Then in the MO-injected embryos, the boundaries

once beca

Then in the MO-injected embryos, the boundaries

once became clear and distinct, but, in the subsequent stages, disappeared, resulting in abnormal muscle morphogenesis. Accumulation of Fibronectin and phosphorylated FAK observed in the initial stage also disappeared. Thus, Mys is crucial for maintenance of the somite boundaries formed at the initial stage. To analyze the mys defect at the cellular level, we placed cells dissociated from the MO-injected embryo on Fibronectin-coated glasses. By this cell spreading assay, we found that the mys-deficient cells reduced the activity to form lamellipodia on Fibronectin while FAK was activated in these cells. Thus, we demonstrate that a novel gene misty somites is essential for epithelialization of the somitic cells and maintenance of the somite boundary. buy EPZ-6438 Furthermore, Mys may play a role in a cellular pathway leading to lamellipodia formation in response to the Fibronectin signaling. We propose that the Tol2 transposon mediated gene trap method is powerful to identify a novel gene involved in vertebrate development. 3-deazaneplanocin A mouse (C) 2008 Elsevier Inc. All rights reserved.”

putative tumor suppressor Mst1, when cleaved to its 36 kDa cleaved form, amplifies apoptotic signals. We found that Mst1 was predominantly expressed VX-809 clinical trial in its full-length form in 76% (17/25 cases) of hepatocellular carcinoma (HCC) tumors. Mst1 cleavage was basically

absent in HCC cells. Ectopic full-length Mst1 expression increased the growth of HCC cells by 55-80% within 3 days after transfection. Expression of exogenous NORE1B, a tumor suppressor commonly lost in HCC tumors (similar to 56% of our cohort), was sufficient to suppress the growth promotion of full-length Mst1. Hence, Mst1 exhibits a growth promoting activity in HCC cells upon NORE1B downregulation. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.”
“Quantifying kill rates and sources of variation in kill rates remains an important challenge in linking predators to their prey. We address current approaches to using global positioning system (GPS)-based movement data for quantifying key predation components of large carnivores. We review approaches to identify kill sites from GPS movement data as a means to estimate kill rates and address advantages of using GPS-based data over past approaches. Despite considerable progress, modelling the probability that a cluster of GPS points is a kill site is no substitute for field visits, but can guide our field efforts. Once kill sites are identified, time spent at a kill site (handling time) and time between kills (killing time) can be determined.

9%), congenital anomaly (5 3%), infection (1 9%), other (4 8%), a

9%), congenital anomaly (5.3%), infection (1.9%), other (4.8%), and unknown (23.1%). The contribution of causes differed over gestational age periods. At lower gestational age, placental and unknown were the most dominant causes of death (34.8% and 41.7%, respectively); at higher gestational age, the relative importance of an unknown cause

decreased and a placental cause increased (16.5% and 77.6%) (P<.001). Placental bed pathology was observed in 33.6% of all fetal deaths, with the highest occurrence between 24 0/7 and 316/7 weeks and a strong decline after 32 weeks. In contrast contribution of developmental placental pathology (17.6%) increased after 32 weeks of gestation (P<.001), as did umbilical cord complications (5.2%) and selleck combined placental pathology (5.4%). Solitary placental parenchyma pathology Nepicastat cost was less frequent (3.1%). Hypertension-related disease was observed in 16.1% (95% confidence interval [CI] 13.6-19.0) of the cohort, small for gestational age fetuses in 37.9% (95% Cl 34.1-41.7), and diabetes-related disease in 4.1% (95% Cl 2.8-5.8).\n\nCONCLUSION: Most fetal deaths were caused by a variety of placental pathologies. These were related to gestational age, and their clinical manifestations

varied during pregnancy. (Obstet Gynecol 2009;114:809-17)”
“Background: Pheochromocytoma is a neuroendocrine (NE) tumor of the adrenal medulla for which surgical resection is the only therapy. However, 10-46% of tumors are metastatic or have malignant features, and are often inoperable. Our lab has demonstrated the importance of the Notch1 signaling pathway in NE neoplasia, indicating that this pathway could be a target for emergent treatments in pheochromocytoma. It has recently become clear that histone deacetylase (HDAC) inhibitors influence Notch1 signaling. We hypothesized that the HDAC inhibitor Sodium Butyrate (NaB)

