These eggs lodge in host tissues, causing inflammatory responses that are the primary cause of morbidity. Because these parasites can live and reproduce within human hosts for decades’, elucidating the mechanisms that promote their longevity is of fundamental importance. Although adult pluripotent stem cells, called neoblasts, drive long-term
homeostatic tissue maintenance in long-lived free-living flatworms(3,4) (for example, planarians), and neoblast-like cells have been described in some parasitic tapeworms’, little is known about whether similar cell types exist in any trematode species. Here we describe a population of neoblast-like cells in the trematode Schistosoma mansoni. These cells resemble planarian neoblasts morphologically and share their ability to proliferate and differentiate learn more into derivatives of multiple germ layers. Capitalizing on available genomic resources(6,7) and RNA-seq-based gene expression profiling, we find that these schistosome neoblast-like cells express a fibroblast growth factor receptor orthologue. Using RNA interference we demonstrate that this gene is
required for the maintenance of these neoblast-like cells. Our observations indicate that adaptation of developmental strategies shared by free-living ancestors to modern-day schistosomes probably contributed to the success of these animals as long-lived obligate parasites. We expect that future studies deciphering the function of these neoblast-like cells will have important implications for understanding the biology of these devastating parasites.”
“A Gram-stain-negative, Selleck BIIB057 Angiogenesis inhibitor ochre-pigmented, strictly aerobic bacterium, designated strain KJ7(T), was isolated from a tidal flat of the Gangjin bay in South Korea. Cells
were halotolerant, non-motile, catalase- and oxidase-positive rods. Growth of strain KJ7(T) was observed at 5-35 degrees C (optimum, 25 degrees C), at pH 6.0-9.5 (optimum, pH 6.5-7.0) and in the presence of 0-9% (w/v) NaCl (optimum, 2%). The major cellular fatty acids were C-18:1 omega 7c(1) C-17:1 omega 6C(1) summed feature 3 (comprising C-16:1 omega 7c and/or C-16:1 omega 6c) and C-16:0. The polar lipid pattern indicated the presence of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, a sphingoglycolipid, an unidentified phospholipid and two unidentified lipids. The G+C content of the genomic DNA was 60.2 +/- 0.9 mol% and the predominant respiratory quinone was Q-10. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain KJ7(T) formed a phyletic lineage distinct from other members of the genus Altererythrobacter and was most closely related to Aftererythrobacter luteolus SW-109(T) and Aftererythrobacter namhicola KYW48(T) (95.6 and 95.0% 16S rRNA gene sequence similarity, respectively).
Extraction protocols are tested for their capability to leach out total selenium and selenomethionine from the samples. Speciation analysis is realised GDC-0994 MAPK inhibitor with the use of HPLC-ICP-MS. Isotope dilution is employed to determine the analytes contents. An uncertainty budget is elaborated with the method recommended by the Guide to the expression of Uncertainty in Measurement (GUM).”
“The aim of the present study was to explore the difference in toxicity mechanism of TiO2 nanoparticles (NPs) at low concentrations (<= 1 mu g mL(-1)), in a freshwater bacterial isolate, Bacillus
licheniformis, under light (UV-illuminated) and dark (non-illuminated) conditions. Standard plate count and MTT assays showed the dose dependent decrease in the bacterial cell viability. The difference in reduction of cell viability under light (20.7%) and dark conditions (21.3%) was statistically non-significant at 1 mu g mL(-1) concentration find more and 2 h interaction period. The fluorescence microscopy of the NP interacted cells (1.0 mu g mL(-1), 2 h) under light and dark conditions
showed the mixture of live and dead cells. A significant dose dependent increase in intracellular ROS generation compared to control was noted. The ROS level after 2 h of interaction was significantly higher under light conditions (7.4 +/- 0.13%) as compared to dark conditions (4.35 +/- 0.12%). The LDH analyses confirmed a statistically significant increase in membrane permeability under dark conditions compared to the light conditions. The NPs were stable against aggregation in sterilized lake water matrix for a period of 24 h, under both light and dark conditions. However, in the presence of bacterial cells an elevated rate of sedimentation was noted under dark conditions. The electron microscopic (SEM, TEM) observations suggested the concentration buildup of NPs near the
plasma membrane leading to selleck chemicals llc internalization. The zeta-potential analysis proved that NP attachment was not charge based. The FTIR studies demonstrated the possible involvement of surface functional groups in the attachment. The concentration of dissolved Ti4+ ions was found to be negligible during the test period. The dominant cytotoxicity mechanism under light conditions was found to be ROS generation, whereas, NP attachment to the cell membrane leading to membrane damage significantly contributed in dark conditions.”
