Persistent expression of certain oncogenes is required for tumor maintenance. This phenotype is referred to as oncogene addiction and has been clinically validated by anticancer therapies that ...specifically inhibit oncoproteins such as BCR-ABL, c-Kit, HER2, PDGFR, and EGFR. Identifying additional genes that are required for tumor maintenance may lead to new targets for anticancer drugs. Although the role of aberrant Wnt pathway activation in the initiation of colorectal cancer has been clearly established, it remains unclear whether sustained Wnt pathway activation is required for colorectal tumor maintenance. To address this question, we used inducible β-catenin shRNAs to temporally control Wnt pathway activation in vivo. Here, we show that active Wnt/β-catenin signaling is required for maintenance of colorectal tumor xenografts harboring APC mutations. Reduced tumor growth upon β-catenin inhibition was due to cell cycle arrest and differentiation. Upon reactivation of the Wnt/β-catenin pathway colorectal cancer cells resumed proliferation and reacquired a crypt progenitor phenotype. In human colonic adenocarcinomas, high levels of nuclear β-catenin correlated with crypt progenitor but not differentiation markers, suggesting that the Wnt/β-catenin pathway may also control colorectal tumor cell fate during the maintenance phase of tumors in patients. These results support efforts to treat human colorectal cancer by pharmacological inhibition of the Wnt/β-catenin pathway.
We have used a novel quantitative trait locus model to study the genetics of survival of F2 progeny of susceptible BALB/cByJ and resistant C57BL/6ByJ mice that have been infected with Listeria ...monocytogenes. This allowed us to map modifiers of L. monocytogenes susceptibility to chromosomes 5 and 13.
Stroke remains one of the most serious complications in atrial fibrillation (AF) patients and has been linked to disturbances of the autonomic nervous system.
The purpose of this study was to test ...the hypothesis that impaired cardiac autonomic function might be associated with an enhanced stroke risk in AF patients.
A total of 1922 AF patients who were in either sinus rhythm (SR group; n = 1121) or AF (AF group; n = 801) on a 5-minute resting electrocardiographic (ECG) recording were enrolled in the study. Heart rate variability triangular index (HRVI), standard deviation of normal-to-normal intervals, root mean square root of successive differences of normal-to-normal intervals, mean heart rate, 5-minute total power, and power in the high-frequency, low-frequency, and very-low-frequency ranges were calculated. Cox regression models were constructed to examine the association of heart rate variability (HRV) parameters with the composite endpoint of stroke or systemic embolism.
Mean age was 71 ± 8 years in the SR group and 75 ± 8 years in the AF group. Thirty-seven patients in the SR group (3.4%) and 60 patients in the AF group (8.0%) experienced a stroke or systemic embolism during follow-up of 5 years. In patients with SR, HRVI <15 was the strongest HRV parameter to be associated with stroke or systemic embolism (hazard ratio 3.04; 95% confidence interval 1.3–7.0; P = .009) after adjustment for multiple confounders. In the AF group, no HRV parameter was found to be associated with the composite endpoint.
HRVI measured during SR on a single 5-minute ECG recording is independently associated with stroke or systemic embolism in AF patients. HRV analysis in SR may help to improve risk stratification in AF patients.
Persistent expression of certain oncogenes is required for tumor maintenance. This phenotype is referred to as oncogene addiction and has been clinically validated by anticancer therapies that ...specifically inhibit oncoproteins such as BCR-ABL, c-Kit, HER2, PDGFR, and EGFR. Identifying additional genes that are required for tumor maintenance may lead to new targets for anticancer drugs. Although the role of aberrant Wnt pathway activation in the initiation of colorectal cancer has been clearly established, it remains unclear whether sustained Wnt pathway activation is required for colorectal tumor maintenance. To address this question, we used inducible β-catenin shRNAs to temporally control Wnt pathway activation in vivo. Here, we show that active Wnt/β-catenin signaling is required for maintenance of colorectal tumor xenografts harboring APC mutations. Reduced tumor growth upon β-catenin inhibition was due to cell cycle arrest and differentiation. Upon reactivation of the Wnt/β-catenin pathway colorectal cancer cells resumed proliferation and reacquired a crypt progenitor phenotype. In human colonic adenocarcinomas, high levels of nuclear β-catenin correlated with crypt progenitor but not differentiation markers, suggesting that the Wnt/β-catenin pathway may also control colorectal tumor cell fate during the maintenance phase of tumors in patients. These results support efforts to treat human colorectal cancer by pharmacological inhibition of the Wnt/β-catenin pathway. PUBLICATION ABSTRACT
Cancer patients have high rates of persistent and disabling symptoms. Evidence suggests that social constraints (e.g., avoidance and criticism) negatively impact symptoms, but pathways linking these ...variables have yet to be identified. This study examined whether cancer-related loneliness (i.e., feeling socially disconnected related to having cancer) mediated the relationships between social constraints and symptoms (i.e., pain interference, fatigue, sleep disturbance, and cognitive complaints) in patients with various cancers (
N
= 182). Patients (51% female, mean age = 59) were recruited from the Indiana Cancer Registry and completed questionnaires assessing social constraints, cancer-related loneliness, and symptoms. Structural equation modeling was used to evaluate the hypothesized relationships among variables. The model demonstrated good fit. Consistent with our hypothesis, cancer-related loneliness mediated the relationships between social constraints and each symptom. Findings suggest that addressing cancer-related loneliness in symptom management interventions may mitigate the negative impact of social constraints on outcomes.
