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Zengin, Gokhan, Mohamad Fawzi Mahomoodally, Kouadio Ibrahime Sinan, Gunes Ak, Ouattara Katinan Etienne, Jugreet B. Sharmeen, Luigi Brunetti, et al. "Chemical Composition and Biological Properties of Two Jatropha Species: Different Parts and Different Extraction Methods." Antioxidants 10, no. 5 (May 17, 2021): 792. http://dx.doi.org/10.3390/antiox10050792.
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Jatropha L. species, in particular, J. curcas and J. gossypiifolia, are well known medicinal plants used for treating various diseases. In the present study, leaf and stem bark extracts of J. curcas and J. gossypiifolia obtained by maceration or homogenizer assisted extraction, were investigated for their phytochemical contents and biological potential as antioxidants, enzyme inhibitors and neuromodulators. In this regard, the gene expression of tumor necrosis factor α (TNFα) and brain-derived neurotrophic factor (BDNF) was investigated in hypothalamic HypoE22 cells. Finally, a bioinformatics analysis was carried out with the aim to unravel the putative mechanisms consistent with both metabolomic fingerprints and pharmacological effects. The leaf extracts of J. curcas showed higher total phenolic content (TPC) and total flavonoid content (TFC) than the stem bark extracts (range: 5.79–48.95 mg GAE/g and 1.64–13.99 mg RE/g, respectively), while J. gossypiifolia possessed TPC and TFC in the range of 42.62–62.83 mg GAE/g and 6.97–17.63 mg RE/g, respectively. HPLC-MS/MS analysis revealed that the leaf extracts of both species obtained by homogenizer assisted extraction are richer in phytochemical compounds compared to the stem bark extracts obtained by the same extraction method. In vitro antioxidant potentials were also demonstrated in different assays (DPPH: 6.89–193.93 mg TE/g, ABTS: 20.20–255.39 mg TE/g, CUPRAC: 21.07–333.30 mg TE/g, FRAP: 14.02–168.93 mg TE/g, metal chelating activity: 3.21–17.51 mg EDTAE/g and phosphomolybdenum assay: 1.76–3.55 mmol TE/g). In particular, the leaf extract of J. curcas and the stem bark extract of J. gossypiifolia, both obtained by homogenizer assisted extraction, showed the most potent antioxidant capacity in terms of free radical scavenging and reducing activity, which could be related to their higher TPC and TFC. Furthermore, anti-neurodegenerative (acetylcholinesterase inhibition: 1.12–2.36 mg GALAE/g; butyrylcholinetserase inhibition: 0.50–3.68 mg GALAE/g), anti-hyperpigmentation (tyrosinase inhibition: 38.14–57.59 mg KAE/g) and antidiabetic (amylase inhibition: 0.28–0.62 mmol ACAE/g; glucosidase inhibition: 0.65–0.81 mmol ACAE/g) properties were displayed differentially by the different extracts. Additionally, the extracts were effective in reducing the gene expression of both TNFα and BDNF, which could be partially mediated by phenolic compounds such as naringenin, apigenin and quercetin. Indeed, the scientific data obtained from the present study complement the several other reports highlighting the pharmacological potentials of these two species, thus supporting their uses as therapeutically active plants.
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AYENI, OLUBIMPE, WAYNE CAREY, and CHANNY MUHN. "Acne Scar Treatment with Subcision Using a 20-G Cataract Blade." Dermatologic Surgery 37, no. 6 (May 23, 2011): 846–47. http://dx.doi.org/10.1111/j.1524-4725.2011.02010..x.
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AYENI, OLUBIMPE, WAYNE CAREY, and CHANNY MUHN. "Acne Scar Treatment with Subcision Using a 20-G Cataract Blade." Dermatologic Surgery 37, no. 6 (June 2011): 846–47. http://dx.doi.org/10.1111/j.1524-4725.2011.02010.x.