might activate Notch1 in pheochromocytoma resulting in altered tumor cell proliferation. Methods: Pheochromocytoma (PC-12) cells were treated with increasing concentrations of NaB. MTT cellular proliferation assay was used to determine the effect of NaB on PC-12 cell growth. Expression of Notch1, NE markers, and cell cycle proteins was studied using Western analysis. Results: Untreated PU-H71 PC-12 cells lack Notch1 activity. Treatment with NaB led to a dose-dependent induction of Notch1 signaling, reduction of NE markers ASCL1 and CgA, and a significant reduction in cellular proliferation. Levels of expression of cyclin D1, p21, cleaved PARP, and cleaved caspase 3 proteins indicated the presence of cell cycle arrest and apoptosis following NaB treatment. Conclusion: NaB activated Notch1 signaling, inhibited cellular proliferation, reduced NE markers, and induced cell cycle arrest and apoptosis in pheochromocytoma cells. This data indicates that activation of Notch1 signaling is a promising potential therapy or palliative measure for pheochromocytoma that warrants further investigation.

Only 17% of non-occupational victims who drowned while boating wo

Only 17% of non-occupational victims who drowned while boating wore a Personal Flotation Device (PFD).\n\nConclusions. The drowning rate in Alaska during 2000-2006 was 8.9

drowning deaths per 100,000 population. This shows a decrease from the rate reported in a 1996 study, but several problems persist. Males and Alaska Natives had elevated risks for drowning. A substantial portion of fatalities were associated with alcohol consumption. PFD use remains low, and child drowning rates were unchanged from earlier studies. Increased data on water temperature and immersion time may help demonstrate the benefits of PFD use to those at risk. Social marketing efforts should be adapted for at-risk populations. (Int J Circumpolar Health 2010; 69(3):253-264)”
“Background: U.S. medical schools have long used the Medical Student Performance Evaluation (MSPE) to represent overall Bafilomycin A1 student performance while comprehensive clinical performance exams (CPX) are Nepicastat inhibitor beginning to emerge as a new standard for determining student competence. Purpose: This study describes the association between the MSPE and CPX in their independent measures of student competence. Methods: We examined the relationship between CPX scores

and student MSPE rating at our institution, which was completed independently of the CPX. Results: Students with higher CPX scores had better MSPE rating, but the associations are small ranging from r(s) = .13 for history-taking skills to r(s) = .31 for interpersonal skills. Conclusions: CPX results are not strongly related to MSPE rating and, thus, they may provide information on clinical competencies that should be included in the MSPE.”
“Health compromising behaviors, such as smoking and other risk behaviors tend to co-occur, and contribute to the leading causes of preventable death, disease, and disability among adolescents and young adults worldwide. The present study assesses a model of the direct and indirect

effects of maternal ACY-241 clinical trial closeness with suicidal ideation on smoking and risky behaviors. The sample consisted of 657 South African youth assessed over two time points with comparison of effects between males and females. Maternal closeness had a significant effect on suicidal ideation among females. Suicidal ideation had a significant effect on risky behaviors among males and lifetime smoking among females. A significant indirect effect was observed from maternal closeness to lifetime smoking among females. These results indicate that suicidal ideation is associated with lifetime smoking and risky behaviors separately among male and female adolescents and highlight the need to focus on the development of mental health preventive interventions for both genders.”
“The ontogeny of the skull has been studied in several marsupial groups such as didelphids, microbiotheriids, and dasyurids.

Susceptibility testing was performed against 7 antifungals (anidu

Susceptibility testing was performed against 7 antifungals (anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole, and voriconazole) using CLSI methods. Rates of resistance to all agents were determined using the new CLSI clinical breakpoints and epidemiological