“Considering neurological emergencies in childhood, cerebral seizures are very common and therefore of outstanding importance. An effective and safe treatment strategy is necessary for the prehospital as well as the hospital setting. Even more seldom, meningoencephalitis and ischemic stroke have to be considered to enable the best possible outcome. The well known ABC algorithm is applicable and helpful also for neurological emergencies as it is for other emergency situations.
Access through a 9-French sheath was necessary to introduce the Amplatzer Vascular III plug. Three-dimensional transesophageal echocardiography (3D-TEE) was used to guide the operator and evaluate the severity of regurgitation postimplantation. Results: In total seven consecutive patients (mean age 72.8 +/- 5.6 years, 86% male) with a history of mitral valve (n = 6) or aortic valve this website replacement and severe PVL, underwent transapical PVL reduction using seven plugs in total (diameter 10-14 mm). Preprocedural median logistic
EuroSCORE was 28.5% (range 17.1-41.1%) and NYHA functional class was >= 3 in all patients. The procedure was successful in all patients, with a median fluoroscopic time of 18.7 min (range 10.1-29.6 min). Postprocedure 3D-TEE showed occlusion of PVL in three patients, and significant reduction in three patients. Postprocedural
complication was a hematothorax requiring surgery in one patient. Median hospitalization duration EX-527 after the procedure was 5 days (range 5-59 days). At 3-month follow-up one patient died, functional class and LDH did not differ significantly and there was a significant increase in hemoglobin. Conclusions: Transapical paravalvular leak reduction might be a good or rather attractive alternative in high-risk patients for major re-do cardiac surgery. (C) 2012 Wiley Periodicals, Inc.”
“Cerebral venous and sinus thrombosis is a still underdiagnosed cause of stroke, with an incidence of about 2.8 events per 100,000 person-years in young women and about 1.3 events per 100,000 person-years in the general population. Puerperium, oral hormonal contraception, and
coagulation disorders remain the most frequently identified risk factors. Initial treatment with heparin is the only proven therapy, although the evidence is based on only two randomized placebo-controlled trials which together included 79 patients. In the case of clinical deterioration under anticoagulation, local thrombolysis and mechanical thrombectomy may be considered, but clinical efficacy is supported only by case reports. Patients with imminent lateral herniation due to large hemorrhagic infarctions should be treated with prompt surgical decompression. Following the acute phase, oral anticoagulation is recommended for 312 months, and only patients suffering from AG-014699 cell line a severe coagulopathy or with recurrent cerebral venous and sinus thrombosis should be considered for long-term anticoagulation. Only insufficient experience is available for novel anticoagulants such as thrombin inhibitors or factor Xa antagonists.”
“Phenylthiocarbamide (PTC) taste sensitivity is an inherited trait determined primarily by allelic variation of the taste-receptor gene TAS2R38 on chromosome 7q. Results of prior studies examining the ability to taste PTC in patients with schizophrenia have been mixed because of the difficulties in measuring PTC taste sensitivity behaviorally.
\n\nConclusion: [111-In] pentetreotide SPECT/CT imaging at
24 hours identifies pathologic disease sites and distinguishes physiologic activity equally well compared to traditional strategies using 2 imaging days. Routine use of SPECT/CT will allow single time-point imaging without loss of diagnostic accuracy, enhancing patient convenience, and clinical throughput.”