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Szabó, K., G. Tax, K. Kis, K. Szegedi, D. G. Teodorescu-Brinzeu, C. Diószegi, A. Koreck, M. Széll, and L. Kemény. "Interleukin-1A +4845(G> T) polymorphism is a factor predisposing to acne vulgaris." Tissue Antigens 76, no. 5 (July 11, 2010): 411–15. http://dx.doi.org/10.1111/j.1399-0039.2010.01530.x.
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Cheraif, Kadour, Boulanouar Bakchiche, Abdelaziz Gherib, Sanaa K. Bardaweel, Melek Çol Ayvaz, Guido Flamini, Roberta Ascrizzi, and Mosad A. Ghareeb. "Chemical Composition, Antioxidant, Anti-Tyrosinase, Anti-Cholinesterase and Cytotoxic Activities of Essential Oils of Six Algerian Plants." Molecules 25, no. 7 (April 8, 2020): 1710. http://dx.doi.org/10.3390/molecules25071710.
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In this study, the essential oils (EOs) of six Algerian plants (Artemisia campestris L., Artemisia herba-alba Asso, Juniperus phoenicea L., Juniperus oxycedrus L., Mentha pulegium L. and Lavandula officinalis Chaix) were obtained by hydrodistillation, and their compositions determined by GC-MS and GC-FID. The antioxidant activity of the EOS was evaluated via 2,2′-diphenyl-1-picrylhydrazyl (DPPH), ferric-reducing/antioxidant power (FRAP) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) assays. Moreover, their cytotoxic effect was evaluated—as well as their tyrosinase, acetyl- and butyryl-cholinesterase (AChE and BuChE) inhibitory activities. The chemical analyses detected 44, 45, 51, 53, 26 and 40 compounds in EOs of A. campestris, A. herba-alba, J. phoenicea, J. oxycedrus, M. pulegium and L. officinalis, respectively. A. campestris EO was mainly composed of β-pinene (20.7%), while A. herba-alba EO contained davanone D (49.5%) as the main component. α-Pinene (41.8%) was detected as the major constituent in both J. phoenicea (41.8%) and J. oxycedrus (37.8%) EOs. M. pulegium EO was characterized by pulegone as the most abundant (76.9%) compound, while linalool (35.8%) was detected as a major constituent in L. officinalis EO. The antioxidant power evaluation revealed IC50 values ranging from 2.61 to 91.25 mg/mL for DPPH scavenging activity, while the FRAP values ranged from 0.97–8.17 µmol Trolox equivalents (TX)/g sample. In the ABTS assay, the values ranged from 7.01 to 2.40 µmol TX/g sample. In the presence of 1 mg/mL of the samples, tyrosinase inhibition rates ranged from 11.35% to 39.65%, AChE inhibition rates ranged from 40.57% to 73.60% and BuChE inhibition rates ranged from 6.47% to 72.03%. A significant cytotoxic effect was found for A. herba-alba EO. The obtained results support some of the traditional uses of these species in food preservation and for protection against several diseases.
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Salleh, Wan Mohd Nuzul Hakimi Wan, Farediah Ahmad, and Khong Heng Yen. "Evaluation of Antioxidant, Anticholinesterase and Antityrosinase Activities of Malaysian Cinnamomum Species." Dhaka University Journal of Pharmaceutical Sciences 14, no. 2 (June 28, 2016): 125–32. http://dx.doi.org/10.3329/dujps.v14i2.28500.
