Evaluation of the use of the fourth version FloTrac system in cardiac output measurement before and after cardiopulmonary bypass.

The FloTrac system is a system for cardiac output (CO) measurement that is less invasive than the pulmonary artery catheter (PAC). The purposes of this study were to (1) compare the level of agreement and trending abilities of CO values measured using the fourth version of the FloTrac system (CCO-FloTrac) and PAC-originated continuous thermodilution (CCO-PAC) and (2) analyze the inadequate CO-discriminating ability of the FloTrac system before and after cardiopulmonary bypass (CPB). Fifty patients were included. After exclusion, 32 patients undergoing cardiac surgery with CPB were analyzed. All patients were monitored with a PAC and radial artery catheter connected to the FloTrac system. CO was assessed at 10 timing points during the surgery. In the Bland-Altman analysis, the percentage errors (bias, the limits of agreement) of the CCO-FloTrac were 61.82% (0.16, - 2.15 to 2.47 L min) and 51.80% (0.48, - 1.97 to 2.94 L min) before and after CPB, respectively, compared with CCO-PAC. The concordance rates in the four-quadrant plot were 64.10 and 62.16% and the angular concordance rates (angular mean bias, the radial limits of agreement) in the polar-plot analysis were 30.00% (17.62°, - 70.69° to 105.93°) and 38.63% (- 10.04°, - 96.73° to 76.30°) before and after CPB, respectively. The area under the receiver operating characteristic curve for CCO-FloTrac was 0.56, 0.52, 0.52, and 0.72 for all, ≥ ± 5, ≥ ± 10, and ≥ ± 15% CO changes (ΔCO) of CCO-PAC before CPB, respectively, and 0.59, 0.55, 0.49, and 0.46 for all, ≥ ± 5, ≥ ± 10, and ≥ ± 15% ΔCO of CCO-PAC after CPB, respectively. When CO < 4 L/min was considered inadequate, the Cohen κ coefficient was 0.355 and 0.373 before and after CPB, respectively. The accuracy, trending ability, and inadequate CO-discriminating ability of the fourth version of the FloTrac system in CO monitoring are not statistically acceptable in cardiac surgery.

Inferring condition-specific targets of human TF-TF complexes using ChIP-seq data.

BACKGROUND: Transcription factors (TFs) often interact with one another to form TF complexes that bind DNA and regulate gene expression. Many databases are created to describe known TF complexes identified by either mammalian two-hybrid experiments or data mining. Lately, a wealth of ChIP-seq data on human TFs under different experiment conditions are available, making it possible to investigate condition-specific (cell type and/or physiologic state) TF complexes and their target genes. RESULTS: Here, we developed a systematic pipeline to infer Condition-Specific Targets of human TF-TF complexes (called the CST pipeline) by integrating ChIP-seq data and TF motifs. In total, we predicted 2,392 TF complexes and 13,504 high-confidence or 127,994 low-confidence regulatory interactions amongst TF complexes and their target genes. We validated our predictions by (i) comparing predicted TF complexes to external TF complex databases, (ii) validating selected target genes of TF complexes using ChIP-qPCR and RT-PCR experiments, and (iii) analysing target genes of select TF complexes using gene ontology enrichment to demonstrate the accuracy of our work. Finally, the predicted results above were integrated and employed to construct a CST database. CONCLUSIONS: We built up a methodology to construct the CST database, which contributes to the analysis of transcriptional regulation and the identification of novel TF-TF complex formation in a certain condition. This database also allows users to visualize condition-specific TF regulatory networks through a user-friendly web interface.

Long-COVID impacts taste and olfactory in individuals with substance use disorder: A retrospective cohort study from the TriNetX US Collaborative Networks.

Substance use disorder (SUD) exacerbates the impact of Long-COVID, particularly increasing the risk of taste and olfactory disorders. Analyzing retrospective cohort data from TriNetX and over 33 million records (Jan 2020-Dec 2022), this study focused on 1,512,358 participants, revealing that SUD significantly heightens the likelihood of experiencing taste disturbances and anosmia in Long-COVID sufferers. Results indicated that individuals with SUD face a higher incidence of sensory impairments compared to controls, with older adults and women being particularly vulnerable. Smokers with SUD were found to have an increased risk of olfactory and taste dysfunctions. The findings underscore the importance of early screening, diagnosis, and interventions for Long-COVID patients with a history of SUD, suggesting a need for clinicians to monitor for depression and anxiety linked to sensory dysfunction for comprehensive care.

