Summary Prolonged fasting (PF) promotes stress resistance but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, four days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems; an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

The AKT2 gene is one of the human homologues of v-akt, the transduced oncogene of the AKT8 virus, which induces lymphomas in mice. In previous studies, AKT2, which codes for a serine-threonine protein kinase, was shown to be amplified and overexpressed in some human ovarian carcinoma cell lines and amplified in primary tumors of the ovary. To confirm and extend these findings, we conducted a large-scale, multicenter study of AKT2 alterations in ovarian and breast cancer. Southern-blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%) ovarian carcinomas and in 3 of 106 (2.8%) breast carcinomas. No AKT2 alteration was detected in 24 benign or borderline tumors. Northern-blot analysis revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which were negative for AKT2 amplification. The difference in the incidence of AKT2 alterations in ovarian and breast cancer suggests a specific role for this gene in ovarian oncogenesis. No significant association was found between AKT2 amplification and amplification of the proto-oncogenes MYC and ERBB2, suggesting that amplification of AKT2 defines an independent subset of breast and ovarian cancers. Ovarian cancer patients with AKT2 alterations appear to have a poor prognosis. Amplification of AKT2 was especially frequent in undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may be associated with tumor aggressiveness.

The unfolded protein response (UPR) is an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to endoplasmic reticulum (ER) stress. Although the UPR has been implicated in tumorigenesis, its precise role in endogenous cancer remains unclear. A major UPR protective response is the induction of the ER chaperone GRP78/BiP, which is expressed at high levels in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells. To determine the physiologic role of GRP78 in in situ-generated tumor and the consequence of its suppression on normal organs, we used a genetic model of breast cancer in the Grp78 heterozygous mice where GRP78 expression level was reduced by about half, mimicking anti-GRP78 agents that achieve partial suppression of GRP78 expression. Here, we report that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth. Our results reveal three major mechanisms mediated by GRP78 for cancer progression: enhancement of tumor cell proliferation, protection against apoptosis, and promotion of tumor angiogenesis. Importantly, although partial reduction of GRP78 in the Grp78 heterozygous mice substantially reduces the tumor microvessel density, it has no effect on vasculature of normal organs. Our findings establish that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis, underscoring its potential value as a novel therapeutic target for dual antitumor and antiangiogenesis activity. [Cancer Res 2008; 68(2):498-505]

Although ovarian epithelial tumors are widely believed to arise in the coelomic epithelium that covers the ovarian surface, it was also suggested that they could instead arise from tissues that are embryologically derived from the mullerian ducts. This article revisits this debate based on recent epidemiological and molecular biological observations as well as evidence based on histopathological observations of surgical specimens from individuals with familial ovarian cancer predisposition. Morphological, embryological, and molecular biological characteristics of ovarian epithelial tumors that must be accounted for in formulating a theory about their cell of origin are reviewed, followed by comments about the ability of these two hypotheses to account for each of these characteristics. An argument is made that primary ovarian epithelial tumors fallopian tube carcinomas, and primary peritoneal carcinomas are all mullerian in nature and could therefore be regarded as a single disease entity. Although a significant proportion of cancers presently regarded as of primary ovarian origin arise in the fimbriated end of the fallopian tube, this site cannot account for an equally significant proportion of these tumors, which are most likely derived from components of the secondary mullerian system.

The rise in childhood asthma prevalence suggests a role for environmental factors in the etiology of this evolving epidemic; however, genetics also influence the occurrence of asthma. Glutathione S-transferase (GST) M1 may play a role in asthma and wheezing occurrence among those exposed to tobacco smoke, as it functions in pathways involved in asthma pathogenesis such as xenobiotic metabolism and antioxidant defenses. Effects of GSTM1 genotype, maternal smoking during pregnancy, and childhood environmental tobacco smoke (ETS) exposure on asthma and wheezing were investigated in 2,950 children enrolled in 4th, 7th, and 10th grade classrooms in 12 Southern California communities. The effects of in utero exposure to maternal smoking on asthma and wheezing occurrence were largely restricted to children with GSTM1 null genotype. Among GSTM1 null children, in utero exposure was associated with increased prevalence of early onset asthma (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.0-2.5), asthma with current symptoms (OR 1.7, 95% CI 1.1-2.8), persistent asthma (OR 1.6, 95% CI 1.1-2.4), lifetime history of wheezing (OR 1.8, 95% CI 1.3-2.5), wheezing with exercise (OR 2.1, 95% CI 1.3-3.3), wheezing requiring medication (OR 2.2, 95% CI 1.4-3.4), and emergency room visits in the past year (OR 3.7, 95% CI 1.9-7.3). Among children with GSTM1 (+) genotype, in utero exposure was not associated with asthma or wheezing. Our findings indicate that there are important long-term effects of in utero exposure in a genetically susceptible group of children.