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The extracts of the leaves and bark of five Cinnamomum species (C. altissimum, C. griffithii, C. javanicum, C. macrocarpum, and C. velutinum) were screened to evaluate their antioxidant, anticholinesterase, and antityrosinase activities. The bark of C. altissimum showed the highest phenolic content (130.1 mg GA/g), free radical scavenging by DPPH (IC50 126.2 ?g/mL) and ferric reducing antioxidant power (FRAP) assays (341.2 mg AA/g). All of the extracts inhibited linoleic acid peroxidation by greater than 70%, with the leaves of C. altissimum exhibiting the highest inhibition of 87.7%. The leaves of C. javanicum revealed the highest inhibition on anticholinesterase (AChE 30.8%) and butyrylcholinesterase (BChE 46.8%) enzymes. The leaves and bark of C. altissimum and C. velutinum exhibited greater than 20% tyrosinase inhibition, with the leaves of C. altissimum having the highest percentage of inhibition (34.6%). These bioactivities indicate that some Cinnamomum species have therapeutic potential in medicinal research and development of new drugs candidates.Dhaka Univ. J. Pharm. Sci. 14(2): 125-132, 2015 (December)
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Comfort Sankem Yusuf, Ibrahim Birma Bwatanglang, Tari Dlama Tizhe, Peter Emmanuel Tosin, and Musa Ira Felister. "Ethnobotany and phytochemical analysis of Jatropha Tanjorensis in Mubi Adamawa State, Nigeria." International Journal of Frontiers in Life Science Research 1, no. 1 (May 30, 2021): 040–47. http://dx.doi.org/10.53294/ijflsr.2021.1.1.0035.
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This study was focused on the ethanobotanical survey, phytochemical and proximate analysis of Jatropha tanjorensis in Mubi. The ethnobotanical survey was carried out in some selected parts of both Mubi North and South local government area through oral interview using traditional medicine practioners and some householders as the interviewee. After air drying, pulverizing and extracting the bioactive constituents of the leaf using ethanol and water as solvents, the phytochemical and proximate analysis were carried out using a standard procedures. The ethnobotanical survey showed that, J. tanjorensis were used in the study area as a remedy to diseases such as: measles, scabies, malaria, high blood pressure, stomach ache, diabetes mellitus, eczema and anaemia with 74 % of the interviewee mentioning leaves as part mostly used. The qualitative phytochemical screening indicated the presence of compounds, namely: tannins, alkaloids, phenols, flavonoids, saponins, terpenoids, glycosides and anthraquinones in both the ethanoic and aqueous leaf extracts except terpenoids which was not detected in the ethanolic extract. The quantitative analysis showed glycosides (4.12 mg/100 g) and flavonoids (3.45 mg/100 g) as the highest compound in the ethanolic and aqueous extracts respectively. Carbohydrate was shown to be the highest proximate constituent with 52.38 % and fat the least with 1.76 %. Therefore, J. tanjorensis is rich in bioactive constituents and the leaves are mostly the plant part used as a remedy to illnesses such measles, scabies, malaria, high blood pressure, stomach ache, diabetes mellitus, eczema and anaemia.
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Hafez, S. L., P. Sundararaj, Z. A. Handoo, A. M. Skantar, L. K. Carta, and D. J. Chitwood. "First Report of the Pale Cyst Nematode, Globodera pallida, in the United States." Plant Disease 91, no. 3 (March 2007): 325. http://dx.doi.org/10.1094/pdis-91-3-0325b.
