82) and stool content at 48 h, increasing the odds for DD over STC (OR per 5% in stool 2.4, 95% CI 1.1 to 5.5, p=0.03).\n\nConclusions DD is associated with delayed overall colonic transit at 48 h and AC t(1/2) compared with healthy controls. Regional scintigraphic transit profiles differentiate DD from STC and facilitate identification of a subgroup of patients with constipation.”
“Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid syndrome, characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of the present study were (i) detection of NKX2-1 mutations Screening Library in patients with CH associated with pneumopathy

and/or BHC, (ii) functional analysis of new mutations in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid syndrome. We identified three new heterozygous missense mutations (L176V, P202L, Q210P), ML323 clinical trial a splice site mutation (376-2A -> G), and one deletion of NKX2-1 at 14q13. Functional analysis of the three missense mutations revealed loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Interestingly, we showed that deficient transcriptional activity of NKX2-1-P202L was completely rescued by cotransfected

PAX8-WT, whereas the synergistic effect was abolished by L176V and Q210P. The clinical spectrum of 6 own and 40 published patients with NKX2-1 mutations ranged from the complete triad of brain-lung-thyroid syndrome (50%), brain and thyroid disease (30%), to isolated BHC (13%). Thyroid morphology was normal (55%) and compensated hypothyroidism occurred in 61%. Lung disease occurred in 54% of patients (IRDS at term 76%; recurrent pulmonary infections 24%). On follow-up, 20% developed severe chronic interstitial lung disease, and 16% died. In conclusion, we describe five new NKX2.1 mutations with, for the first time, complete rescue by PAX8 of the deficient transactivating capacity

in one case. Additionally, our review VX-680 datasheet shows that the majority of affected patients display neurological and/or thyroidal problems and that, although less frequent, lung disease is responsible for a considerable mortality.”
“The spatial and temporal organization of molecules within a cell is critical for coordinating the many distinct activities carried out by the cell. In an increasing number of biological signaling processes, scaffold proteins have been found to play a central role in physically assembling the relevant molecular components. Although most scaffolds use a simple tethering mechanism to increase the efficiency of interaction between individual partner molecules, these proteins can also exert complex allosteric control over their partners and are themselves the target of regulation. Scaffold proteins offer a simple, flexible strategy for regulating selectivity in pathways, shaping output behaviors, and achieving new responses from preexisting signaling components.

Soil moisture field measurements and MODIS images of relevant

dates have been acquired. Normalized Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI) and Normalized Difference Water Index (NDWI) are calculated from MODIS images. In addition, MODIS Land Surface Temperature (LST) data (MOD11A1) are used in this analysis. Four different soil moisture estimation models, which are based on NDVI-LST, EVI-LST, NDVI-LST-NDWI and EVI-LST-NDWI, are developed and their accuracies are assessed. Statistical analysis shows that replacing EVI with NDVI in the model that is based on LST and NDVI increases the accuracy of soil moisture estimation. Luminespib order Accuracy evaluation of soil moisture estimation using check points shows that the model based on LST, EVI and NDWI values gives a higher accuracy than that based on LST and EVI values. It is concluded that the model based on the three indices is a suitable model to estimate soil moisture through MODIS imagery.”
“Postnatal

growth patterns in eight species of herons and egrets (Ciconiiformes: Ardeidae). Avian postnatal growth has received considerable attention and its ecological implications have been deeply analyzed. In this current paper. I describe the patterns see more of culmen and tarsus growth, as well as of weight gain patterns in eight species of herons and egrets (Ayes: Ardeidae) found in the Birama Swamp in Eastern Cuba. Between 1998 and 2006,714 nestlings of the following species were measured every two days: Butorides virescens, Bubulcus ibis, Egretta thula, E. tricolor, E. caerulea, E. rufescens, Ardea alba and Nycticorax nycticorax. Logistic and Gompertz equations were adjusted to data using non-lineal regression models with adult values as the asymptote. For each species, the following were determined