“Background: Percutaneous nephrolithotomy (PCNL) can be performed in the prone or in the supine position. Comparisons between the two techniques in obese patients are rare in the current literature.\n\nMethods: The records of obese patients (body mass index >30) who underwent PCNL in the prone or complete supine positions were reviewed. All patients had a noncontrast CT before and after the procedure. Stones were graded according to the Guy stone
score and complications according to the Clavien HM781-36B grading. The stone-free rates, operative time, surgical complications, and hospital stay were analyzed.\n\nResults: A total of 56 PCNL were performed in 42 patients. Twenty-four PCNL were performed in the prone and 32 in the total supine position. Stone-free rate on the first postoperative day was 50% in the prone and 46.9% in the supine ALK inhibitor position (P = 1.0). Final stone-free rates were 83.3% and 78.1%, respectively (P = 0.74). Mean operative time was 164.6 minutes in the prone and 120.3 minutes in the supine position (P = 0.0017), and hospital stay was 4.38 and 2.68 days (P = 0.014), respectively. The transfusion rate was 20.8% in the prone and zero in the supine position patients (P = 0.01).
Excluding Guy IV stones, transfusion rate was 8.3% in the prone position (P = 0.1). Significant surgical complications rate was 12.5% in the prone and 3.1% in the supine position (P = 0.302).\n\nConclusion: PCNL performed in the prone or in the complete supine position in obese patients presents similar outcomes. The supine decubitus position has the advantages of a significantly shorter operative time and hospital Combretastatin A4 research buy stay.”
“Objective: To assess the efficacy of upper airway surgical intervention in patients with Prader-Willi syndrome (PWS). Due to reports of sudden death in children undergoing treatment with growth hormone for PWS, detection of sleep-disordered breathing by polysomnography (PSG) has been recommended.\n\nDesign: Retrospective study.\n\nSetting: Multidisciplinary PWS Center at a tertiary care children’s hospital.\n\nPatients: Thirteen pediatric patients with PWS who underwent adenotonsillectomy (T&A) with pre-PSG and post-PSG.\n\nMain Outcome Measures: Comparison of PSG results before and after T&A.\n\nResults: Six of our patients were girls (46%); 8 had genetic characteristics consistent with deletion (61%), and the remaining 5 had genetic characteristics consistent with uniparental disomy (39%). The median age at T&A was 3 years (age range, 6 months to 11 years), and the median age at start of growth hormone treatment was 8.5 months (range, 2 months to 6 years).
In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited
enzyme into an active phospho-Ub-dependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to CX-6258 these substrates can in turn be phosphorylated by PINK1, which triggers further check details cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For
instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKIN-mediated mitophagy by PTMs. It is therefore
evident that further insight into how PTMs regulate the PINK1-PARKIN pathway will be critical for our understanding of mitochondrial quality control.”
“Brook trout Salvelinus fontinalis (Mitchill, 1814) chromosomes selleckchem have been analyzed using conventional and molecular cytogenetic techniques enabling characteristics and chromosomal location of heterochromatin, nucleolus organizer regions (NORs), ribosomal RNA-encoding genes and telomeric DNA sequences. The C-banding and chromosome digestion with the restriction endonucleases demonstrated distribution and heterogeneity of the heterochromatin in the brook trout genome. DNA sequences of the ribosomal RNA genes, namely the nucleolus-forming 28S (major) and non-nucleolus-forming 5S (minor) rDNAs, were physically mapped using fluorescence in situ hybridization (FISH) and primed in situ labelling. The minor rDNA locus was located on the subtelo-acrocentric chromosome pair No. 9, whereas the major rDNA loci were dispersed on 14 chromosome pairs, showing a considerable inter-individual variation in the number and location. The major and minor rDNA loci were located at different chromosomes. Multichromosomal location (3-6 sites) of the NORs was demonstrated by silver nitrate (AgNO3) impregnation. All Ag-positive i.e. active NORs corresponded to the GC-rich blocks of heterochromatin.