HLJ1 is a novel caspase-3 substrate and its expression enhances UV-induced apoptosis in non-small cell lung carcinoma.

Carcinogenesis is determined based on both cell proliferation and death rates. Recent studies demonstrate that heat shock proteins (HSPs) regulate apoptosis. HLJ1, a member of the DnaJ-like Hsp40 family, is a newly identified tumor suppressor protein closely related to relapse and survival in non-small cell lung cancer (NSCLC) patients. However, its role in apoptosis is currently unknown. In this study, NSCLC cell lines displaying varying HLJ1 expression levels were subjected to ultraviolet (UV) irradiation, followed by flow cytometry. Interestingly, the percentages of apoptotic cells in the seven cell lines examined were positively correlated with HLJ1 expression. Enforcing expression of HLJ1 in low-HLJ1 expressing highly invasive cells promoted UV-induced apoptosis through enhancing JNK and caspase-3 activation in NSCLC. Additionally, UV irradiation led to reduced levels of HLJ1 predominantly in apoptotic cells. The pan-caspase inhibitor, zVAD-fmk and caspase-3-specific inhibitor, DEVD-fmk, prevented UV-induced degradation of HLJ1 by the late stage of apoptosis. Further experiments revealed a non-typical caspase-3 cleavage site (MEID) at amino acid 125-128 of HLJ1. Our results collectively suggest that HLJ1 is a novel substrate of caspase-3 during the UV-induced apoptotic process.

Mitochondrial activity is the key to the protective effect of ß-Lapachone, a NAD+ booster, in healthy cells against cisplatin cytotoxicity.

BACKGROUND: Cisplatin (CDDP) is a first-line chemotherapeutic drug for treating various cancers. However, CDDP also damages normal cells and causes many side effects. Recently, CDDP has been demonstrated to kill cancer cells by targeting mitochondria. Protecting mitochondria might be a potential therapeutic strategy for CDDP-induced side effects. ß-Lapachone (ß-lap), a recognized NAD+ booster, has been reported to regulate mitochondrial activity. However, it remains unclear whether maintaining mitochondrial activity is the key factor in the protective effects of ß-lap in CDDP-treated normal cells. PURPOSE: In this study, the protective effects of ß-lap on mitochondria against CDDP cytotoxicity in normal cells were evaluated. STUDY DESIGN: In vitro cell models were used in this study, including 3T3 fibroblasts, human dermal fibroblasts, MCF-7 breast cancer cells, and MDA-MB-231 breast cancer cells. METHODS: Cells were treated with CDDP and ß-lap, and cell survival, NAD+, mitochondrial activity, autophagy, and ATP production were measured. Various inhibitors and siRNAs were used to confirm the key signal underlying the protective effects of ß-lap. RESULTS: The results demonstrated that ß-lap significantly decreased CDDP cytotoxicity in normal fibroblasts. With various inhibitors and siRNAs, ß-lap reduced CDDP-induced damage to normal fibroblasts by maintaining mitochondrial activity and increasing autophagy through the NQO1/NAD+/SIRT1 axis. Most importantly, the protective effects of ß-lap in fibroblasts did not affect the therapeutic effects of CDDP in cancer cells. This study indicated that mitochondrial activity, energy production, and NQO1 levels might be crucial responses separating normal cells from cancer cells under exposure to CDDP and ß-lap. CONCLUSION: ß-lap could be a good synergistic drug for reducing the side effects of CDDP without affecting the anticancer drug effect.

Acidic stress facilitates tyrosine phosphorylation of HLJ1 to associate with actin cytoskeleton in lung cancer cells.