and recorded: growth rate, age at inflexion, instantaneous growth rates at each age interval, and time taken to reach 90% of adult size. Reported MEK162 chemical structure hatchling sizes were similar in other localities, with a variation coefficient ranging between 10-19%. At hatch, each species exhibited differing sizes relative to adult values. In all cases, Gompertz equations were best fitted to explain more variance and lesser residuals. Rates of weight change and tarsus growth were alometrically related to the log of adult weight. Two main growth processes were identified: a physical extension in dimensions of each measurement reflecting inter-specific morphometric differences, and a lineal increase of the growth period from Green Heron to Great Egret. The Black-crowned Night Heron, Cattle Egret and Reddish Egret exhibited some unique measurement characteristics in comparison to the remaining members of the family. All results support the hypothesis that hypermorphosis, as the main evolutionary process in the microevolution of Ardeidae, is caused by a delayed final moment of growth. Rev. Biol. Trop. 59(2): 771-787. Epub 2011 June 01.

Transcript abundance of selleck kinase inhibitor catalase gene in S. litura larvae treated for 1, 24 and 48 h was investigated in the whole body. The same was studied in a temporal fashion i.e. midgut, fat body, salivary gland, Malphigian tubule and haemocytes of S. litura. The maximum catalase transcript level was observed in the fat body which is a detoxifying organ and the least in salivary gland which was prone to maximum damage

upon exposure to the toxin. (C) 2010 Elsevier Inc. All rights reserved.”
“Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6-12 months platinum-free interval (PFI)] is unclear.\n\nPatients and methods: Within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup.\n\nResults: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) = 0.65, 95% confidence interval (CI), 0.45-0.92; P = 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR = 0.59; 95% CI, 0.43-0.82; EVP4593 mw P = 0.0015; median survival

23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR = 0.63; P = 0.0357; median 13.3 versus 9.8 months).\n\nConclusion: This hypothesis-generating analysis Selleckchem PXD101 demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 6-12 months).”
“As nearly 5% of all endometrial cancers occur because of a predisposition, this possibility has systematically to be explored. The hallmarks of predisposition,

a young age at diagnosis, a personal or a familial history of cancer, have to be searched systematically. The identification of a predisposition in a family has a major impact on the management of the proband or his relatives. The endometrial cancer main predisposition is Lynch’s syndrome. In this review, we will focus on this condition and describe its clinical manifestations, the underlying molecular mechanisms, the cancer risks and the management guidelines. We will also get onto some far less frequent other predispositions. triangle”
“We hypothesized an anatomical/physiological sphincter and investigated this hypothesis in current communication. The histomorphologic and morphometric studies were carried out in 14 cadavers and radiologic studies in 20; endoscopy studies were done in 16 healthy volunteers.

Tibia peripheral quantitative computed tomography measures included polar section modulus (Zp; mm(3)), periosteal and endosteal circumference (mm), cortical area (mm(2)), and volumetric bone mineral density (vBMD; mg/cm(3)) at the 38% site, and muscle cross-sectional area (CSA; mm(2)), at the 66% site. Physical activity (average hours per week) was assessed by questionnaire. Log linear regression was used to assess determinants of muscle specific force (MSF; torque relative to muscle CSA) and Zp adjusted for age and

tibia length. MSF was greater in blacks than whites (p < 0.05) and lower in females than males (p < 0.001). Zp was greater in blacks than whites (p = 0.002) in Tanner selleck stages 1-4, but the difference was attenuated in Tanner 5 (interaction, p=0.02); R(2)=0.87. Muscle CSA, muscle torque, body weight, and physical activity were added to the model and each load covariate was independently and significantly (all, p < 0.02) associated with Zp (R(2) = 0.92), periosteal circumference, and cortical area. Inclusion of these measures attenuated but did not eliminate the significant race differences. Only muscle CSA was positively associated

with endosteal circumference, while none of the load covariates were Alvocidib nmr associated with vBMD.\n\nIn conclusion, bone geometry is associated with several factors that define the mechanical load on bone, independent of age, tibia length, maturation, race, and sex. Race differences in Zp were not explained by these measures of mechanical load. Given that inclusion of muscle torque,