click here cutoff value criteria, as appropriate. Sequencing of fks hot spots was performed for echinocandin non-wildtype (WT) strains. Isolates included 3,107 from 21 Candida spp., 146 from 9 Aspergillus spp., 84 from Cryptococcus neoformans, 40 from 23 other mold species, and 41 from 9 other yeast species. Among Candida spp., resistance to the echinocandins was low (0.0 to 1.7%). Candida albicans and Candida glabrata that were resistant to anidulafungin, caspofungin, or micafungin were shown to have fks mutations. Resistance to fluconazole was low among the isolates of C. albicans (0.4%), Candida tropicalis (1.3%), and Candida parapsilosis (2.1%); however, 8.8% of C. glabrata isolates were resistant to fluconazole. Among echinocandin-resistant C. glabrata isolates from 2011, 38% were fluconazole resistant. Voriconazole was active against all Candida spp. except C. glabrata (10.5% non-WT), whereas posaconazole showed decreased activity against C. albicans (4.4%) and Candida krusei (15.2% non-WT). All agents except for the echinocandins were active

against C. neoformans, and the triazoles were active against other yeasts (MIC90, 2 mu g/ml). The echinocandins and triazoles were active against Aspergillus spp. (MIC90/minimum effective NOV120101 concentration [MEC90] range, 0.015 to 2 mu g/ml), but the echinocandins were this website not active against other molds (MEC90 range, 4 to > 16 mu g/ml). Overall, echinocandin and triazole resistance rates were low; however, the fluconazole and echinocandin coresistance

among C. glabrata strains warrants continued close surveillance.”
“One reason given for placing capacitors in series with stimulation electrodes is that they prevent direct current flow and therefore tissue damage under fault conditions. We show that this is not true for multiplexed multi-channel stimulators with one capacitor per channel. A test bench of two stimulation channels, two stimulation tripoles and a saline bath was used to measure the direct current flowing through the electrodes under two different single fault conditions. The electrodes were passively discharged between stimulation pulses. For the particular condition used (16 mA, 1 ms stimulation pulse at 20 Hz with electrodes placed 5 cm apart), the current ranged from 38 to 326 mu A depending on the type of fault. The variation of the fault current with time, stimulation amplitude, stimulation frequency and distance between the electrodes is given. Possible additional methods to improve safety are discussed.

Few clinical studies have compared these agents in warfarin rever

Few clinical studies have compared these agents in warfarin reversal. We compared warfarin reversal in patients who received either 3 factor PCC (PCC3) or low-dose rFVIIa

(LDrFVIIa) for reversal of warfarin anticoagulation. Methods: Data were collected from medical charts of patients who received at least one dose of PCC3 (20 units/kg) or LDrFVIIa (1000 or 1200 mcg) for emergent warfarin reversal from August 2007 to October 2011. The primary end-points were achievement of an INR 1.5 or less for efficacy and thromboembolic events for safety. Results: Seventy-four PCC3 and 32 LDrFVIIa patients were analyzed. Baseline demographics, reason for warfarin reversal, and initial INR were equivalent. There was no difference in the use

of vitamin K or fresh frozen plasma. More LDrFVIIa patients achieved an INR of 1.5 or less (71.9% vs. 33.8%, p = 0.001). The follow-up PF-6463922 inhibitor INR was lower after LDrFVIIa (1.25 vs. 1.75, p smaller than 0.05) and the percent change in INR was larger after LDrFVIIa BMS-777607 manufacturer (54.1% vs. 38.8%, p = 0.002). There was no difference in the number of thromboembolic events (2 LDrFVIIa vs. 5 PCC3, p = 1.00), mortality, length of hospital stay, or cost. Conclusions: Based on achieving a goal INR of 1.5 or less, LDrFVIIa was more likely than PCC3 to reverse warfarin anticoagulation. Thromboembolic events were equivalent in patients receiving PCC3 and LDrFVIIa.”
“Objective The objective of the study was to determine whether women significantly have more frequently right ventricular infarction than men. Methods The study population consisted of consecutive patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous intervention. The following criteria were used for the diagnosis of right ventricular infarction: ST-segment elevation in one of the right precordial leads V4R-V6R for equal or more than 1 mm together with ST-segment elevation in at least two contiguous inferior leads. The odds ratio for the diagnosis was calculated according to gender. Searching PubMed, nine more

relevant studies that used the same criteria for the diagnosis of right ventricular infarction Bindarit concentration were identified and a meta-analysis was conducted. Results In our group of 517 consecutive patients with STEMI, 32 (23.5%) of 136 women and 42 (11.0%) of 381 men had RVI (odds ratio (OR) = 2.48, 95% confidence interval (CI): 1.49-4.13; P=0.001). Two hundred and seventy-five patients had inferior STEMI and among them 32 (42.7%) of 75 women and 42 (23.1%) of 182 men, had a right ventricular infarction (OR=2.48, 95%CI: 1.40-4.40; P=0.002). In a meta-analysis, a total number of 4,326 patients with inferior STEMI were included. Four hundred and thirty-seven (41.4%) out of 1,056 women and 1,221 (37.3%) out of 3,270 men, had been diagnosed with RVI (OR = 1.27, 95%CI: 1.09-1.48; P=0.021). Conclusion Right ventricular infarctions occur more frequently in women than in men.