001). However, TH increased phase singularity number (wavebreaks) during VF (P<0.05) and Si pacing (P<0.05). TH resulted in earlier onset of APD alternans (P<0.001), which was predominantly SDA (P<0.05), and increased pacing-induced VF episodes (P<0.05). TH also decreased CV, shortened wavelength, and enhanced APD dispersion and the spatial heterogeneity of CV restitution.\n\nConclusions: TH (30 degrees C) increased the vulnerability of pacing-induced VF by (1) facilitating wavebreaks during VF and Si pacing, and (2) enhancing proarrhythmic electrophysiological parameters, including promoting
earlier onset of APD alternans (predominantly SDA) during ALK inhibitor drugs S1 pacing. (Circ J 2009; 73: 2214-2222)”
“Brain metastasis has become an increasing cause of
morbidity EGFR inhibitor and mortality in cancer patients as the treatment of systemic disease has improved. Brain metastases frequently are highly vascularized, a process driven primarily by VEGF. VEGF mediates numerous changes within the vasculature including endothelial cell retraction and increased permeability, vasodilation, and new vessel formation. Here we describe a xenograft brain metastasis model that mimics the critical steps of metastasis including tumor cell dissemination and vascular adhesion, tumor growth and tumor associated angiogenesis. Magnetic resonance (MR) imaging was used to evaluate two aspects of the functional response of brain metastasis to the anti-VEGF receptor therapeutic, AZD2171 (Cediranib, RECENTIN (TM)). MR tracking of individual cells demonstrated that cediranib did not impede tumor
cell extravasation into the brain parenchyma despite evidence that anti-VEGF treatment decreases the permeability of the blood brain barrier. In a second assay, blood volume imaging using ultrasmall superparamagnetic iron oxide revealed that treatment of well-developed brain metastasis with cediranib for 7 days led to a heterogeneous response with respect to individual tumors. Overall, there was a significant average decrease in the tumor vascular bed volume. The majority of large tumors demonstrated substantially reduced central blood volumes relative to normal brain while retaining a rim of elevated blood volume at BIX 01294 supplier the tumor brain interface. Small tumors or occasional large tumors displayed a static response. Models and assays such as those described here will be important for designing mechanism-based approaches to the use of anti-angiogenesis therapies for the treatment of brain metastasis.”
“Objective: We describe the short-term results of the patients who underwent transapical treatment of a paravalvular leak (PVL) in our centre. Background: Increasing experience with transapical aortic valve implantation has inspired us to explore this approach for prosthetic paravalvular leak reduction in high risk patients.
hMTH1 expression protected these cells from 3-NP and H2O2-induced killing, by counteracting the mutant hit-dependent increased vulnerability and accumulation of nuclear and mitochondrial DNA 8-hydroxyguanine levels. hMTH1 expression reverted the decreased mitochondrial membrane potential characteristic of Hdh(Q111) cells and delayed the increase in mitochondrial reactive oxygen species associated with 3-NP treatment. selleck inhibitor Further indications of hMTH1-mediated mitochondrial protection are the partial reversion of 3-NP-induced alterations in mitochondrial morphology and the modulation of DRP1 and MFN1 proteins, which control fusion/fission rates of mitochondria. Finally,
in line with the in vitro findings, upon 3-NP in vivo treatment, 8-hydroxyguanine levels in mitochondrial DNA from heart, muscle and brain are significantly lower in transgenic hMTH1-expressing mice than in wild-type Torin 1 price animals. (C) 2012 Elsevier Inc. All rights reserved.”
“BACKGROUND. MiR-145 is down-regulated in various human cancers. We previously demonstrated
that some actin-binding proteins were targeted by several microRNAs (miRNAs), including miR-145, in bladder and prostate cancer (CaP). The aim of this study is to determine a novel oncogenic gene targeted by miR-145 by focusing on actin-binding proteins in CaP.\n\nMETHODS. We focused on the SWAP switching B-cell complex 70 kDa subunit (SWAP70), which is an F-actin binding protein involved in activating B-cell transformation. A luciferase reporter assay was used to identify the actual binding sites between miR-145 and SWAP70 mRNA. Cell viability was evaluated by cell proliferation, wound healing, and matrigel invasion assays in si-SWAP70 transfectants. A total of 75 clinical prostate specimens were subjected to immunohistochemistry of SWAP70.\n\nRESULTS. see more Molecular target searches of this miRNA and the luciferase reporter assay showed that SWAP70 was directly regulated by miR-145. Silencing of SWAP70 studies demonstrated
significant inhibitions of cell migration and invasion in CaP cell lines. The SWAP70 positive-staining was significantly higher in percentage in the CaP than in benign prostate hyperplasia tissue.\n\nCONCLUSIONS. Down-regulation of miR-145 was a frequent event in CaP, and it may have a tumor suppressive function. SWAP70 may be a target of miR-145, and it might have a potential oncogenic function. The novel molecular networks though which miR-145 acts, may provide new insights into the underlying molecular mechanisms of CaP. Prostate 71: 1559-1567, 2011. (C) 2011 Wiley-Liss, Inc.”