body weight, and physical activity resulted in a nominal increase in the R(2), muscle size is an adequate surrogate for the mechanical load on bone in healthy participants. (C) 2011 Elsevier Navitoclax cell line Inc. All rights reserved.”
“A series of alisol A derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities and cytotoxicities in vitro. The preliminary investigation demonstrates that simple modifications of the parent structure of alisol A can produce a number of potentially important derivatives against HBV. The most active anti-HBV compound 6a showed high activities against the secretion of HBV surface antigen (IC(50) = 0.024 mM), HBV e antigen (IC(50) = 0.028 mM) and remarkable selective indices (SI(HBsAg) > 108, SI(HBeAg) > 93), which was selected for further evaluation as a novel HBV inhibitor. (C) 2008 Elsevier Ltd. All rights reserved.”
“Aim: The present Study has been designed to investigate the involvement of the nitric oxide mechanism in the protective effect of lycopene against 3-nitropropionic acid-induced Huntington’s disease-like symptoms in rats.\n\nMain methods: The present experimental protocol design includes systemic 3-nitropropionic acid ( 10 mg/kg i.p) treatment for 14 days. Lycopene (2.5, 5 and 10 mg/kg) was given orally, once a day, 1 h before 3-nitropropionic acid treatment for 14 days.

69 +/- 0.18 vs. 0.61 +/- 0.19, P = 0.048). During 1, 6, and 12 months of follow-ups, the procedures did not demonstrate a significant difference in IPSS, QoL score, Qmax, AG-014699 cell line or PVR (P bigger than 0.05). Mean peri-operative decrease of hemoglobin in the HoLEP group was similar to the ThuVEP group (17.1 +/- 12.0 g/L vs. 15.2 +/- 10.1 g/L, P = 0.415). Early and late incidences of complications were

low and did not differ significantly between the two groups of 120-W ThuVEP and HoLEP patients (P bigger than 0.05). Conclusions: 120-W ThuVEP and HoLEP are potent, safe and efficient modalities of minimally invasive surgeries for patients with LUTS due to BPH. Compared with HoLEP, 120-W ThuVEP offers advantages of reduction of laser enucleation time and improvement of laser efficiency.”
“Objective: The aim of this study was to determine the prevalence of hepatitis B virus (HBV) subgenotypes, the spectrum of mutations in the precore/core region through phylogenetic analysis, and the relevance of viral characteristics in disease progression in Korean patients. Methods: 133 patients with chronic HBV infection were enrolled. The precore and core region of HBV was amplified and sequenced. Phylogenetic analysis was performed for subgenotyping and the changes of nucleotides and amino acid were compared in liver disease stages. Results: HBV/C2 find more subgenotype was predominant in chronic HBV carriers (98.5%), followed by HBV/A2

(0.75%) and HBV/C7 (0.75%). The mutations of the precore region were not different between liver disease stages. However, amino acid changes in the cytotoxic T lymphocyte epitope (p < 0.020), CD4+ T cell epitope (p < 0.027), or B cell check details epitope (p < 0.029) were significantly higher in liver cirrhosis patients than in chronic hepatitis patients, but not in hepatocellular carcinoma patients. Conclusion: HBV/C2 is the most prevalent subgenotype in Korea, and HBV/C7 subgenotype found in the Philippines was first identified in the Korean population. Mutations in immune epitopes within the core gene were significantly associated with disease progression.

Copyright (C) 2011 S. Karger AG, Basel”
“Background and purpose: The aim of this study was to compare MRI-based morphological gross tumour volumes (GTVs) to biological tumour volumes (BTVs), defined by the pathological radiotracer uptake in positron emission tomography (PET) imaging with (18)F-fluoroethyltyrosine (FET), subsequently clinical target volumes (CTVs) and finally planning target volumes (PTVs) for radiotherapy planning of glioblastoma.\n\nPatients and methods: Seventeen patients with glioblastoma were included into a retrospective protocol. Treatment-planning was performed using clinical target volume (CTV = BTV + 20 mm or CTV = GTV + 20 mm + inclusion of the edema) and planning target volume (PTV = CTV + 5 mm). Image fusion and target volume delineation were performed with OTP-Masterplan (R).