The continued use of both cell-based approaches and animal models

The continued use of both cell-based approaches and animal models will be key to fully unraveling OCRL1 function, how its loss leads to disease and, importantly, the development of therapeutics to treat patients.”
“The brain responds to injury and infection by activating innate defense and tissue repair mechanisms. Working upon the hypothesis that the brain defense response involves common genes and pathways across diverse pathologies, we analysed global gene

expression in brain from mouse models representing three major central nervous system disorders, cerebral stroke, multiple sclerosis and Alzheimer’s disease compared to normal brain using DNA microarray expression profiling. A comparison of dysregulated genes across disease models revealed common genes and pathways including key components of estrogen and TGF-beta signaling pathways that have been associated with neuroprotection CX-6258 in vitro as well as

a neurodegeneration mediator, TRPM7. Further, for each disease model, we discovered collections of differentially expressed genes that provide novel insight into the individual pathology and its associated mechanisms. Our data provide a resource for exploring the complex molecular mechanisms that underlie brain neurodegeneration and a new approach for identifying generic and disease-specific targets for therapy. (C) 2010 Elsevier Inc. selleck chemicals llc All rights reserved.”
“Breast cancer metastases develop in the bone more frequently than any other site and are a common cause of morbidity in the form of bone pain, pathological fractures, nerve compression and life-threatening hypercalcemia. Despite ongoing research efforts, the molecular and cellular mechanisms that regulate breast cancer cell homing to and colonization of the bone as well as resultant pathological check details bone alteration remain poorly understood. To identify key mediators promoting breast cancer metastasis to bone, we utilized an immunocompetent, syngeneic murine model of breast cancer metastasis

employing the mammary tumor cell line NT2.5. Following intracardiac injection of NT2.5 cells in neu-N mice, metastases developed in the bone, liver and lung, closely mimicking the anatomical distribution of metastases in patients with breast cancer. Using an in vivo selection process, we established NT2.5 sublines demonstrating an enhanced ability to colonize the bone and liver. Genome-wide cDNA microarray analysis comparing gene expression between parental NT2.5 cells and established sublines revealed both known and novel mediators of bone metastasis and osteolysis, including the transcriptional co-activator CITED2. In further studies, we found that expression of CITED2 was elevated in human primary breast tumors and bone metastasis compared to normal mammary epithelium and was highest in breast cancer cell lines that cause osteolytic bone metastasis in animal models.

An immunohistochemical

staining technique was used to det

An immunohistochemical

staining technique was used to detect the expression of matrix metalloproteinase (MMP)-2, -9, and -13, membrane type (MT)1-MMP, estrogen receptor (ER), and progesterone receptor (PR) in the main tumor and hyperostotic portions of the studied samples.\n\nIn the non-hyperostosis group, expression of MMP-13, MT1-MMP, and ER was significantly less than in the main tumor portion of hyperostotic meningiomas, while there was no difference in the expression of MMP-2 and -9 and PR in the main tumor between the two Sapanisertib research buy groups. In the hyperostosis group, the immunoreactivity of MMP-2 in the hyperostotic portion revealed a higher pattern of expression than the main tumor (p < 0.002). The expression of MMP-9, MT1-MMP, ABT-263 in vivo ER, and PR had relatively positive immunoreactivity in the main tumor portion (P < 0.05).\n\nIncreased expression of MMP-13 and MT1-MMP in the tumor portion of hyperostosis of meningiomas might contribute to the initiation of osteolysis. Activated MMP-2 in hyperostotic lesions may change the physiological metabolism of the skull bone, thus playing an