“An increasing number of studies have documented that sublethal pesticide exposure can change predator-prey interactions. Most of these studies have focused on effects of long-term pesticide exposure on only one type of antipredator traits and have not directly linked changes in these traits to mortality by predation.
Published by Elsevier Inc. All rights reserved.”
“Background: Many countries are facing concentrated HIV epidemics among vulnerable populations, including men who have sex with men (MSM). Unprotected anal intercourse (UAI) is the main HIV transmission route among them and its understanding in the different cultures and how it relates to HIV transmission, re-infection and development of HIV antiretroviral resistance has important public health implications. Data on UAI among Brazilian MSM are scarce. This study aims to evaluate the prevalence and associated factors of UAI
among Nutlin-3 mw HIV-infected MSM who had sex with seronegative or male partners with an unknown serostatus. Method: A cross-sectional study nested in a cohort was conducted in Rio de Janeiro, Brazil. The one hundred and fifty five MSM included in the study answered an ACASI interview and provided biological samples. Generalized linear models were used to identify variables associated with UAI. Results: Overall, UAI with an HIV-negative or unknown serostatus male partner was reported by 40.6% (63/155) of MSM. Lifetime sexual abuse or domestic violence was reported by 35.9%, being more frequent among MSM who reported UAI compared to those who did not (P = 0.001). Use of stimulants before sex was reported by 20% of the MK-2206 PI3K/Akt/mTOR inhibitor MSM, being slightly higher among those who reported UAI (27.0% vs. 15.2%; P =
0.072). Commercial sex was frequent among all MSM (48.4%). After multivariate modeling, the report of sexual abuse or domestic violence (OR = 2.70; 95% CI: 1.08-7.01), commercial sex (OR = 2.28; 95% CI: 1.04-5.10), the number of male sexual partners (p = 0.039) and exclusively receptive anal intercourse (OR = 0.21; 95% CI: 0.06-0.75) remained associated with UAI. CD4 levels, HIV viral load and antiretroviral therapy were not associated with
UAI. Conclusion: The UAI prevalence found with negative or unknown HIV status HDAC inhibitor partners points out that other interventions are needed as additional prevention tools to vulnerable MSM. The main factors associated with UAI were a lifetime history of violence, commercial sex and the number of male sexual partners. This clustering of different behavioral, health and social problems in this population reinforce the need of a comprehensive approach on treating and preventing HIV among MSM.”
“Objective. To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit. Methods. We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose = 25 mg/week) concurrently with folate supplementation.
8 (1.3-5.8), and women 2.0 (1.2-3.4) were successively lost with increasing adjustment.\n\nConclusions: Insufficient sleep seems independently associated with IGT in men, while low vitality was not independently associated with IGT neither in men nor women, when multiple confounders are considered. IGT should be considered in patients presenting these symptoms, and underlying mechanisms further explored.”
“Background: In pediatric emergency departments (EDs), adolescents at risk for suicide often escape detection and successful referral for outpatient mental health care.\n\nObjective: This study aimed to assess
the effectiveness of a brief, ED-based mental health service engagement intervention to increase linkage to outpatient mental health services.\n\nDesign/Methods: Adolescents presenting to a pediatric ED who were not currently receiving mental health services were screened for suicide-related buy Galardin risk factors (Columbia Suicide Scale). If positive, youths were then screened for impairment, alcohol use, and depression. Those screening positive on the Columbia Suicide Scale and the alcohol, impairment, or depression screen were randomly assigned to see more the intervention (short motivational interview, barrier reduction, outpatient appointment established, reminders before scheduled appointment) or standard referral (telephone number for a mental health provider).