OE was induced by a 20% fat diet, and control groups were fed a balanced diet (4% fat). Serum leptin levels and adiposity index indicate that all groups were obese, RepSox molecular weight except for O1. Three progressive levels of impaired metabolic status were observed: O1 presented insulin resistance, O2 were insulin resistant and obese, and groups O3, O4, and O5 were insulin resistant, obese, and diabetic. These three levels of metabolic damage were proportional to the increase of leptin and decreased circulating testosterone. The impairment in the daily sperm production (DSP) paralleled

these three levels of metabolic and hormonal damage being marginal in O1, increasing in O2, and being higher in groups O3, O4, O5, and O6. None of the OE periods affected the sperm transit time in the epididymis, and the lower sperm reserves were caused

mainly by impaired DSP. In conclusion, GSI-IX OE during sexual maturation markedly reduces the DSP at adulthood in the rat. A severe reduction in the DSP also occurs in OE exposure during gestation/lactation but not in gestation, indicating that breast-feeding is a critical period for spermatogenic impairment under obesogenic conditions.”
“Thongon N, Nakkrasae L, Thongbunchoo J, Krishnamra N, Charoenphandhu N. Enhancement of calcium transport in Caco-2 monolayer through PKC zeta-dependent Ca(v)1.3-mediated transcellular and rectifying paracellular pathways by prolactin. Am J Physiol Cell Physiol 296: C1373-C1382, 2009. First published April 1, 2009; doi:10.1152/ajpcell.00053.2009.-Previous investigations suggested

that prolactin (PRL) stimulated the intestinal calcium absorption through phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), and RhoA-associated coiled-coil forming kinase (ROCK) signaling pathways. However, little was known regarding its detailed mechanisms for the stimulation of transcellular and voltage-dependent learn more paracellular calcium transport. By using Ussing chamber technique, we found that the PRL-induced increase in the transcellular calcium flux and decrease in transepithelial resistance of intestinal-like Caco-2 monolayer were not abolished by inhibitors of gene transcription and protein biosynthesis. The PRL-stimulated transcellular calcium transport was completely inhibited by the L-type calcium channel blockers (nifedipine and verapamil) and plasma membrane Ca2+-ATPase (PMCA) inhibitor (trifluoperazine) as well as small interfering RNA targeting voltage-dependent L-type calcium channel Ca(v)1.3, but not TRPV6 or calbindin-D-9k. As demonstrated by Ca-45 uptake study, PI3K and PKC, but not ROCK, were essential for the PRL-enhanced apical calcium entry. In addition, PRL was unable to enhance the transcellular calcium transport after PKC zeta knockdown or exposure to inhibitors of PKC zeta, but not of PKC alpha, PKC beta, PKC epsilon, PKC mu, or protein kinase A.

63-22.64 kcal/mol. A combined experimental and theoretical vibrational analysis indicates the existence

of intramolecular H-bonding between pyrrole N-H as proton donor and N atom of cyanide as proton acceptor. To investigate the strength and nature of H-bonding, topological and energetic parameters at bond critical points (BCP) have been analyzed by ‘Quantum theory of Atoms in molecules’ (QTAIM). Global see more electrophilicity index (omega = 4.58 eV) shows that title molecule (3) is a strong electrophile. The maximum values of local electrophilic reactivity descriptors (P-k(+), f(k)(+), omega P-k(+),NPk+) at vinyl carbons (C6/C22) of (3) indicate that they are more prone to nucleophilic attack. (C) 2013 Elsevier B.V. All rights reserved.”
“The quaternary isoquinoline alkaloid, sanguinarine (SG) plays an important role in both traditional and modern medicine, exhibiting a wide range of biological activities. Under physiological conditions, there is an equilibrium between the MDV3100 clinical trial quaternary cation (SG(+)) and a pseudobase (SGOH) forms of SG. In the gastrointestinal tract, SG is converted to dihydrosanguinarine (DHSG). All forms

exhibit bright fluorescence. However, their spectra overlap, which limited the use of powerful techniques based on fluorescence spectroscopy/microscopy. Our experiments using a combination of steady-state and time-resolved techniques enabled the separation of individual components. The results revealed that (a) the equilibrium constant between SG(+) and SGOH is pK (a) = 8.06, while fluorescence of DHSG exhibited no changes in the pH range 5-12, (b) the SGOH has excitation/emission spectra with maxima at 327/418 nm and excited-state lifetime 3.2 ns, the spectra of the SG(+) have maxima at 475/590 nm and excited-state lifetime 2.4 ns. The DHSG spectra have maxima at 327/446 nm and 2-exponential decay with components 4.2 and 2.0 ns, (c) NADH is able to convert SG to DHSG, while there is no apparent interaction between ICG-001 NADH and DHSG. These techniques are applicable for monitoring

