The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases1. As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis2,3. Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of mitochondrial malic enzyme-deficient cells revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 (branched chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched chain amino acids to α-ketoglutarate (α–KG)4thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime ‘collateral lethality’ therapeutic strategy for the treatment of a substantial fraction of patients suffering from this intractable disease.

Ferroptosis is a type of iron-dependent regulated necrosis induced by lipid peroxidation that occurs in cellular membranes. Among the various lipids, polyunsaturated fatty acids (PUFAs) associated with several phospholipids, such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC), are responsible for ferroptosis-inducing lipid peroxidation. Since the de novo synthesis of PUFAs is strongly restricted in mammals, cells take up essential fatty acids from the blood and lymph to produce a variety of PUFAs via PUFA biosynthesis pathways. Free PUFAs can be incorporated into the cellular membrane by several enzymes, such as ACLS4 and LPCAT3, and undergo lipid peroxidation through enzymatic and non-enzymatic mechanisms. These pathways are tightly regulated by various metabolic and signaling pathways. In this review, we summarize our current knowledge of how various lipid metabolic pathways are associated with lipid peroxidation and ferroptosis. Our review will provide insight into treatment strategies for ferroptosis-related diseases.

This study examined the effectiveness of self-assessment among 254 young learners of English as a foreign language. This study looked at 6th grade students in South Korea, who were asked to perform self-assessments on a regular basis for a semester during their English classes. The students improved their ability to self-assess their performance over time. A series of quantitative analyses found some positive effects of self-assessment on the students' English performance as well as their confidence in learning English, though the effect sizes were rather small. The study also found that teachers and students perceived the effectiveness of self-assessment differently depending on their teaching/learning contexts. Individual teachers' views towards assessment also influenced their perceived effectiveness in implementing the new self-assessment practice. A number of interesting insights were discovered through interviews with teachers regarding how best to implement self-assessment as part of foreign language instruction in contexts where teacher-centered teaching and measurement-driven assessment have been traditionally valued.

Rationale: Bone marrow (BM) cells play an important role in physiological and therapeutic neovascularization.However, it remains unclear whether any specific uncultured BM cell populations have higher angiogenic and vasculogenic activities. Moreover, there has been controversy regarding the vasculogenic ability of BM cells.Objective: Preliminary flow cytometric analysis showed that CD31, traditionally a marker for endothelial cells, is expressed in certain nonendothelial BM mononuclear cells in both human and mouse. Based on the conserved CD31 expression in the axis of hematopoietic stem/progenitor cells (HSC/HPCs) to endothelial cells, we further sought to determine the comprehensive vasculogenic and angiogenic characteristics of human and mouse BM-derived CD31 ؉ cells. Methods and Results: Flow cytometric analysis demonstrated that all CD31؉ cells derived from BM were CD45 ؉ and expressed markers for both HSC/HPCs and endothelial cells. Comprehensive gene expression analyses revealed that BM-CD31؉ cells expressed higher levels of angiogenic genes than CD31 ؊ cells. Endothelial progenitor cells, as well as HSC/HPCs, were almost exclusively confined to the CD31 ؉ cell fraction, and culture of CD31؉ cells under defined conditions gave rise to endothelial cells. Finally, injection of CD31 ؉ cells into ischemic hindlimb repaired ischemia, increased expression of angiogenic and chemoattractive factors, and, in part, directly contributed to vasculogenesis, as demonstrated by both 3D confocal microscopy and flow cytometry. Conclusions: These data indicate that BM-CD31؉ cells represent highly angiogenic and vasculogenic cells and can be a novel and highly promising source of cells for cell therapy to treat ischemic cardiovascular diseases. (Circ Res. 2010;107:602-614.) Key Words: bone marrow Ⅲ CD31 (PECAM-1) angiogenesis Ⅲ vasculogenesis Ⅲ peripheral vascular disease F ormation of new blood vessels (neovascularization) consists of 2 processes, vasculogenesis and angiogenesis. Vasculogenesis refers to the de novo development of blood vessels from endothelial progenitor cells (EPCs) or angioblasts which differentiate into endothelial cells (ECs). In contrast, angiogenesis is the formation of new vasculature from preexisting blood vessels through proliferation, migration, and remodeling of differentiated ECs. The identification of circulating EPCs in adult vertebrates suggested a role for BM cells in postnatal vasculogenesis, 1-3 and led to trials of BM cells for therapy for ischemic cardiovascular diseases.However, conflicting results from recent clinical trials 4,5 suggests a need for the discovery of new cell types 6 and more thorough investigation of the therapeutic mechanisms.Two of the most important questions in current EPC biology are whether the reported cultured EPCs or similar BM cells have true vasculogenic potential and whether a specific marker can prospectively identify true EPCs or vasculogenic cells. The endothelial differentiation or vasculogenic potential of early EPCs has been questioned. 7,3,8 -11 ...

Background-Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence suggested that diabetic neuropathy is causally related to impaired angiogenesis and deficient growth factors. Accordingly, we investigated whether diabetic neuropathy could be reversed by local transplantation of EPCs. Methods and Results-We found that motor and sensory nerve conduction velocities, blood flow, and capillary density were reduced in sciatic nerves of streptozotocin-induced diabetic mice but recovered to normal levels after hind-limb injection of bone marrow-derived EPCs. Injected EPCs were preferentially and durably engrafted in the sciatic nerves.A portion of engrafted EPCs were uniquely localized in close proximity to vasa nervorum, and a smaller portion of these EPCs were colocalized with endothelial cells. Multiple angiogenic and neurotrophic factors were significantly increased in the EPC-injected nerves. These dual angiogenic and neurotrophic effects of EPCs were confirmed by higher proliferation of Schwann cells and endothelial cells cultured in EPC-conditioned media. Conclusions-We demonstrate for the first time that bone marrow-derived EPCs could reverse various manifestations of diabetic neuropathy. These therapeutic effects were mediated by direct augmentation of neovascularization in peripheral nerves through long-term and preferential engraftment of EPCs in nerves and particularly vasa nervorum and their paracrine effects. These findings suggest that EPC transplantation could represent an innovative therapeutic option for treating diabetic neuropathy. Key Words: angiogenesis Ⅲ diabetes mellitus Ⅲ progenitor cells Ⅲ diabetic neuropathy P eripheral neuropathy is the most common complication of diabetes mellitus, affecting up to 60% of diabetic patients. 1 Loss of sensation in the feet, the most frequent manifestation of diabetic neuropathy (DN), frequently leads to foot ulcers and may progress into amputation of the limb. 2,3 Despite a continuous increase in the incidence of diabetes mellitus and DN, current treatments have yet to effectively treat DN. Our group reported that experimental DN is characterized by reduced microcirculation in peripheral nerves caused by the destruction of the vasa nervorum and thus administration of angiogenic factors such as vascular endothelial growth factors (VEGFs), sonic hedgehog (SHh), and statin could restore neural function by augmenting angiogenesis. 4 -6 In addition, deficiency of neurotrophic factors is regarded as one of the most plausible mechanisms underlying DN. 7 Alterations of nerve growth factor, ciliary neurotrophic factor, glial-derived neurotrophic factor, and brain-derived neurotrophic factor have been reported. 8 -12 However, in clinical trials, single neurotrophic cytokines turned out to be ineffective for treating DN. 13 Recently, many classic angiogenic factors were shown to possess neurotrophic activities and vice versa. VEGF, [14][15][16]17,18 Received April 29, 2008; accepted November 28, 2008. Cli...