Inherited and noninherited sources of variation in metastasis and the growth rate of tumors: Implications for tumor evolution and therapy

I have undertaken measurements of the genetic (or inherited) and nongenetic (or noninherited) components of the variability of metastasis formation and tumor diameter doubling time in more than 100 metastatic lines from each of three murine tumors (sarcoma SANH, sarcoma SA4020, and hepatocarcinoma HCA-I) syngeneic to C3Hf/Kam mice. These lines were isolated twice from lung metastases and analysed immediately thereafter to obtain the variance to spontaneous lung metastasis and tumor diameter doubling time. Additional studies utilized cells obtained from within 4 passages of isolation. Under the assumption that no genetic differences in metastasis formation or diameter doubling time existed among the cells of a given line, the variance within a line would estimate nongenetic variation. The variability derived from differences between lines would represent genetic origin. The estimates of the genetic contribution to the variation of metastasis and tumor diameter doubling time were significantly greater than zero, but only in the metastatic lines of tumor SANH was genetic variation the major source of metastatic variability (contributing 53% of the variability). In the tumor cell lines of SA4020 and HCA-I, however, the contribution of nongenetic factors predominated over genetic factors in the variability of the number of metastasis and tumor diameter doubling time. A number of other parameters examined, such as DNA content, karyotype, and selection and variance analysis with passage in vivo, indicated that genetic differences existed within the cell lines and that these differences were probably created by genetic instability. The mean metastatic propensity of the lines may have increased somewhat during their isolation and isotransplantation, but the variance was only slightly affected, if at all. Analysis of the DNA profiles of the metastatic lines of SA4020 and HCA-I revealed differences between these lines and their primary parent tumors, but not among the SANH lines and their parent tumor. Furthermore, there was a direct correlation between the extent of genetic influence on metastasis formation and the ability of the tumor cells to develop resistance to cisplatinum. Thus although nongenetic factors might predominate in contributing to metastasis formation, it is probably genetic variation and genetic instability that cause the progression of tumor cells to a more metastatic phenotype and leads to the emergence of drug resistance. ^

Evidence for a Frozen Bed, Byrd Glacier, Antarctica

Ice thickness, computed within the fjord region of Byrd Glacier on the assumptions that Byrd Glacier is in mass-balance equilibrium and that ice velocity is entirely due to basal sliding, are on average 400 m less than measured ice thicknesses along a radio-echo profile. We consider four explanations for these differences: (1) active glacier ice is separated from a zone of stagnant ice near the base of the glacier by a shear zone at depth; (2) basal melting rates are some 8 m/yr; (3) internal shear occurs with no basal sliding in much of the region above the grounding zone; or (4) internal creep and basal sliding contribute to the flow velocity in varying proportions above the grounding zone. Large gradients of surface strain rate seem to invalidate the first explanation. Computed values of basal shear stress (140 to 200 kPa) provide insufficient frictional heat to melt the ice demanded by the second explanation. Both the third and fourth explanations were examined by making simplifying assumptions that prevented a truly quantitative evaluation of their merit. Nevertheless, there is no escaping the qualitative conclusion that internal shear contributes strongly to surface velocities measured on Byrd Glacier, as is postulated in both these explanations.

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

Fish Faunal Resurgence in Lake Nabugabo, East Africa

In Lake Nabugabo, Uganda, a small satellite of the equatorial Lake Victoria, approximately 50% of the indigenous fish species disappeared from the open waters subsequent to establishment of the introduced predatory Nile perch (Lates niloticus). However, several of these species persisted in wetland refugia. Over the past decade, Nile perch in Lake Nabugabo have been intensively fished. Herein we report a resurgence of some indigenous species in open waters. In a multiyear study, we used annual transects in inshore and offshore waters of exposed (no wetland) and wetland habitats to document the pattern of resurgence. In 1995, haplochromine cichlids were largely confined to inshore areas, particularly wetland ecotones, and were rare in Nile perch stomachs, as were most other indigenous species. By 2000 haplochromine cichlids were abundant in inshore and offshore areas of both exposed and wetland transects. Several indigenous noncichlids also reappeared in the main lake, including three of the four original mormyrid species. Between 1995 and 1999, there was a dramatic increase in the proportion of haplochromines in the diet of Nile perch. When haplochromines were rare (1995), Nile perch switched from an invertebrate-dominated diet to piscivory at a large size (30 cm total length). In 2000, however, Nile perch were strongly piscivorous by 5–10 cm total length. The pattern of faunal loss and recovery in Lake Nabugabo demonstrates the importance of refugia in providing the seeds of resurgence and provides a model with which to understand some changes in Lake Victoria.

Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Glucose-Induced Temporary Visual Recovery in Primary Open-Angle Glaucoma: A Double-Blind, Randomized Study

Purpose To investigate the effect of topical glucose on visual parameters in individuals with primary open-angle glaucoma (POAG). Design Double-blind, randomized, crossover study. Participants Nondiabetic pseudophakic patients with definite POAG were recruited; 29 eyes of 16 individuals participated in study 1. A follow-up study (study 2) included 14 eyes of 7 individuals. Intervention Eyes were randomly allocated to receive 50% glucose or saline eye drops every 5 minutes for 60 minutes. Main Outcome Measures The contrast sensitivity and best-corrected logarithm of the minimum angle of resolution (logMAR). Results The 50% glucose reached the vitreous in pseudophakic but not phakic individuals. Glucose significantly improved the mean contrast sensitivity at 12 cycles/degree compared with 0.9% saline by 0.26 log units (95% confidence interval [CI], 0.13–0.38; P���< 0.001) and 0.40 log units (95% CI, 0.17–0.60; P���< 0.001) in the follow-up study. The intraocular pressure, refraction, and central corneal thickness were not affected by glucose; age was not a significant predictor of the response. Conclusions Topical glucose temporarily improves psychophysical visual parameters in some individuals with POAG, suggesting that neuronal energy substrate delivery to the vitreous reservoir may recover function of “sick” retinal neurons.

Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts

IMPORTANCE Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD). OBJECTIVE To assess the association between differences in thyroid function within the reference range and CHD risk. DESIGN, SETTING, AND PARTICIPANTS Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline. EXPOSURES Thyroid function as expressed by serum thyrotropin levels at baseline. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status. RESULTS Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results. CONCLUSIONS AND RELEVANCE Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis

OBJECTIVE The objective was to determine the risk of stroke associated with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels. DATA EXTRACTION AND SYNTHESIS We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. CONCLUSIONS Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

The Optimal Capital Structure of Banks: Balancing Deposit Insurance, Capital Requirements and Tax-Advantaged Debt

The capital structure and regulation of financial intermediaries is an important topic for practitioners, regulators and academic researchers. In general, theory predicts that firms choose their capital structures by balancing the benefits of debt (e.g., tax and agency benefits) against its costs (e.g., bankruptcy costs). However, when traditional corporate finance models have been applied to insured financial institutions, the results have generally predicted corner solutions (all equity or all debt) to the capital structure problem. This paper studies the impact and interaction of deposit insurance, capital requirements and tax benefits on a bankÇs choice of optimal capital structure. Using a contingent claims model to value the firm and its associated claims, we find that there exists an interior optimal capital ratio in the presence of deposit insurance, taxes and a minimum fixed capital standard. Banks voluntarily choose to maintain capital in excess of the minimum required in order to balance the risks of insolvency (especially the loss of future tax benefits) against the benefits of additional debt. Because we derive a closed- form solution, our model provides useful insights on several current policy debates including revisions to the regulatory framework for GSEs, tax policy in general and the tax exemption for credit unions.

MS 066 Guide to the Howard B. Hamilton, MD, papers; 1945-1997

The Howard B. Hamilton, MD, papers, MS 66, includes material from 1945-1997 related to the Atomic Bomb Casualty Commission (ABCC) and the Radiation Effects Research Foundation (RERF). Hamilton was the Chief of Clinical Laboratories for the Atomic Bomb Casualty Commission from 1956 until its dissolution in 1975. He served in the same capacity for the Radiation Effects Research Foundation, which succeeded the ABCC, until 1984. This collection encompasses this period of time in Dr. Hamilton's career, as well as his related scholarly work after his retirement from RERF. Dr. Hamilton donated his collection of letters, reprints, newspaper articles, photographs, memos, and ephemera to the John P. McGovern Historical Collections and Research Center between 1985 and 2002. The collection is in good condition and consists of 3.75 cubic feet (10 boxes).