Acidosis is a common stress in solid tumours and is also a major determinant of tumour growth, metabolism, and metastasis. During cellular stress, heat shock proteins play an important role in actin cytoskeleton stability. HLJ1, a member of the DnaJ-like heat shock protein 40, has been characterised as a tumour suppressor gene; however, the effect of acidic stress on HLJ1 is unknown. In this study, we found that the migration ability of human lung adenocarcinoma cells was significantly impaired following the increased protein level of HLJ1 under acidic culture conditions. However, HLJ1 transcriptional activity was no different in the normal and acidic culture medium. Incubation of the cells in an acidic extracellular pH (pHe 6.4) caused up-regulated tyrosine phosphorylation of HLJ1 within 2h. We further identified the sub-cellular distribution of tyrosine phospho-HLJ1 and its tyrosine-phosphorylated sites. Most importantly, acidic stress was observed to remarkably enhance the interaction between HLJ1 and ß-actin, which was a tyrosine phosphorylation-dependent association. In conclusion, our results not only validate that HLJ1 is a tyrosine phosphoprotein, but also suggest that the increased level of tyrosine phospho-HLJ1 is crucial for binding with the actin cytoskeleton, especially in acidic pHe. We propose that acidic stress increases the association between HLJ1 and ß-actin to modulate migration of human lung cancer cells.

Paired-like homeodomain 2B contributes to tumour progression and anti-autophagy in human lung cancer.

Paired-like homeodomain transcription factor 2 (PITX2) is well known to play an essential role in normal embryonic development. Emerging evidence suggests that PITX2 may be involved in human tumorigenesis, but the role of PITX2 in tumour progression remains largely unclear. The expression levels of PITX2 in lung cancer cells were determined by qRT-PCR and Western blot analyses. Gain- and loss-of-function experiments were conducted to investigate the biological roles of PITX2 in the phenotype of lung cancer cells. Immunofluorescence staining and transmission electron microscopy were used to observe autophagy. The expression level and clinical significance of PITX2 were determined in a Taiwanese cohort and the Gene Expression Omnibus (GEO) database, respectively. Here, we show that PITX2B is the most abundant isoform of the bicoid homeodomain family in lung cancer cells. The enforced expression of PITX2B promoted lung cancer tumorigenesis and progression in vitro and in vivo. The mechanistic analysis revealed that the nuclear localization of PITX2B is correlated with its oncogenic functions and two important nuclear localization signals. In addition, PITX2B knockdown in lung cancer cells caused a marked increase in autophagy and apoptosis, suggesting that PITX2B plays an important role in lung cancer cell survival. Moreover, a high expression of PITX2B was associated with a poor overall survival (P<0.05) in both Taiwanese non-small-cell lung cancer patients and GEO lung cancer cohorts. These results provide new insight into the contribution of PITX2B to lung cancer progression, implicate PITX2B as an important component of cell survival signals and further establish PITX2B as a therapeutic target for lung cancer treatment.

Increased FIO2 influences SvO2 interpretation and accuracy of Fick-based cardiac output assessment in cardiac surgery patients: A prospective randomized study.

INTRODUCTION: The study aimed to reveal how the fraction of inspired oxygen (FIO2) affected the value of mixed venous oxygen saturation (SvO2) and the accuracy of Fick-equation-based cardiac output (Fick-CO). METHODS: Forty two adult patients who underwent elective cardiac surgery were enrolled and randomly divided into 2 groups: FIO2 < 0.7 or >0.85. Under stable general anesthesia, thermodilution-derived cardiac output (TD-CO), SvO2, venous partial pressure of oxygen, hemoglobin, arterial oxygen saturation, arterial partial pressure of oxygen, and blood pH levels were recorded before surgical incision. RESULTS: Significant differences in FIO2 values were observed between the 2 groups (0.56 ±â€Š0.08 in the <70% group and 0.92 ±â€Š0.03 in the >0.85 group; P < .001). The increasing FIO2 values lead to increases in SvO2, venous partial pressure of oxygen, and arterial partial pressure of oxygen, with little effects on cardiac output and hemoglobin levels. When comparing to TD-CO, the calculated Fick-CO in both groups had moderate Pearson correlations and similar linear regression results. Although the FIO2 <0.7 group presented a less mean bias and a smaller limits of agreement, neither group met the percentage error criteria of <30% in Bland-Altman analysis. CONCLUSION: Increased FIO2 may influence the interpretation of SvO2 and the exacerbation of Fick-CO estimation, which could affect clinical management. TRIAL REGISTRATION: ClinicalTrials.gov ID number: NCT04265924, retrospectively registered (Date of registration: February 9, 2020).

pLG72 induces superoxide radicals via interaction and aggregation with SOD1.

G72 has been characterised as a susceptibility gene that can have wide-ranging effects in a number of neurodegenerative diseases, including schizophrenia and major depression. Indeed, its product, pLG72, is a potential serum biomarker for schizophrenia. Previous transcriptomic and biochemical studies have indicated that pLG72 may induce the production of mitochondrial reactive oxygen species (ROS), resulting in cell damage. Here, we investigated the mechanism of pLG72 by transfecting a human U87 glioblastoma cell line with a G72 construct. By employing ROS-specific scavengers, we discovered that superoxide radicals were specifically induced in the pLG72-expressing cells. We also found that pLG72 interacted and co-localised with superoxide dismutase 1 (SOD1), resulting in aggregation of SOD1 with a concomitant 23% or 74% reduction of total SOD activity, depending on the amount of G72 transfection plasmid. Finally, we found that transfection of U87 cells with the G72 construct caused a 29% decrease in cell proliferation. The observed loss of SOD1 function in pLG72-expressing cells may explain the elevated ROS levels and inhibition of U87 cell proliferation and has implications for understanding the onset of neurodegenerative diseases in humans.

Phosphatase of regenerating liver-3 inhibits invasiveness and proliferation in non-small cell lung cancer by regulating the epithelial-mesenchymal transition.

Phosphatase of regenerating liver-3 (PRL-3) has been reported to be associated with colon and gastric cancer metastasis. However, the role and function of PRL-3 in human non-small cell lung cancer cells is unknown. Our studies showed that the expression of PRL-3mRNA and protein are higher in less invasive human lung adenocarcinoma cells than in highly invasive cell lines. Ectopic expression of PRL-3 reduced cell capacity for anchorage-dependent growth, anchorage-independent growth, migration, and invasion in vitro, as well as tumorigenesis in vivo. Conversely, catalytic (C104S) and prenylation-site (C170S) mutants enhanced cell invasion. Microarray profiling of PRL-3 transfectants revealed the pathways potentially involving PRL-3, including the epithelial-mesenchymal transition (EMT), extracellular matrix remodeling, and the WNT signaling pathway. Furthermore, we demonstrated that increased PRL-3 reduced Slug and enhanced E-cadherin gene expression through the AKT/GSK3ß/ß-catenin pathway. In conclusion, our data suggest that PRL-3 might play a tumor suppressor role in lung cancer, distinct from other cancers, by inhibiting EMT-related pathways.

Digoxin Suppresses Tumor Malignancy through Inhibiting Multiple Src-Related Signaling Pathways in Non-Small Cell Lung Cancer.

Non-small cell lung cancer is the predominant type of lung cancer, resulting in high mortality worldwide. Digoxin, a cardiac glycoside, has recently been suggested to be a novel chemotherapeutic agent. Src is an oncogene that plays an important role in cancer progression and is therefore a potential target for cancer therapy. Here, we investigated whether digoxin could suppress lung cancer progression through the inhibition of Src activity. The effects of digoxin on lung cancer cell functions were investigated using colony formation, migration and invasion assays. Western blotting and qPCR assays were used to analyze the mRNA and protein expression levels of Src and its downstream proteins, and a cell viability assay was used to measure cellular cytotoxicity effects. The results of the cell function assays revealed that digoxin inhibited the proliferation, invasion, migration, and colony formation of A549 lung cancer cells. Similar effects of digoxin were also observed in other lung cancer cell lines. Furthermore, we found that digoxin significantly suppressed Src activity and its protein expression in a dose- and time-dependent manner as well as reduced EGFR and STAT3 activity. Our data suggest that digoxin is a potential anticancer agent that may suppress lung cancer progression through inhibiting Src and the activity of related proteins.

Rhodomycin A, a novel Src-targeted compound, can suppress lung cancer cell progression via modulating Src-related pathways.

Src activation is involved in cancer progression and the interplay with EGFR. Inhibition of Src activity also represses the signalling pathways regulated by EGFR. Therefore, Src has been considered a target molecule for drug development. This study aimed to identify the compounds that target Src to suppress lung cancer tumourigenesis and metastasis and investigate their underlying molecular mechanisms. Using a molecular docking approach and the National Cancer Institute (NCI) compound dataset, eight candidate compounds were selected, and we evaluated their efficacy. Among them, rhodomycin A was the most efficient at reducing the activity and expression of Src in a dose-dependent manner, which was also the case for Src-associated proteins, including EGFR, STAT3, and FAK. Furthermore, rhodomycin A significantly suppressed cancer cell proliferation, migration, invasion, and clonogenicity in vitro and tumour growth in vivo. In addition, rhodomycin A rendered gefitinib-resistant lung adenocarcinoma cells more sensitive to gefitinib treatment, implying a synergistic effect of the combination therapy. Our data also reveal that the inhibitory effect of rhodomycin A on lung cancer progression may act through suppressing the Src-related multiple signalling pathways, including PI3K, JNK, Paxillin, and p130cas. These findings will assist the development of anti-tumour drugs to treat lung cancer.