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In 2006, a cyst nematode was discovered in tare dirt at a potato (Solanum tuberosum) processing facility in eastern Idaho. The nematode was found during a routine survey conducted jointly by the Idaho State Department of Agriculture and the USDA Animal and Plant Health Inspection Service through the Cooperative Agricultural Pest Survey program. Extensive additional sampling from two suspect fields led to the identification of the same nematode in a 45-acre (18.2-ha) field located in northern Bingham County. The morphology of cysts and second-stage juveniles and molecular analyses established the identity of the species as the pale cyst nematode Globodera pallida (Stone 1973) Behrens 1975. Morphological characters used for identification included cyst shape, characteristics of cyst terminal cone including nature of fenestration, cyst wall pattern, anal-vulval distance, number of cuticular ridges between anus and vulva, and Granek's ratio (1,4). The second-stage juvenile morphologies critical for identification were the following: body and stylet length, shape of stylet knobs, shape and length of tail and hyaline tail terminus, and number of refractive bodies in the hyaline part of tail (1,4). Diagnosis as G. pallida was clearly confirmed by two molecular tests. First, PCR-RFLP (restriction fragment length polymorphism) profiles of a ribosomal DNA fragment using restriction enzymes RsaI, TaqI, and AluI (2) were consistent with a G. pallida control and not G. rostochiensis. Second, the ribosomal DNA region that extends from the 3′ end of the 18S ribosomal subunit and includes all of ITS1, 5.8S, and ITS2 to the 5′ end of the 28S ribosomal subunit was used to generate sequence for the most accurate species determination. Sequences obtained from three individual juveniles were compared with those from several Globodera species (3), revealing unequivocal similarity to G. pallida. This detection represents a new country record for G. pallida in the United States. Collection of additional information regarding distribution of this nematode within the region is underway. References: (1) J. G. Baldwin and M. Mundo-Ocampo. Heteroderinae, Cyst- and Non-cyst-forming Nematodes. Pages 275-362 in: Manual of Agricultural Nematology. W. R. Nickle, ed. Marcel Dekker, New York, 1991. (2) V. C. Blok et al. J. Nematol. 30:262, 1998. (3) L. A. Pylypenko et al. Eur. J. Plant Pathol. 111:39, 2005. (4) A. R. Stone. Nematologica 18:591, 1973.
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Álvaro, J. Javier, and Jorge Esteve. "Reply to Comment on: Álvaro J.J., Esteve, J. & Zamora, S. 2019. Morphological assessment of the earliest paradoxidid trilobites (Cambrian Series 3) from Morocco and Spain [Geological Magazine] by Geyer G, Nowicki J, Żylińska A & Landing E." Geological Magazine 157, no. 12 (April 13, 2020): 1971–82. http://dx.doi.org/10.1017/s0016756820000217.
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AbstractTwo research teams have different opinions regarding the number of paradoxidine species close to the base of the Miaolingian in Morocco and Spain. Geyer & Vincent (2015) recognized five species based on a mosaic of overlapping characters that include some relative length and width ratios, qualitative descriptions of cranidial and pygidial outlines, and relief observations. In contrast, Álvaro et al. (2018) conducted a morphometric analysis of all these specimens from the Cambropallas telesto acme level of the Assemame quarry and concluded that the Moroccan material had been taxonomically over-split and was represented by only two species, Acadoparadoxides mureroensis and A. nobilis. Subsequently, Geyer et al. (2019) commented that we had not analysed some diagnostic characters, and applied the stratigraphic setting of their morphospecies as a diagnostic character for taxonomic identification. After sampling the Cambropallas telesto acme level in the Taroucht quarry, where the other team purchased its collection, and re-analysing the diagnostic characters claimed by Geyer et al. (2019), our conclusions are maintained: (i) morphometric values of several paratype specimens fall outside the purported ranges of diagnostic characters; (ii) all 2D morphometric analyses incorporating the diagnostic characters of the morphospecies are unable to detect interspecific differences, except for A. nobilis; and (iii) the slight concavity displayed by some pygidia, strongly controlled by preservation, is in need of 3D biometrical analysis. Hence, our proposed synonymy should be maintained until 3D statistical analyses are available on material preserved in carbonate or concretions.
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Mahomoodally, Mohamad Fawzi, Nabeelah Bibi Sadeer, Gokhan Zengin, Zoltán Cziáky, József Jekő, Alina Diuzheva, Kouadio Ibrahime Sinan, Kishneth Palaniveloo, Doo Hwan Kim, and Kannan R. R. Rengasamy. "In Vitro Enzyme Inhibitory Properties, Secondary Metabolite Profiles and Multivariate Analysis of Five Seaweeds." Marine Drugs 18, no. 4 (April 8, 2020): 198. http://dx.doi.org/10.3390/md18040198.
