80), and T2D (n=38), evaluating subcutaneous doses of 7, 15, or 30 U of URLi and Humalog®. An 8 to10-h euglycemic clamp was conducted to assess pharmacodynamics. Meta-analysis showed a ∼5 min faster (95% CI:-5.38, -4.12 min) onset of appearance with URLi vs. Humalog. The early insulin exposure was ∼8 times greater (95% CI:6.63, 8.51) in first 15 min and 3 times greater (95% CI:2.74, 3.22) in the first 30 min after URLi vs. Humalog. URLi reduced the late insulin exposure after 3 hours by 43% (ratio 0.57; 95% CI:0.53, 0.60) and the duration of exposure by 68 min (95% CI:-76.86, -59.53 min) vs. Humalog. URLi had a faster onset of action occurring 10 min earlier (95% CI:-12.01, -8.64 min), and early action was increased 3-fold in the first 30 min (95% CI:2.72, 3.50 min) with URLi vs. Humalog. Late insulin action (glucose infused 4 h to end of the clamp) was reduced by 35% (ratio 0.65; 95% CI:0.61, 0.70) and duration of action was 44 min shorter with URLi (95% CI:-58.60, -29.02 min). Total exposure and glucose infused during the clamp was similar between URLi vs. Humalog across the dose range and in each study population. Across the studied dose range and study populations, URLi consistently had faster absorption, reduced late exposure, and an overall shorter exposure duration compared to Humalog. URLi demonstrated an earlier insulin action while reducing the late insulin action compared to Humalog across the studied dose range and study populations.
Disclosure
J. Leohr: None. M.A. Dellva: Employee; Self; Eli Lilly and Company. K. Carter: None. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson & Johnson, Novartis AG. H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
•Heightened response to unpredictable threats characterizes internalizing disorders.•Functioning is important and separable from symptoms, but rarely assessed.•Threat responding predicted worse ...functioning over time independent of symptoms.•Neurobiological vulnerability markers have added utility in predicting functioning.
Heightened responsivity to unpredictable, and perhaps predictable, threat characterizes some internalizing disorders and may be vulnerability factors for psychopathology as well. However, few studies have directly tested whether individual differences in unpredictable and/or predictable threat responding longitudinally predict symptoms of psychopathology and functional outcomes. Examining functioning is particularly important given that functioning is separable from symptoms of psychopathology. The present study examined whether electromyography startle measures of predictable and/or unpredictable threat responding was associated with interviewer-assessed symptoms of internalizing psychopathology and functional impairment at baseline (n = 409) and one-year follow-up (n = 104). Elevated startle responding to unpredictable and predictable threat longitudinally predicted a worsening of functioning over time and this effect was independent of change of symptoms over time. Importantly, threat responding at baseline predicted functional impairment during the follow-up independent of the effects of DSM-defined fear-based (e.g., panic disorder) or distress-misery (e.g., major depressive disorder) internalizing disorders. These findings provide initial support for the incremental validity of neurobiological vulnerability markers of threat responding over and above DSM disorders and highlight the importance of distinguishing functional outcomes from symptom outcomes.
The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing ...guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years.
A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs.
The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in
,
, and
were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in
,
,
, and
were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in
,
, and
.
This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with
and
PVs and perhaps with
and
PVs should be considered for magnetic resonance imaging screening.
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