Cytochrome c release and the mitochondrial permeability transition (PT), including loss of the transmembrane potential (⌬), play an important role in apoptosis. Using isolated mitochondria, we found that recombinant Bax and Bak, proapoptotic members of the Bcl-2 family, induced mitochondrial ⌬ loss, swelling, and cytochrome c release. All of these changes were dependent on Ca 2؉ and were prevented by cyclosporin A (CsA) and bongkrekic acid, both of which close the PT pores (megachannels), indicating that Bax-and Bak-induced mitochondrial changes were mediated through the opening of these pores. Bax-induced mitochondrial changes were inhibited by recombinant Bcl-x L and transgenederived Bcl-2, antiapoptotic members of the Bcl-2 family, as well as by oligomycin, suggesting a possible regulatory effect of F 0 F 1 -ATPase on Bax-induced mitochondrial changes. Proapoptotic Bax-and Bak-BH3 (Bcl-2 homology) peptides, but not a mutant BH3 peptide nor a mutant Bak lacking BH3, induced the mitochondrial changes, indicating an essential role of the BH3 region. A coimmunoprecipitation study revealed that Bax and Bak interacted with the voltage-dependent anion channel, which is a component of PT pores. Taken together, these findings suggest that proapoptotic Bcl-2 family proteins, including Bax and Bak, induce the mitochondrial PT and cytochrome c release by interacting with the PT pores.

BACKGROUNDAlthough the histologic classification of thymic epithelial tumors has been confusing and controversial, an agreement on the universal classification system for thymic epithelial tumors was achieved by the World Health Organization (WHO) in 1999. The authors previously reported that the WHO histologic classification system reflects invasiveness and immunologic function of thymic epithelial tumors. In this subsequent study, they examined the prognostic significance of this classification system.METHODSClinical features as well as postoperative survival of patients with thymoma, but not thymic carcinoma, were examined with reference to WHO histologic classification based on an experience with 273 patients over a 44‐year period.RESULTSThere were 18 type A tumors, 77 type AB tumors, 55 type B1 tumors, 97 type B2 tumors, and 26 type B3 tumors. In patients with type A, AB, B1, B2, and B3 tumors, the respective proportions of invasive tumor were 11.1%, 41.6%, 47.3%, 69.1%, and 84.6%; the respective proportions of tumors with involvement of the great vessels were 0%, 3.9%, 7.3%, 17.5%, and 19.2%; and the respective 20‐year survival rates were 100%, 87%, 91%, 59%, and 36%. According to the Masaoka staging system, the 20‐year survival rates were 89%, 91%, 49%, 0%, and 0% in patients with Stage I, II, III, IVa, and IVb disease, respectively. By multivariate analysis, the Masaoka staging system and the WHO histologic classification system were significant independent prognostic factors, whereas age, gender, association with myasthenia gravis, completeness of resection, or involvement of the great vessels were not significant independent prognostic factors.CONCLUSIONSThis study showed that histologic appearance reflects the oncologic behavior of thymoma when the WHO classification system is adopted. The WHO classification system may be helpful in clinical practice for the assessment and treatment of patients with thymoma. Cancer 2002;94:624–32. © 2002 American Cancer Society.DOI 10.1002/cncr.10225

The proto-oncogene bcl-2, isolated from the t(14;18) chromosomal breakpoint in follicular B-lymphoma, and a bcl-2-related gene bcl-x (ref. 4) prevent apoptotic cell death induced by various treatments. Although a mechanism has been proposed that involves Bcl-2 activity on reactive oxygen species (ROS), expression of Bcl-2 or Bcl-xL prevents cell death induced by withdrawal of oxygen (hypoxia), which drastically decreases the net formation of oxygen free radicals and does not increase oxidized lipid, protein or DNA. Furthermore, neither ROS scavenger nor inhibitor of ROS scavenger affects cell death, regardless of the expression of Bcl-2 or Bcl-xL. Thus our data suggest that Bcl-2 and Bcl-xL exert an anti-cell death function by a mechanism other than regulation of ROS activity.

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We and others have recently shown that loss of the mitochondrial membrane potential (⌬) precedes apoptosis and chemical-hypoxia-induced necrosis and is prevented by Bcl-2. In this report, we examine the biochemical mechanism used by Bcl-2 to prevent ⌬ loss, as determined with mitochondria isolated from a cell line overexpressing human Bcl-2 or from livers of Bcl-2 transgenic mice. Although Bcl-2 had no effect on the respiration rate of isolated mitochondria, it prevented both ⌬ loss and the permeability transition (PT) induced by various reagents, including Ca 2؉ , H 2 O 2 , and tert-butyl hydroperoxide. Even under conditions that did not allow PT, Bcl-2 maintained ⌬, suggesting that the functional target of Bcl-2 is regulation of ⌬ but not PT. Bcl-2 also maintained ⌬ in the presence of the protonophore SF6847, which induces proton inf lux, suggesting that Bcl-2 regulates ion transport to maintain ⌬. Although treatment with SF6847 in the absence of Ca 2؉ caused massive H ؉ inf lux in control mitochondria, the presence of Bcl-2 induced H ؉ eff lux after transient H ؉ inf lux. In this case, Bcl-2 did not enhance K ؉ eff lux. Furthermore, Bcl-2 enhanced H ؉ eff lux but not K ؉ f lux after treatment of mitochondria with Ca 2؉ or tert-butyl hydroperoxide. These results suggest that Bcl-2 maintains ⌬ by enhancing H ؉ eff lux in the presence of ⌬-loss-inducing stimuli.

Myoblast sheets repaired the impaired myocardium, reduced fibrosis, and prevented remodeling in association with recruitment of hematopoietic stem cells through the release of stromal-derived factor 1 and other growth factors. Our experiment indicates a therapy for patients with severe heart failure.

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