important role in hyperostosis formation.”
“We report on the phase separation in Au-Ge system leading to the formation of lobe-lobe (bi-lobed) Au-Ge nanostructures under ultra high vacuum (UHV) conditions (approximate to 3 x 10(-10) mbar) on clean Si(100) surfaces. For this study, approximate to 2.0 nm thick Au samples were grown on the substrate surface by molecular beam epitaxy. Thermal annealing was carried out inside the UHV chamber at temperature approximate to 500 degrees C and following this, nearly square shaped AuxSi(1-x) nano structures of average length approximate to 48 nm were formed. A approximate to 2 nm Ge film was further deposited on the above surface while the substrate was kept at a temperature of approximate to 500 degrees C. Well ordered Au-Ge nanostructures where Au and Ge residing side by side (lobe-lobe structures) were formed. In our systematic studies, we show that, gold-silicide

nanoalloy formation at the substrate (Si) surface is necessary for forming phase separated Au-Ge bibbed nanostructures. These results show that the Au-Ge bonding is unstable in nature. Electron microscopy (TEM, STEM-EDS, SEM) studies were carried out to determine the structure of Au-Ge nano DUB inhibitor systems. Rutherford backscattering spectrometry measurements show gold inter-diffusion into substrate while it is absent for Ge. (C) 2012 American Institute of Physics. []“
“In this communication, we present novel nanofilled polymer composites prepared using a poly(L-lactic acid) (PLLA) matrix and amyloid fibers. Amyloid fibers are made from protein sources’ and share many of the same material properties as spider silk, but exist at significantly smaller length scales with diameters of 5-10 nm.

We report a case of mutism with persistent dysarthria in a patien

We report a case of mutism with persistent dysarthria in a patient receiving tacrolimus-based immunosuppression following allogeneic liver transplantation. A 59-year-old check details female patient with end-stage liver disease secondary to primary sclerosing cholangitis underwent successful allogeneic liver transplantation. The patient was started on tacrolimus for prevention of allograft rejection and subsequently developed complete mutism. Following consultation of the medical toxicology service, tacrolimus was discontinued and the patient’s mutism gradually improved. However, the patient still has moderate dysarthria more than 2 years after tacrolimus discontinuation. The Naranjo

probability scale revealed a probable adverse CAL 101 reaction of mutism and dysarthria associated with tacrolimus therapy. Mutism is an uncommon complication of calcineurin inhibitors. Both cyclosporine and tacrolimus have been associated with mutism, though mutism may be more common in patients treated with tacrolimus. The mechanism of injury has not been delineated, although liver transplant patients and patients with preexisting hepatic encephalopathy or neurologic disease may be at increased

risk for this complication. The mainstay of treatment is tacrolimus dose reduction or discontinuation, although benzodiazepine therapy may be beneficial in the treatment of this disorder. Clinicians should be aware of the potential adverse effects associated with calcineurin inhibitor toxicity in transplant patients and should advocate for aggressive and rapid treatment of this serious adverse drug effect.”
“Background: Hypericum elegans LY3039478 nmr is used in Bulgarian folk medicine for treatment of wounds, depression, gastrointestinal and bacterial diseases. Objective: Recently, new natural benzophenones: Elegaphenone and O-glycosides: Hypericophenonoside,

Neoannulatophenonoside and Elegaphenonoside as well as already known 7-Epiclusianone were isolated from the titled species. The aim of the present study was to evaluate the antioxidant and acetyl cholinesterase inhibitory potential of the isolated compounds. Materials and Methods: 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) di-ammonium salt (ABTS) free radicals, ferric reducing antioxidant power (FRAP) assay as well as inhibition of lipid peroxidation in linoleic acid system were used for determination of antioxidant activity. Modified Ellmans colorimetric method was carried out to assess the acetyl cholinesterase inhibition potential. Hyperoside and Galantamine hydrobromide were used as positive controls. Results: Hypericophenonoside was found to possess the strongest DPPH radical scavenging activity (IC 50 = 181.85 6.82 M), while Neoannulatophenonoside showed the highest ABTS (IC 50 = 0.25 0.005 M) and lipid peroxidation inhibitor activity. FRAP activity was demonstrated only by prenylated aglycones – Elegaphenone [942.16 4.

