Prolongation of culture-isolated neonatal islet xenografts without immunosuppression

Xenogeneic transplantation of 300-400 neonatal rat islets (Fischer 344) to the kidney subcapsular site of streptozotocin-induced nonimmunosuppressed diabetic adult mice (C57BL/6ByJ) resulted in a return to normoglycemia in 87% of the recipients. Of the 13 successfully reversed recipients, 5 exhibited graft rejection (hyperglycemia of +250 mg/dl) within 2 weeks posttransplantation, and 2 mice had rejected their rat islets by 3 weeks. The 6 remaining recipients exhibited significantly prolonged survival of the cultured islets: 1 remained reversed until 4 weeks posttransplantation, 2 remained normoglycemic for 5 weeks, in 3 diabetes remained reversed for more than 7 weeks--in one of these animals the disease was reversed for 17 weeks. Transplanted islets were isolated from neonatal rat pancreas during a period in culture that varied from 8 to 17 days. Although morphological integrity of the endocrine cells was confirmed by ultrastructural study, nonendocrine cells were not identifiable within the islets after 8 days of culture. Xenografted islets examined morphologically prior to obtaining physiological evidence of rejection were associated with extensive peripheral lymphocytic accumulation. Modification of islet immunogenicity leading to prolonged xenograft survival may reflect the degree to which the in vitro environment permits the differential survival of endocrine cells while purging the islet of cells initiating the immune response.     

Clinical and pathologic features correlated with rare favorable survival in patients with BRAFV600E mutated colorectal cancer

BackgroundBRAF^V600E mutations occur in fewer than 10% of all patients with metastatic colorectal cancer (CRC) and arise from sessile serrated adenomas. Despite efficacy with targeted therapies against MAPK signaling and with immunotherapies in this population, survival outcomes for patients with BRAF^V600E mutated metastatic CRC in general are poor. Characteristics distinguishing patients with BRAF^V600E mutated metastatic CRC with favorable versus unfavorable outcomes have not been well annotated.MethodsRecords of 187 patients with BRAF^V600E mutated metastatic CRC evaluated at MD Anderson Cancer Center between 2005–2020 were reviewed. Patients with the shortest and longest metastatic survival (N=25 for each group) were compared. Associations between prognostic group and clinical/pathologic features were measured by odds ratio and for median survival by log-rank testing.ResultsMedian metastatic survival differed between the 2 BRAF^V600E mutated metastatic CRC populations (8.6 vs. 83.9 months, hazard ratio 32; P<0.0001). Patients with poor survival more commonly had hepatic involvement [75% vs. 28%, odds ratio (OR) 8.1, 95% confidence interval (CI): 2.3–29; P=0.001]. Patients with favorable survival were more likely to develop metachronous metastases (52% vs. 16%, OR 5.7, 95% CI: 1.5–21; P=0.01) and undergo definitive locoregional therapy to metastatic disease (40% vs. 0%, OR 34.5, 95% CI: 1.9–630; P=0.01). Microsatellite instability (36% vs. 4%, OR 19.8, 95% CI: 2.2–180; P=0.008) and prior tobacco exposure (44% vs. 16%, OR 4.1, 95% CI: 1.1–15.6, P=0.04) were associated with a favorable prognosis. Durable responses to MAPK-targeted therapies and immunotherapy were noted in the favorable group.ConclusionsA small fraction of patients with BRAF^V600E mutated metastatic CRC can achieve excellent long-term survival which belies conventional context and is driven by either surgical metastectomy or by systemic treatment options. While poor overall prognosis remains the recognized outcome for most patients with BRAF^V600E mutated metastatic CRC, it is possible that few may achieve exceptionally favorable survival.     

BARRIERS TO CANCER SCREENING AMONGST WOMEN WITH MENTAL HEALTH PROBLEMS

The involvement of women with mental health problems in cancer screening was examined in order to explore service delivery options among this particular group. Structured interviews were used to identify the utilization of cancer screening and barriers experienced in accessing such screening among this group. The sample of women reported similar utilization rates of cancer screening as the general female population of the same Australian state. However, they identified a number of barriers to effective access to cancer screening. In response to the interview finding that consumers valued screening services from a well-known provider in a familiar environment, a series of women's health clinics were offered within a mental health service. This experience is described and was used to try to better understand barriers to cancer screening experienced by women with mental health problems. The women's health clinics were most efficiently offered in conjunction with hospital-based psychiatric services.     