The location and translocation of ndh genes of chloroplast origin in the Orchidaceae family.

The NAD(P)H dehydrogenase complex is encoded by 11 ndh genes in plant chloroplast (cp) genomes. However, ndh genes are truncated or deleted in some autotrophic Epidendroideae orchid cp genomes. To determine the evolutionary timing of the gene deletions and the genomic locations of the various ndh genes in orchids, the cp genomes of Vanilla planifolia, Paphiopedilum armeniacum, Paphiopedilum niveum, Cypripedium formosanum, Habenaria longidenticulata, Goodyera fumata and Masdevallia picturata were sequenced; these genomes represent Vanilloideae, Cypripedioideae, Orchidoideae and Epidendroideae subfamilies. Four orchid cp genome sequences were found to contain a complete set of ndh genes. In other genomes, ndh deletions did not correlate to known taxonomic or evolutionary relationships and deletions occurred independently after the orchid family split into different subfamilies. In orchids lacking cp encoded ndh genes, non cp localized ndh sequences were identified. In Erycina pusilla, at least 10 truncated ndh gene fragments were found transferred to the mitochondrial (mt) genome. The phenomenon of orchid ndh transfer to the mt genome existed in ndh-deleted orchids and also in ndh containing species.

Molecular mechanisms of ZD1839-induced G1-cell cycle arrest and apoptosis in human lung adenocarcinoma A549 cells.

Epithelial growth factor receptor (EGFR) has been proposed as a target for anticancer therapy. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is under clinical use in cancer patients. However, the molecular mechanisms involved in ZD1839-mediated anticancer effects remain largely uncharacterized. In this study, exposure of human lung adenocarcinoma A549 cells to ZD1839 caused G1 arrest, and subsequently induced apoptosis. Moreover, ZD1839 increased the protein levels of p27(KIP1) and retinoblastoma-related Rb2/p130 while decreased the expression of cyclin-dependent kinase-2 (CDK2), CDK4, CDK6 and cyclin-D1, cyclin-D3. In vitro kinase assay showed that ZD1839 decreased these CDKs expression in A549 cells, leading to significantly reduce their kinase activities. In addition, ZD1839-induced death of A549 cells with characteristics of apoptosis including apoptotic morphological changes, DNA fragmentation and enhancement of TUNEL-positive cell. These events were accompanied by a marked increase of Fas protein expression, and activation of caspase-2, -3, -8. Co-treatment of cells with Fas antagonist antibody significantly blocked ZD1839-induced apoptosis. Caspase-8 and caspase-3 inhibitors, but not a caspase-9 inhibitor, were also capable of restoring cell viability. Our results indicate that downregulation of the expression and function of CDK2, CDK4, CDK6, cyclin-D1 and cyclin-D3, as well as upregulation of p27(KIP1) and pRb2/p130, are strong candidates for the cell cycle regulator that arrests ZD1839-treated A549 cells at G1 phase. Furthermore, upregulation of Fas appears to play a major role in the initiation of ZD1839-induced apoptosis, activation of caspase-8/caspase-3 cascade is involved in the execution phase of this death program.

Draft Genome Sequence of the Serratia marcescens Strain VGH107, a Taiwanese Clinical Isolate.

Serratia marcescens, a member of the family Enterobacteriaceae, is the causative agent of various types of wound infections. We report a high-quality draft genome sequence of S. marcescens strain VGH107, which was isolated from a patient with an infection from a snakebite wound.

Dimethyl sulfoxide promotes the multiple functions of the tumor suppressor HLJ1 through activator protein-1 activation in NSCLC cells.