The NCC and

AP projected bilaterally to the secondary gen

The NCC and

AP projected bilaterally to the secondary general visceral nucleus (SVN), four diencephalic nuclei (the preglomerular general visceral nucleus [pVN], nucleus of the lateral recess, posterior thalamic nucleus, and lateral tuberal area), CP-868596 preoptic area, and ventral telencephalon (supracommissural, dorsal, and ventral parts) in addition to the glossopharyngeal and vagal lobes and medullary reticular formation. Injections to the SVN resulted in labeled terminals in the forebrain structures that receive fibers from the primary centers and additionally in the diffuse nucleus of the inferior lobe, lateral torus, and inferior subdivision of lateral torus. The present study suggests that the ascending general visceral projections arising GSI-IX cost from the brainstem centers in teleosts are quite similar to those in mammals and birds. Descending pathways were also

notable. In addition to descending projections from the SVN and medullary structures to the primary centers, long descending pathways to the SVN, NCC, and AP were found to originate from the pVN, nucleus of the lateral recess, posterior thalamic nucleus, and preoptic area. The SVN was found to receive fibers from the ventral telencephalon as well. Therefore, the present study indicates that most of the general visceral structures in the forebrain are reciprocally connected with the brainstem centers. J. Comp. Neurol. 518:3570-3603, 2010. (C) 2010

Wiley-Liss, Inc.”
“Metastatic malignant melanoma remains one of the most dreaded skin cancers worldwide. Numerous factors contribute to its resistance to hosts of treatment regimes and despite significant scientific advances over the last decade in the field of chemotherapeutics and melanocytic targets, there still remains the need for improved therapeutic modalities. Photodynamic therapy, a minimally invasive therapeutic modality has been shown to be effective in a number of oncologic and non-oncologic conditions. Using second-generation stable, lipophilic photosensitizers with optimised wavelengths, PDT may be a promising tool for adjuvant therapy in combating GM6001 supplier melanoma. Potential targets for PDT in melanoma eradication include cell proliferation inhibition, activation of cell death and reduction in pro-survival autophagy and a decrease in the cellular melanocytic antioxidant system. This review highlights the current knowledge with respect to these characteristics and suggests that PDT be considered as a good candidate for adjuvant treatment in post-resected malignant metastatic melanoma. Furthermore, it suggests that primary consideration must be given to organelle-specific destruction in melanoma specifically targeting the melanosomes – the one organelle that is specific to cells of the melanocytic lineage that houses the toxic compound, melanin.

In zebrafish, IL-22 expression was detected primarily in the myel

In zebrafish, IL-22 expression was detected primarily in the myeloid innate linage. It was found during early developmental stages when the adaptive immune response is not yet functional and in rag1(-/-) fish that lack an adaptive immune system. Our results clarify the conserved role of IL-22 in lower vertebrates. We suggest for the first time that IL-22 constitutes a key regulator of inflammatory homeostasis even in distant species such as teleosts, which diverged from mammals more than 350 million years ago. (C) 2013 Elsevier Ltd. All rights reserved.”
“Human carbonic anhydrase II (HCA II) is a monomeric zinc-containing metalloenzyme that catalyzes the hydration Of

CO2 to form bicarbonate and a proton. The properties of the zinc have been extensively elucidated in catalysis but less well studied as a contributor to structure and stability. Apo-HCA II (without zinc) was prepared and compared to holo-HCA II: in crystallographic structural features, in backbone amide H/D exchange, and in thermal stability. The removal of zinc from the active site has no effect on either the topological fold of the enzyme S3I-201 or the ordered water network in the active site. However, the removal of the zinc alters the collective electrostatics of the apo-HCA II that result in the following differences from that of the holoenzyme: (1) the main thermal unfolding transition of the apo-HCA II is lowered by 8 degrees C, (22) the

relative increase in thermal mobility of atoms of the apo-HCA II was not observed in the vicinity of the active site but manifested on the surface of the enzyme, and (3) the side chain of His 64, the proton shuttle A-1210477 in vitro residue that sits oil the rim of the active site, is oriented outward and is associated with additional ordered “external” waters, as opposed to a near equal inward and outward orientation in the holo-HCA II.”
“Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological

responses. They are produced by oxidation of arachidonic acid (AA) by cyclo- oxygenases (COX-1 and COX-2) followed by metabolism of endoperoidde intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2′-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity.