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1. SUMMARY Introduction Evidence is limited on how the onset of health conditions affects tobacco/nicotine use. We report analyses from adults in the U.S. PATH study relating changes in established cigarette and/or e-cigarette use between Waves 1 and 4 to onset of conditions in Waves 2 or 3. Methods Nine conditions had sufficient onsets for analysis. The main analyses adjusted for sex and age. Additional analyses excluded other tobacco/nicotine product users, controlled for more variables, restricted changes in one product to never users of the other, or restricted attention to changes occurring after onset of the condition. Results In the main analyses, onset of each condition predicted significantly increased overall e-cigarette initiation rates, with highest odds ratios (OR) for any major respiratory condition (2.86, 95% confidence interval (CI) 2.10–3.90) and cancer (2.51, 1.52–4.14). Each onset also predicted higher cigarette smoking initiation rates, but ORs were lower than for e-cigarette initiation, and only significant for any cardiovascular condition (1.65, 1.31–2.08), high blood pressure (1.34, 1.13–1.58), and any major smoking-related condition (1.35, 1.12–1.62). For quitting smoking only six conditions showed increased ORs, significant only for high cholesterol (1.29, 1.02–1.62). The additional analyses generally confirmed these patterns. Relationships with re-initiating cigarettes or becoming dual users of cigarettes and e-cigarettes were inconsistent. Onset of conditions also tended to reduce amount smoked by smokers. Conclusions While PATH is nationally representative, its sample size does not always allow precise estimates. There is concern about accuracy of statements by some older participants claiming to be Wave 1 never smokers but Wave 4 ever smokers. Nevertheless the previously unreported association between onset of the health conditions and e-cigarette initiation (which mainly occurs in Wave 1 cigarette smokers) appears real. [Contrib. Tob. Nicotine Res. 32 (2023) 1–10]

Summary Background Smoking is associated with cancer and cardio-respiratory mortality. Reducing smoking prevalence will lead to fewer deaths and more life-years. Here, we estimate the impact of hypothetical introduction of reduced-risk products (heat-not-burn products and e-cigarettes) in Germany from 1995 to 2015 on mortality from lung cancer, chronic obstructive pulmonary disease, ischaemic heart disease, and stroke in men and women aged 30–79 years. Methods We used a previously described population health impact model, with individuals with a defined baseline cigarette smoking distribution followed under a “Null Scenario”, with reduced-risk products never introduced, and various “Alternative Scenarios” where they are. Transition probabilities allow product use to change annually, with the individual product histories allowing estimation of risks, relative to never users, which are then used to estimate reductions in deaths and life-years lost for each Alternative Scenario. Results In the Null Scenario, we estimated 852,000 deaths from cigarette smoking (42,600 per year), with 8.61 million life-years lost. Had everyone ceased smoking in 1995, and with no use of reduced-risk products, these numbers would reduce by 217,000 and 2.88 million. Compared to the Null Scenario, the estimated reductions would be 159,000 and 2.06 million with an immediate complete switch to heat-not-burn products and 179,000 and 2.34 million with 50% of smokers immediately switching to heat-not-burn products and 50% to e-cigarettes. In four Scenarios with a more gradual switch, the estimated decreases were 39,800–81,000 deaths and 0.50–1.05 million life-years, representing 17.5%–37.5% of the effect of immediate cessation in 1995. These estimates assume that switching to heat-not-burn products and e-cigarettes involves risk decreases of 80% and 95% of those from quitting, respectively. The reductions in mortality would be greater with more diseases and a wider age range considered or with a longer follow-up period, as the decreases increased markedly with time. Various limitations are discussed, none affecting the conclusion that introducing these new products into Germany in 1995 could have substantially reduced deaths and life-years lost. Conclusions Deaths from cigarette smoking could be substantially reduced not only by cessation but additionally by switching to reduced-risk products. Respective public health campaigns might increase such switching.

Summary Background We previously estimated the impact of introducing heat-not-burn products and e-cigarettes in Germany on smoking-related disease mortality in men and women aged 30–79 years between 1995 and 2015. Here, we estimate the impact by socioeconomic group. Methods Individuals with a defined baseline cigarette smoking distribution were followed under a “Null Scenario” (no reduced-risk products) and “Alternative Scenarios” (reduced-risk products introduced). Transition probabilities allowed estimation of annual product use changes, with individual product histories used to estimate reductions in deaths and life-years lost. Here, however, individuals were classified into two socioeconomic groups defined by income and education, with allowance for variation by group in initial smoking prevalence and the probability of changing product use, or of changing socioeconomic group. Results With no allowance for socioeconomic group, deaths would have reduced by 217,000 (from 852,000 for continued smoking) had everyone immediately ceased smoking in 1995 and by 40,000 to 179,000 had one or two types of reduced-risk products – the heat-not-burn product and the e-cigarette – been adopted by smokers to varying extents. With such allowance, we estimate substantial drops in each socioeconomic group. Where all cigarette smokers switched immediately, half of them to heat-not-burn products, half to e-cigarettes, the estimated drops in deaths were 60,000 in group A (higher socioeconomic group) and 122,000 in group B (lower), about 82% of the drops associated with immediate cessation (73,000 in A and 148,000 in B). With more gradual conversion, the drops were 26,648 in A and 53,000 in B, about 35% of those from cessation. The drops in deaths and life-years saved were about 2 and 1.5 times higher in group B, respectively, associated with its greater numbers, older age, and higher smoking prevalence. The estimated reductions would increase upon considering more diseases, a wider age range, or longer follow-up. Methodological limitations would not affect the conclusion that introducing these products in 1995 in Germany could have substantially reduced deaths and life-years lost in both groups, more so in B. Conclusions Although cessation is optimal for reducing mortality, switching to reduced-risk products also provides substantial health gains. A public health approach encouraging lower socioeconomic group smokers to switch to reduced-risk products could diminish smoking-related health inequalities relative to continued smoking.

Adobe PDF - MCT-06-0767--Suppl_Materials.pdf from 2-Methoxy antimycin reveals a unique mechanism for Bcl-xL inhibition

Overexpression of Bcl-xL in multiple cancers correlates with resistance to chemotherapy and radiation therapy, and provides a rationale for development of small-molecule Bcl-xL inhibitors. Based on knockout studies, nonneoplastic cells also require Bcl-xL survival functions, particularly when challenged with cytotoxic agents. We analyze the selective cytotoxicity of one Bcl-xL inhibitor, 2-methoxy antimycin A, toward cells with excess exogenous Bcl-xL in isogenic cell line pairs. This selectivity, characteristic of a gain-of-function mechanism, is not shared by other known Bcl-xL inhibitors, including BH3I-2, HA14-1, ABT-737, gossypol, or the stapled BH3 helical peptide SAHB-BID. We show that Bcl-xL overexpression induces a shift in energy metabolism from oxidative phosphorylation to glycolysis. Treatment with 2-methoxy antimycin A acutely reverses the metabolic effects of Bcl-xL, causing mitochondrial hyperpolarization and a progressive increase in mitochondrial NAD(P)H. We identify an additional small-molecule Bcl-xL inhibitor, NSC 310343, establishing a class of Bcl-xL inhibitors with gain-of-function activity. In contrast to other Bcl-xL inhibitors, combining gain-of-function Bcl-xL inhibitors with a standard inducer of apoptosis, staurosporine, enhances selective cytotoxicity toward Bcl-xL–overexpressing cells. These results provide an example of the intersection of bioenergetic metabolism and Bcl-xL functions and suggest a metabolic basis for the gain-of-function mechanism of Bcl-xL inhibitors. [Mol Cancer Ther 2007;6(7):2073–80]