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Seaweeds have been exploited as both food products and therapeutics to manage human ailments for centuries. This study investigated the metabolite profile of five seaweeds (Halimeda spp., Spyridia hypnoides (Bory de Saint-Vincent) Papenfuss, Valoniopsis pachynema (G. Martens) Børgesen, Gracilaria fergusonii J. Agardh and Amphiroa anceps (Lamarck) Decaisne using ultra-high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (UHPLC-ESI-MS/MS). Furthermore, these seaweeds were assessed for antioxidant and inhibitory effects against α-amylase, α-glucosidase, acetyl-cholinesterase (AChE), butyryl-cholinesterase (BChE) and tyrosinase. Valoniopsis pachynema and A. anceps yielded the highest flavonoid (4.30 ± 0.29 mg RE/g) and phenolic content (7.83 ± 0.08 mg RE/g), respectively. Additionally, A. anceps exhibited significant antioxidant properties with all assays and significantly depressed BChE (IC50 = 6.68 ± 0.83 mg/mL) and α-amylase activities (IC50 = 5.34 ± 0.14 mg/mL). Interestingly, the five seaweeds revealed potent inhibitory effects against tyrosinase activity. In conclusion, A. anceps might be considered as a key source of phytoantioxidants and a potential candidate to develop nutritional supplements. Besides, the five tested seaweeds warrant further study and may be exploited as promising natural sources for managing hyperpigmentation.
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Wang, Rongqi, Alex Zagariya, Edmund Ang, Olivia Ibarra-Sunga, and Bruce D. Uhal. "Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction." American Journal of Physiology-Lung Cellular and Molecular Physiology 277, no. 6 (December 1, 1999): L1245—L1250. http://dx.doi.org/10.1152/ajplung.1999.277.6.l1245.
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Recent works from this laboratory demonstrated potent inhibition of Fas-induced apoptosis in alveolar epithelial cells (AECs) by the angiotensin-converting enzyme (ACE) inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 ( Lung Cell. Mol. Physiol. 19): L1013–L1017, 1998] and induction of dose-dependent apoptosis in AECs by purified angiotensin (ANG) II [R. Wang, A. Zagariya, O. Ibarra-Sunga, C. Gidea, E. Ang, S. Deshmukh, G. Chaudhary, J. Baraboutis, G. Filippatos and B. D. Uhal. Am. J. Physiol. 276 ( Lung Cell. Mol. Physiol. 20): L885–L889, 1999]. These findings led us to hypothesize that the synthesis and binding of ANG II to its receptor might be involved in the induction of AEC apoptosis by Fas. Apoptosis was induced in the AEC-derived human lung carcinoma cell line A549 or in primary AECs isolated from adult rats with receptor-activating anti-Fas antibodies or purified recombinant Fas ligand, respectively. Apoptosis in response to either Fas activator was inhibited in a dose-dependent manner by the nonthiol ACE inhibitor lisinopril or the nonselective ANG II receptor antagonist saralasin, with maximal inhibitions of 82 and 93% at doses of 0.5 and 5 μg/ml, respectively. In both cell types, activation of Fas caused a significant increase in the abundance of mRNA for angiotensinogen (ANGEN) that was unaffected by saralasin. Transfection with antisense oligonucleotides against ANGEN mRNA inhibited the subsequent induction of Fas-stimulated apoptosis by 70% in A549 cells and 87% in primary AECs (both P < 0.01). Activation of Fas increased the concentration of ANG II in the serum-free extracellular medium 3-fold in primary AECs and 10-fold in A549 cells. Apoptosis in response to either Fas activator was completely abrogated by neutralizing antibodies specific for ANG II ( P < 0.01), but isotype-matched nonimmune immunoglobulins had no significant effect. These data indicate that the induction of AEC apoptosis by Fas requires a functional renin-angiotensin system in the target cell. They also suggest that therapeutic control of AEC apoptosis is feasible through pharmacological manipulation of the local renin-angiotensin system.
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Hossain, M. I., M. I. Hossain, M. M. Kamal, M. A. Mannan, and M. A. B. Bhuyain. "Effects of Probiotics on Growth and Survival of Shrimp (Penaeus monodon) in Coastal Pond at Khulna, Bangladesh." Journal of Scientific Research 5, no. 2 (April 23, 2013): 363–70. http://dx.doi.org/10.3329/jsr.v5i2.11815.
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The study was carried out for 138 days to know the growth and survival rate of P. monodon by applying probiotics in Gazi Fish Culture Ltd. Dacope, Khulna, Bangladesh. Six experimental ponds (4000 m2 in size i.e. one acre) were selected of which three were probiotic ponds and three were controlled. After pond preparation, PL15 (average weight of each 4.75±0.09 g) was stocked at the rate of 13 per m2 following polymerase chain reaction (PCR) test. CP NASA shrimp feed was used during the study period. Transparency, salinity, pH, dissolved oxygen (DO), temperature, total Ammonia Nitrogen (TAN) were recorded by standard measurements. The average final body weight of the harvested shrimp is 37.67±1.15 g in probiotics ponds and 27.33±0.58 g in controlled ponds and the difference was significant (P < 0.01) between these two productions. The average survival rate was 90.67±1.15 % in probiotic pond and 71.00±3.0 % in controlled pond. The average daily gain (ADG) in weight was 0.27±0.01 g and 0.19±0.01 g in probiotic and controlled ponds, respectively. The result showed that probiotic plays an important role in maintaining water quality parameters, soil quality and health management as well as increases the growth and survival of shrimp.Key words: Probiotics; P. monodon; Water quality parameter; Growth rate; Survival rate.© 2013 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi: http://dx.doi.org/10.3329/jsr.v5i2.11815 J. Sci. Res. 5 (2), 363-370 (2013)
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Rao, B. Ramalingeswara, Mohana R. Katiki, Kommula Dileep, C. Ganesh Kumar, G. Narender Reddy, Jagadeesh B. Nanubolu, and M. S. R. Murty. "Synthesis and Biological Evaluation of Benzothiazole-piperazinesulfonamide Conjugates and Their Antibacterial and Antiacetylcholinesterase Activity." Letters in Organic Chemistry 16, no. 9 (July 5, 2019): 723–34. http://dx.doi.org/10.2174/1570178615666181113094539.
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Two series of N-2-benzothiazolyl-4-(arylsulfonyl)-1-piperazineacetamides/propanamides were synthesized from substituted 2-aminobenzothiazoles and were assayed for their in vitro antimicrobial activities against a panel of different pathogenic bacterial strains such as Micrococcus luteus, S. aureus, S. aureus MLS-16, B. subtilis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella planticola and Candida albicans. Among the synthesized compounds 5e,f,g and 6g,h,i showed promising antifungal activity against C. albicans as compared to the reference drug, miconazole. Further, compounds 6g,h,i showed broad spectrum antibacterial activity against all the tested bacterial strains, while the compounds 6a-f,j-m showed significant antibacterial activity against all the tested bacterial strains as compared to the reference drug, ciprofloxacin. In addition, the target compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity, and, among the tested, compounds 5j,k,l and 6i showed promising AChE inhibitory activity.
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Tsakiris, Stylianos, Panagiota Kouniniotou-Krontiri, Kleopatra H. Schulpis, and John C. Stavridis. "ʟ-Phenylalanine Effect on Rat Brain Acetylcholinesterase and Na+,K+-ATPase." Zeitschrift für Naturforschung C 53, no. 3-4 (April 1, 1998): 163–67. http://dx.doi.org/10.1515/znc-1998-3-404.