To identify situations and thoughts that may precipitate or protect against loneliness experienced by patients with cancer.
Qualitative.
The hematology/oncology clinic at the Indiana University ...Melvin and Bren Simon Cancer Center, an outpatient oncology center in Indianapolis.
Purposive sample of 15 patients undergoing treatment for multiple myeloma or non-Hodgkin lymphoma.
Individual, semistructured qualitative interviews were conducted. Theoretical thematic analysis was used to analyze interview data.
Factors that appeared to precipitate loneliness included several situations (e.g., physical isolation, social constraints such as criticism) and thoughts (e.g., unmet expectations for visits or questions about health, belief that others do not understand their cancer experience). Several situations (e.g., social support, normal routine) and thoughts (e.g., beliefs that time alone is desirable and that others' discomfort with cancer-related discussions is normative) appeared to protect against loneliness. Certain social situations were loneliness-inducing for some patients and not for others, suggesting that patients' thoughts about their situations, rather than the situations themselves, have the greatest impact on their loneliness.
The current study fills gaps in loneliness theory by identifying cancer-related situations and thoughts that patients associate with their loneliness. Consistent with theory, patients reported feeling lonely when they had negative thoughts about their social situations.
Findings inform nursing assessment and intervention strategies to incorporate into care plans. For instance, when conducting assessments, nurses should be more attentive to patients' satisfaction with their social environment than actual characteristics of the environment. Normalizing patients' experiences and encouraging positive thoughts about others' behavior may reduce patients' loneliness.
Purpose
Family caregivers of advanced colorectal cancer patients may be at increased risk for psychological distress. Yet their key challenges in coping with the patient’s illness are not well ...understood. Soliciting both patient and caregiver perspectives on these challenges would broaden our understanding of the caregiving experience. Thus, the purpose of this research was to identify caregivers’ key challenges in coping with their family member’s advanced colorectal cancer from the perspective of patients and caregivers.
Methods
Individual, semi-structured qualitative interviews were conducted with 23 advanced colorectal cancer patients and 23 primary family caregivers. Interview data were analyzed via thematic analysis.
Results
In nearly all cases, patient and caregiver reports of the caregiver’s key challenge were discrepant. Across patient and caregiver reports, caregivers’ key challenges included processing emotions surrounding the patient’s initial diagnosis or recurrence and addressing the patient’s practical and emotional needs. Other challenges included coping with continual uncertainty regarding the patient’s potential functional decline and prognosis and observing the patient suffer from various physical symptoms.
Conclusions
Findings suggest that eliciting the perspectives of both patients and caregivers regarding caregivers’ challenges provides a more comprehensive understanding of their experience. Results also point to the need to assist caregivers with the emotional and practical aspects of caregiving.
The formation of heterochromatin at the centromeres in fission yeast depends on transcription of the outer repeats. These transcripts are processed into siRNAs that target homologous loci for ...heterochromatin formation. Here, high throughput sequencing of small RNA provides a comprehensive analysis of centromere‐derived small RNAs. We found that the centromeric small RNAs are Dcr1 dependent, carry 5′‐monophosphates and are associated with Ago1. The majority of centromeric small RNAs originate from two remarkably well‐conserved sequences that are present in all centromeres. The high degree of similarity suggests that this non‐coding sequence in itself may be of importance. Consistent with this, secondary structure‐probing experiments indicate that this centromeric RNA is partially double‐stranded and is processed by Dicer in vitro. We further demonstrate the existence of small centromeric RNA in rdp1Δ cells. Our data suggest a pathway for siRNA generation that is distinct from the well‐documented model involving RITS/RDRC. We propose that primary transcripts fold into hairpin‐like structures that may be processed by Dcr1 into siRNAs, and that these siRNAs may initiate heterochromatin formation independent of RDRC activity.
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