Effect of Retinoic Acid on Ferritin H Expression During Brain Development and Neuronal Differentiation

Abstract

We have previously shown that brain ferritin H expression, which has been associated with iron utilization, is developmentally regulated. Because retinoic acid (RA) regulates gene expression and is involved in cellular differentiation, we tested the hypothesis that RA regulates ferritin H during brain development and neuronal differentiation. RA, administered to rats on postnatal day 1, produced a 4-fold increase in brain ferritin H mRNA (p<0.01) after 24 h. To examine whether RA-stimulated neuronal differentiation contributed to this up-regulation, ferritin and ferritin H mRNA were measured in human neuronal precursor cells (NTera-2, NT2) before and after 4-weeks of RA-stimulated differentiation into post-mitotic neurons. Differentiation resulted in a 2-fold increase in both ferritin and ferritin H mRNA (p<0.05). Immunocytochemistry and Northern analysis showed significant elevations in ferritin expression that began as early as 24 h after RA treatment. While there was also a significant increase in the labile iron pool after RA treatment, this did not occur until 72 h. These data show that RA regulates ferritin H expression during rat brain development and neuronal differentiation and suggests a new role for RA in brain iron metabolism.     

Subject Index to Volume 3

By monodimensional thin-layer electrophoresis on 5 X 10-cm cellulose layers o-aminolevulinic acid (oAL) is rapidly separated from interfering substances. Detection with a cupric nitrate-Ninhydrin sequence adds specificity and permits detection of as little as 10 ng/lLl of urine. Confirmation can be obtained on two-dimensional chromatograms (5 X 5 em) with the use of either Ninhydrin or a modified MauzeraUasGranick reagent for detection. The quantity of (’)Al can be estimated by visual or densitometric comparison with standards. The method is rapid and inexpensive and is suggested for use in conjunction with the more expensive column chromatographic technique.     

The effect of comorbid illness on mortality outcomes in cardiac surgery

HYPOTHESIS: Comorbid conditions are associated with the risk of death from coronary artery bypass graft surgery. DESIGN: Prospective cohort study data were collected on patient and disease characteristics and comorbid conditions including hypertension, diabetes, obesity, vascular disease, chronic obstructive pulmonary disease, cancer (excluding nonmelanoma skin cancer), dialysis-dependent renal failure, liver disease, and dementia. Statistical analysis used logistic regression for the calculation of adjusted odds ratios (ORs) and 95% confidence intervals (CIs). SETTING: Regional cardiac surgery database. PATIENTS: A total of 27,239 consecutive patients undergoing isolated coronary artery bypass graft surgery. MAIN OUTCOME MEASURE: In-hospital mortality rate. RESULTS: The prevalence of comorbid conditions was as follows: hypertension, 64.3%; diabetes, 30.1%; obesity, 24.6%; severe obesity, 7.2%; vascular disease, 18.3%; chronic obstructive pulmonary disease, 10.9%; peptic ulcer, 7.5%; cancer, 3.8%; renal failure, 1.5%; liver disease, 0.6%; and dementia, 0.1%. After adjustment for patient and disease characteristics, including age, sex, previous cardiac surgery, priority of surgery, degree of left main coronary stenosis, number of diseased coronary arteries, and left ventricular ejection fraction, the following comorbid conditions were significant predictors of in-hospital mortality: diabetes (OR, 1.19; 95% CI, 1.01-1.40; P =.03), vascular disease (OR, 1.67; 95% CI, 1.41-1.97; P<.001), chronic obstructive pulmonary disease (OR, 1.57; 95% CI, 1.29-1.91; P<.001), peptic ulcer (OR, 1.34; 95% CI, 1.05-1.71; P =.02), and dialysis-dependent renal failure (OR, 3.68; 95% CI, 2.65-5.13; P<.001). There was no significant association between in-hospital mortality and hypertension, obesity or severe obesity, cancer, liver disease, or dementia. CONCLUSION: Even after adjustment for other patient and disease characteristics, comorbid conditions (especially diabetes, vascular disease, chronic obstructive pulmonary disease, peptic ulcer disease, and dialysis-dependent renal failure) are associated with significantly increased risk of death after coronary artery bypass graft surgery.