The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from ...dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial.
Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75-100%) vs the lower three quartiles (0-25, 25-50 and 50-75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation.
A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1-3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08-0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53-4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates.
These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.
Background: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in β-carotene (a violet to yellow plant pigment that acts as an ...antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum β-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg β-carotene and 25 000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18 314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg β-carotene and 25 000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. Purpose: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention. Methods: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for β-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the.05 α value, and all P values were derived from two-sided statistical tests. Results: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval CI = 1.07–1.73; P =.01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13–2.23; P =.01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28–3.09; test for heterogeneity of RR among quartiles of alcohol intake has P =.01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09–3.26; test for heterogeneity among histologic categories has P =.35), but not with base-line serum B-carotene concentrations. Conclusions: CARET participants receiving the combination of β-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for β-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29 133 male smokers in Finland. Implications: Individuals at high risk of developing lung cancer, i.e., current smokers and asbestos-exposed workers, should be discouraged from taking supplemental β-carotene (and the combination of β-carotene with vitamin A). Safety and efficacy should be demonstrated before recommending use of vitamin supplements in any population. J Natl Cancer Inst 1996; 88: 1550–9
d , l -α-difluoromethylornithine (DFMO) was synthesized over 20 years ago. It was hoped that this enzyme-activated, irreversible
inhibitor of ornithine decarboxylase, the first enzyme in polyamine ...synthesis, would be effective as a chemotherapy for hyperproliferative
diseases, including cancer and/or infectious processes. DFMO was generally found to exert cytostatic effects on mammalian
cells and tissues, and its effectiveness as a therapeutic agent has been modest. DFMO was also found to cause treatment-limiting
(but reversible) ototoxicity at high doses. This side effect, along with its minimal therapeutic activity, contributed to
the loss of interest by many clinicians in further developing DFMO as a cancer therapeutic agent. However, DFMO was subsequently
shown to inhibit carcinogen-induced cancer development in a number of rodent models, and interest in developing this compound
as a preventive agent has increased. The rationale for the inhibition of ornithine decarboxylase as a cancer chemopreventive
agent has been strengthened in recent years because this enzyme has been shown to be transactivated by the c- myc oncogene in certain cell/tissue types and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. Recent clinical cancer chemoprevention trials, using dose de-escalation
designs, indicate that DFMO can be given over long periods of time at low doses that suppress polyamine contents in gastrointestinal
and other epithelial tissues but cause no detectable hearing loss or other side effects. Current clinical chemoprevention
trials are investigating the efficacy of DFMO to suppress surrogate end point biomarkers ( e.g. , colon polyp recurrence) of carcinogenesis in patient populations at elevated risk for the development of specific epithelial
cancers, including colon, esophageal, breast, cutaneous, and prostate malignancies.
We assessed Ki-ras mutations by single-strand conformation polymorphism followed by DNA sequencing, p53 expression by immunohistochemistry, ploidy status, and S-phase fraction in 66 stage II and 163 ...stage III colon cancer patients enrolled on a randomized trial of surgery followed by observation or adjuvant levamisole or 5-fluorouracil (5FU) plus levamisole (Intergroup Trial 0035) to see whether these factors were independently associated with survival or with differential effects of adjuvant therapy. A Cox proportional hazards survival model was used to describe marker effects and therapy by marker interactions, with adjustment for the clinical covariates affecting survival. A Bonferroni adjustment was used to account for multiple testing. Mutation of the Ki-ras gene was found in 41% of the cancers and was associated with a poor prognosis in stage II but not stage III. In stage II, 7-year survival was 86% versus 58% in those with wild type versus Ki-ras mutations. After adjustment for treatment and clinical variables, the hazard ratio (HR) for death was 4.5; 95% confidence interval (CI), 1.7-12.1 (P = 0.012). p53 overexpression was found in 63% of cancers and was associated with a favorable survival in stage III but not stage II. Seven-year survival in stage III was 56% with p53 overexpression versus 43% with no p53 expression (HR, 2.2; 95% CI, 1.3-3.6; P = 0.012). Aneuploidy was more common in stage III than in stage II (66 versus 47%; P = 0.009) but was not independently related to survival in either group. The proliferative rate was greater in aneuploid than in diploid cancers but was not related to survival. There was no benefit of adjuvant therapy in stage II nor in any of the stage II subgroups defined by mutational status. In stage III, adjuvant therapy with 5FU plus levamisole improved 7-year survival in patients with wild-type Ki-ras (76 versus 44%; HR, 0.4; 95% CI, 0.2-0.8) and in those without p53 overexpression (64 versus 26%; HR, 0.3; 95% CI, 0.1-0.7). Adjuvant therapy did not benefit those with Ki-ras mutations or p53 overexpression. The effects of adjuvant therapy did not differ according to ploidy status or proliferative rate. Ki-ras mutation is a significant risk factor for death in stage II, and the absence of p53 expression is a significant risk factor for death in stage III colon cancer after adjustment for treatment and clinical covariates. Exploratory analyses suggest that patients with stage III colon cancer with wild-type Ki-ras or no p53 expression benefit from adjuvant 5FU plus levamisole, whereas those with Ki-ras mutations or p53 overexpression do not. An independent study will be required to determine whether response to adjuvant therapy in colon cancer depends on mutational status.