the SG to DHSG conversion in hepatocytes.”
“The superior vena cava syndrome encompasses a constellation of symptoms and signs resulting from obstruction of the superior vena cava. We report a successful surgical management after failed endovascular stenting for superior vena cava syndrome, caused by a post-radiation fibrosis after conventional radiotherapy for breast cancer. We emphasize the rarity of this uncommon surgical procedure and the bailout procedure for failed angioplasty and intravascular stenting. Key points of superior vena cava syndrome and its management are discussed.”
“Most models of spoken production predict that shorter utterances should be initiated faster than longer ones. However, whether word-length effects in single word production exist is at present controversial. A series of experiments did not find evidence for such an effect.

Then, we demonstrated that decreased expression of Beclin1 was associated with T stage, clinical stage

and differentiation. Furthermore, we showed that activation CT99021 manufacturer of autophagy by rapamycin suppressed proliferation, migration and invasion while inhibition of autophagy by 3-MA promoted proliferation, migration and invasion in TSCC cells.\n\nConclusionTaken together, these data suggest that autophagy plays a pivotal role in the progression of TSCC.”
“Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed countries, with an increasing prevalence due to an aging population. The pathology underpinning CVD is atherosclerosis, a chronic inflammatory state involving the arterial wall. Accumulation of low density lipoprotein (LDL) laden macrophages in the arterial wall and their subsequent transformation into foam cells lead

to atherosclerotic plaque formation. Progression of atherosclerotic lesions may gradually lead to plaque related complications and clinically manifest as acute vascular syndromes including acute myocardial or cerebral ischemia. Nanotechnology offers emerging therapeutic strategies, which may have advantage overclassical treatments for atherosclerosis. In this review, we present the potential P5091 inhibitor applications of nanotechnology toward prevention, identification and treatment of atherosclerosis. (C) 2012 Elsevier Inc. All rights reserved.”
“Sixty weaned piglets (33 d, 7.96 +/- 1.09 kg BW) were divided into

4 groups with 15 pigs each and fed identical diets in which meal was coarsely ground (CM), coarsely ground and pelleted (CP), finely ground and pelleted (FP), or coarsely ground and extruded (CE) for 4 wk. At the end of the trial the pigs were killed and samples of the digesta were taken from the stomach, the end of the small intestine, and the cecum for microbiological, DM, pH, and lactic acid analyses. Differences (P < 0.05) regarding the counts of bacteria were mainly found between the CM and the FP group, but the CP and the CE diet mostly resulted in intermediate values. Pigs fed the CM diet had the SYN-117 purchase highest numbers of lactobacilli in the stomach content (P < 0.01) and the cecal digesta (P < 0.05). Perhaps due to a more efficient stomach barrier, characterized by high lactobacilli counts and a marked pH gradient in the stomach content (cardia, 5.15 +/- 0.475; pylorus, 2.83 +/- 1.06; P < 0.01), the lowest counts of coliform bacteria were found in the distal part of the small intestine in pigs fed the CM diet (P < 0.05).”
“Study Design. Quantitative gene expression analysis and immunohistochemistry were used to investigate the temporal and spatial expression of bone morphogenic proteins (BMPs) and BMP antagonists in a posterolateral spine fusion model in rabbits.\n\nObjective.

Although the pericardium was opened, left ventricular function remained depressed, necessitating extracorporeal membrane oxygenation, which was withdrawn after

48 h of assistance when left ventricular function had recovered. The patient was extubated on the seventh postoperative day but died of multiorgan failure on the 64th postoperative day.”
“The World Health Organization (WHO) issued a recommendation (Technical Consultation: Paris 2006, Luxembourg 2007) that salt consumption, as a risk factor for hypertension, atherosclerosis, myocardial infarction, stroke, and select cancers, should be restricted. The European Commission looked to adhere to this recommendation by creating the High Level Croup on Nutrition and Physical Activity. According to WHO\n\nrecommendations, a daily allowance of AZD1152 5 g NaCl (i.e., DZNeP Epigenetics inhibitor 2 g Na) for individual salt consumption should not be exceeded. At present, mean individual salt consumption in Poland totals 13.5 g, of which salt used in household constitutes 8.8 g. In some regions of Poland, this number reaches upwards of 15.0 g/person. The Position Paper on Initiatives