BACKGROUND: Dimethyl sulfoxide (DMSO) is an amphipathic molecule that displays a diversity of antitumor activities. Previous studies have demonstrated that DMSO can modulate AP-1 activity and lead to cell cycle arrest at the G1 phase. HLJ1 is a newly identified tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. Its transcriptional activity is regulated by the transcription factor AP-1. However, the effects of DMSO on HLJ1 are still unknown. In the present study, we investigate the antitumor effects of DMSO through HLJ1 induction and demonstrate the mechanisms involved. METHODS AND FINDINGS: Low-HLJ1-expressing highly invasive CL1-5 lung adenocarcinoma cells were treated with various concentrations of DMSO. We found that DMSO can significantly inhibit cancer cell invasion, migration, proliferation, and colony formation capabilities through upregulation of HLJ1 in a concentration-dependent manner, whereas ethanol has no effect. In addition, the HLJ1 promoter and enhancer reporter assay revealed that DMSO transcriptionally upregulates HLJ1 expression through an AP-1 site within the HLJ1 enhancer. The AP-1 subfamily members JunD and JunB were significantly upregulated by DMSO in a concentration-dependent manner. Furthermore, pretreatment with DMSO led to a significant increase in the percentage of UV-induced apoptotic cells. CONCLUSIONS: Our results suggest that DMSO may be an important stimulator of the tumor suppressor protein HLJ1 through AP-1 activation in highly invasive lung adenocarcinoma cells. Targeted induction of HLJ1 represents a promising approach for cancer therapy, which also implied that DMSO may serve as a potential lead compound or coordinated ligand for the development of novel anticancer drugs.

Tumor suppressor HLJ1 binds and functionally alters nucleophosmin via activating enhancer binding protein 2alpha complex formation.

HLJ1, a member of the heat shock protein 40 chaperone family, is a newly identified tumor suppressor that has been implicated in tumorigenesis and metastasis in non-small cell lung cancer. However, the mechanism of HLJ1 action is presently obscure. In this study, we report that HLJ1 specifically interacts with the nuclear protein nucleophosmin (NPM1), forming a multiprotein complex that alters the nucleolar distribution and oligomerization state of NPM1. Enforced accumulation of NPM1 oligomers by overexpression in weakly invasive but high HLJ1-expressing cells induced the activity of signal transducer and activator of transcription 3 (STAT3) and increased cellular migration, invasiveness, and colony formation. Furthermore, silencing HLJ1 accelerated NPM1 oligomerization, inhibited the activity of transcription corepressor activating enhancer binding protein 2alpha (AP-2alpha), and increased the activities of matrix metalloproteinase-2 (MMP-2) and STAT3. Our findings suggest that HLJ1 switches the role of NPM1, which can act as tumor suppressor or oncogene, by modulating the oligomerization of NPM1 via HLJ1-NPM1 heterodimer formation and recruiting AP-2alpha to the MMP-2 promoter.

Inhibition of poly(ADP-ribose) polymerase activation attenuates beta-lapachone-induced necrotic cell death in human osteosarcoma cells.

beta-Lapachone, a novel anticancer drug, induces various human carcinoma cells to undergo apoptotic cell death. However, we report here that, in human osteocarcinoma (U2-OS) cells, beta-lapachone induces necrosis rather than apoptosis. beta-Lapachone-induced necrotic cell death in U2-OS cells was characterized by propidium iodide uptake, cytochrome c release, a decreased mitochondrial membrane potential, and ATP depletion. The mitochondrial potential transition (MPT), including the reduction of the mitochondrial transmembrane potential and the release of mitochondrial cytochrome c, occurred in beta-lapachone-treated cells; cotreatment of these cells with cyclosporin A, an inhibitor of MPT pore, failed to prevent necrotic cell death. This indicates that the MPT transition does not play a crucial role in this process. Furthermore, beta-lapachone-induced necrosis was independent of oxidative stress and caspase activation. However, excessive poly(ADP-ribose) polymerase (PARP) activation and subsequent depletion of intracellular NAD(+) and ATP were seen in beta-lapachone-treated U2-OS cells. Cotreatment with a PARP inhibitor, 3-aminobenzamide, decreased beta-lapachone-induced PARP activation and provided significant protection from necrosis by preventing depletion of intracellular NAD(+) and ATP. Taken together, our results suggest that PARP plays an important role in the signaling pathway for beta-lapachone-induced necrosis in U2-OS cells.