This article examines how Anglophone scholars approached the question of Maoist China's relationship with empire between 1949 and 1976. My analysis sheds light on three discursive frameworks. First, ...I discuss scholars that portrayed China as part of a Sino-Soviet empire. Second, I investigate academic studies that argued that the CCP sought to revive China's old empire with new characteristics. Third, I look at scholarship that depicted the CCP as seeking to create a post-colonial order both at home and abroad. Finally, in the conclusion, I address how these three discursive frameworks continue to circulate in contemporary discourse about Sino-American relations.
Lung cancer is the leading cause of death from cancer in the United States, accounting for approximately 29 percent of deaths from cancer and 6 percent of all deaths.
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New approaches are essential ...to prevent lung cancer in persons who have smoked cigarettes or who have had occupational exposure to asbestos. Twenty-nine percent of men and 25 percent of women who are 45 to 64 years of age currently smoke,
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and at least 40 percent of men and 20 percent of women in this age group are former smokers.
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An estimated 4000 to 6000 deaths from lung cancer per year . . .
A recently published collection of archival documents provides not just a trove of records on the history of one particular development campaign but also a rich resource for the study of political ...dynamics and socioeconomic patterns in Mao’s China and the early years of the Reform era. The collection, titled Xin zhongguo xiao sanxian jianshe dangan wenxian zhengli huibian (Compilation of archival documents about New China’s Small Third Front; Shanghai: Shanghai kexue jishu wenxian chubanshe, 2021), is the product of a research group headed by Xu Youwei. Documents spanning the 1960s, 1970s, and 1980s in the compilation’s eight volumes shed light on industrial policy, government-enterprise and civil-military relations, factional politics of the Cultural Revolution, welfare benefits, the urban-rural divide, cultural activities, the education sector, family life, gendered practices, and elements of everyday life, among other topics.
Polyamine metabolic genes are downstream targets of several genes commonly mutated in colon adenomas and cancers. Inhibitors of ornithine decarboxylase, such as difluoromethylornithine (DFMO), and ...agents that stimulate polyamine acetylation and export, such as non-steroidal anti-inflammatory drugs (NSAIDS), act at least additively to arrest growth in human cell models and suppress intestinal carcinogenesis in mice. These preclinical studies provided the rationale for colon cancer prevention trials in humans. A Phase IIb clinical study comparing the combination of DFMO and the NSAID sulindac versus placebo was conducted. Endpoints were colorectal tissue polyamine and prostaglandin E2 contents and overall toxicity to participants. Participants in the Phase IIb study served as a vanguard for a randomized, placebo-controlled prospective Phase III trial of the combination of DFMO and sulindac with the primary study endpoint the prevention of colon polyps. Seventy percent of participants will have completed the three years of treatment in December 2006.
This article examines Republican-era efforts to turn the Yangzi River into an engine of national development by building the Three Gorges Dam (abbreviated as TGD). Beginning with Sun Yat-sen's ...initial proposal in 1919 and ending with a Sino-American attempt in the 1940s, it analyzes how Chinese and foreign actors went about developing such a dream. Every endeavor ran into a similar problem: China did not have the industrial, administrative, or financial capacity to accommodate the gargantuan hydraulic feat, an issue which critics repeatedly raised. Undeterred, the dam's backers pushed for China to overcome a domestic lack of capital by collaborating with foreign technocrats. A joint venture would purportedly benefit both China and foreigners by not only facilitating trade with inland areas and producing a huge monument to the powers of modern engineering, but also because the dam's immense electrical output would boost China's transformation into an industrial powerhouse, one that would increasingly desire foreign goods. Although the Three Gorges Dam was not realized in the Republican Period, Chinese and foreign actors continued to pursue their infrastructure dream in order to fuel national industrialization on both sides of the Taiwan Straits during the Cold War.
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