Aimed at Decreasing Salt Consumption in Poland, developed by an expert group at the National Food and Nutrition Institute, set the course for intervention, including changing recipes for mass-produced food products and large-scale catering, improving oversight by food control agencies, and continuing legislative changes. These interventions should also include education directed towards consumers, food producers, public health professionals, healthcare workers, and media representatives. The Position Paper of the Polish

Hypertension Society also sets the course for promoting restricted salt consumption and controlling hypertension on a population level. However, household RG-7112 mouse salt is the main carrier of iodine in the Polish model of iodine prophylaxis. Thus, any interventions also require synchronized action with the Polish Council for Control of Iodine Deficiency Disorders. Current efforts aimed at preventing iodine-deficiency look to increase consumption of other iodine-rich products (e.g., milk, mineral water) with standardized levels of iodine. Once they achieve an iodine concentration of 0.1-0.2 mg, these products can easily supplement any decrease in physiological iodine levels resulting from reduced salt consumption. Also required are wide-ranging educational campaigns which will be coordinated by the new designated WHO Collaborating Centre for Nutrition at the Chair of Endocrinology at Jagiellonian University, Collegium Medicum in Krakow.

Furthermore, the recombinant strain T55 exhibited almost a fourfold increase in carboxylesterase activity compared with PG63 strain when both were cultured without inducers. Based on the secondary structure

and multiple sequence alignments with carboxylesterases, cholinesterase and lipase, a three-dimensional model was obtained. The / barrel topology, that is typical of esterases and lipases, was indicated for the CARB protein with Ser213-Glu341-His456 as the selleck putative catalytic triad. CARB preferentially hydrolysed acyl chains with eight carbon atoms, and its activity was optimal at a pH of 7 center dot 0 and a temperature of 25 degrees C. CARB exhibited stability in alkaline pH, high activity under

mesophilic conditions and stability in organic solvents. Conclusion The CARB protein is potentially useful in bioremediation, food and chemical/pharmaceutical industries. Significance and Impact of the Study This study is the first to report the development of a recombinant strain superproducing a Penicillium sp. carboxylesterase.”
“Sphingosine 1-phosphate (S1P) this website and ceramide have been implicated in both autophagy and apoptosis. However, the roles of these sphingolipid metabolites in the links between these two processes are not completely understood. Depletion of S1P phosphohydrolase-1 (SPP1), which degrades intracellular S1P, induces the unfolded protein response and endoplasmic reticulum stress-induced autophagy (Lepine, S., Allegood, J. C., Park, M., Dent, P., Milstien, S., and Spiegel, S. (2011) Cell Death Differ. 18, 350-361). Surprisingly, however, treatment with doxorubicin, which by itself also induced autophagy, markedly reduced the extent of autophagy mediated by depletion of SPP1. Concomitantly, doxorubicin-induced apoptosis was greatly enhanced by down-regulation of SPP1. Autophagy and apoptosis seemed to be sequentially linked because inhibiting autophagy with 3-methyladenine also markedly attenuated

apoptosis. Moreover, silencing Atg5 or the three sensors of the unfolded protein response, IRE1 alpha, ATF6, and PKR-like eIF2 alpha kinase (PERK), significantly decreased both autophagy and apoptosis. Doxorubicin CX-6258 datasheet stimulated calpain activity and Atg5 cleavage, which were significantly enhanced in SPP1-depleted cells. Inhibition or depletion of calpain not only suppressed Atg5 cleavage, it also markedly decreased the robust apoptosis induced by doxorubicin in SPP1-deficient cells. Importantly, doxorubicin also increased de novo synthesis of the pro-apoptotic sphingolipid metabolite ceramide. Elevation of ceramide in turn stimulated calpain; conversely, inhibiting ceramide formation suppressed Atg5 cleavage and apoptosis. Hence, doxorubicin switches protective autophagy in SPP1-depleted cells to apoptosis by calpain-mediated Atg5 cleavage.