Study groups were compared with respect to screen acceptability and outpatient mental health care linkage and change in depression symptoms at 60 days after the index ED visit.\n\nResults: A total of 204 families were enrolled. Overall, 24 adolescents (12%) screened positive for suicide risk factors and were randomized to the intervention (n = 11) or standard referral (n = 13) groups. The groups did not significantly differ on several measures of screen acceptability. As compared with the standard referral group (15.4%), the intervention
group (63.6%) was significantly more likely to attend a mental health appointment during the follow-up Selleckchem CBL0137 period (Fisher exact test, P = 0.03). There was also a nonsignificant trend toward greater improvement of depressive symptoms in the intervention than standard referral group (t = 1.79, df = 18, P = 0.09).\n\nConclusions: When adolescents are identified in the ED with previously unrecognized mental health problems that increase suicide risk, a brief motivational and barrier-reducing intervention improves linkage to outpatient mental health services.”
“Hyponatremia’s effects can be insidious, particularly in patients with heart failure, cirrhosis, and pneumonia. Appreciating its prevalence in hospitalized patients, recognizing its symptoms, characterizing its etiology, and employing appropriate management promptly will help reduce morbidity and mortality among hyponatremic patients. Journal of Hospital Medicine 2012; 7:S1S5.
Published by Elsevier Ltd. All rights reserved.”
investigate if inflammatory stress increases intracellular accumulation of unmodified low-density lipoprotein (LDL) in human monocyte cell line (THP-1) macrophages by disrupting the sterol regulatory element binding proteins (SREBPs) cleavage-activating protein (SCAP)-SREBP2-mediated feedback regulation of LDL receptor.\n\nMaterials and methods THP-1 macrophages were incubated in serum-free Selleck PD0332991 medium in the absence or presence of LDL alone, LDL plus lipopolysaccharide (LPS) and LPS alone, then intracellular cholesterol content, tumor necrosis factor alpha level in the supernatants, mRNA and protein expression of LDL receptor, and SREBP2 and SCAP in the treated cells were assessed by Oil
Red O staining, cholesterol enzymatic assay, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and Western blotting analysis, respectively.\n\nResults We demonstrated that LPS enhanced transformation of THP-1 macrophages into foam cells by increased uptake of unmodified LDL as evidenced by Oil Red O staining and direct assay of intracellular cholesterol. In the absence of LPS, 25 mu g/ml LDL decreased LDL receptor mRNA and this website protein expression (p < 0.05). However, LPS enhanced LDL receptor expression, overcoming the suppression of LDL receptor induced by 25 mu g/ml LDL and inappropriately increasing LDL uptake (p < 0.05). Exposure to LPS also caused overexpression of mRNA and protein of SCAP and SREBP2 (p check details < 0.05). These observations indicate that LPS disrupts cholesterol-mediated LDL receptor feedback regulation, permitting intracellular accumulation of unmodified LDL and causing foam-cell formation.\n\nConclusion The implication of these findings is that inflammatory stress may contribute to intracellular LDL accumulation in THP-1 macrophages without previous modification of LDL.”
“The Inhibitor of Apoptosis Proteins
(IAPs) are important regulators of programmed cell death. XIAP is the most potent among them and is over-expressed in several hematological malignancies. Its activity is endogenously antagonized by SMAC/DIABLO, and also by small molecules mimicking Smac that can induce apoptosis in tumor cells. Here we describe the activity of 56 newly synthesized Smac-mimetics in human leukemic cell lines and normal CD34(+) progenitor cells. Our compounds bind to XIAP with high affinity, reduce the levels of cIAP1 and are cytotoxic at nanomolar or low micromolar concentrations. Furthermore, the Smac-mimetics synergize with Cytarabine, Etoposide and especially with TRAIL in combination treatments. Apoptosis activation was clearly detectable by the occurrence of sub G(1) apoptotic peak and the accumulation of cleaved PARP, caspase 8 and caspase 3. Interestingly, the down-regulation of XIAP sensitized Jurkat cells to drugs too, confirming the role of this protein in drug-resistance.