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Abstract The effect of different L-phenylalanine (Phe) concentrations (0 .1-12.1 mᴍ) , on acetylcholinesterase (AChE ) and Na+,K+-ATPase activities of brain homogenate and pure enzymes, was investigated at 37 °C. AChE and Na+,K+-ATPase activities were determined according to Ellman G. L., Courtney D., Andres V. and Featherstone R. M. (1961), Biochem. Pharmacol. 7, 88 - 95 and Bowler K. and Tirri R. (1974), J. Neurochem. 23, 611-613 ) respectively, after preincubation with Phe. AChE activity in brain homogenate or in pure eel E.electricus enzyme showed a decrease, which reached up to 18% with concentrations of 0.9-12.1 mᴍ. Brain homogenate Na+,K+-ATPase activity showed an increase 16-65% with 0.24-0.9 mᴍ of Phe, while an activity increase of 60 -65% appeared with 0.9-12.1 mᴍ of Phe. Pure enzyme activity (from porcine cerebral cortex) was not affected by high Phe concentrations, while it was increased by low concentrations. The above results suggest: a) A direct effect of Phe on AChE, b) A direct effect of low Phe concentrations and an indirect effect of high ones on Na+,K+-ATPase.
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Gibson, Courtenay St John, and Catherine O. Ringen. "Icelandic umlaut in Optimality Theory." Nordic Journal of Linguistics 23, no. 1 (June 2000): 49–64. http://dx.doi.org/10.1080/033258600750045778.
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This paper presents an analysis of Icelandic umlaut in Optimality Theory. We account for umlaut in sal[œ]t-[Y]m ‘lettuce’ (dat. pl.) and d[œ:]g-[Y]m ‘day’ (dat. pl.), in which /a/ is fronted and rounded when followed by [Y], as well as forms such as j[œ]kli ‘glacier’ (dat. sg.) and b[œ]rn ‘child’ (ace. pl.) with an umlauted vowel, but no overt trigger. We explain why there is no umlaut in forms such as dal-n[Y]m ‘valley’ (def.), kakt[Y]s ‘cactus’ (nom. sg.), or d[a:]g-[Y]r ‘day’ (nom. sg.) despite the fact that /a/ occurs in the umlaut environment. We also explain why there is one umlauted vowel in sal[œ]t-[Y]m ≪ /salat + Ym/, but two umlauted vowels in f[œ]t-n[Y]ð-[Y]m ≪ /fat + nað + Ym/ ‘clothing’ (dat. pl.) and why the umlauted vowel is sometimes [Y] and sometimes [œ].
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Li, Yanwei, Likai Du, Yueming Hu, Xiaomin Sun, and Jingtian Hu. "Theoretical study on the aging and reactivation mechanism of tabun-inhibited acetylcholinesterase by using the quantum mechanical / molecular mechanical method." Canadian Journal of Chemistry 90, no. 4 (April 2012): 376–83. http://dx.doi.org/10.1139/v2012-007.
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The organophosphorous compound tabun is highly neurotoxic because of its irreversible inhibition on acetylcholinesterase (AChE). It is wildly used as a warfare agent in the military. In this work, the aging and reactivation mechanism of tabun-inhibited AChE were studied by using the quantum mechanical / molecular mechanical (QM/MM) method. Geometry optimization of the stationary points were performed at the B3LYP/6–31G(d) level. Single-point energies were computed at the B3LYP/6–311++G(d,p) level. On the basis of the QM/MM results, a conclusion that the C–O bond scission is caused by water attack on the ethoxy group in the aging mechanism can be drawn. The reactivation process initialed by the antidotes CH2NO– or HLÖ-7 consists of three elemental steps, the nucleophilic attack on the P atom by the antidote, the dephosphorylation process, and the decomposition of the antidote–tabun complex. The highest energy barriers of the aging reaction, CH2NO–-induced reactivation, and HLÖ-7-induced reactivation are 19.9, 20.0, and 14.8 kcal/mol (1 cal = 4.184 J), respectively. The relative lower overall energy barrier of HLÖ-7-induced reactivation compared with that of the aging reaction indicates that HLÖ-7 is able to reactivate tabun-inhibited AChE. In addition, whether a newly designed antidote is able to reactivate tabun-inhibited AChE can be examined by the inequation X < 19.9 kcal/mol,where X means the highest energy barrier of the reactivation reaction of the newly designed antidote.
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Fontes-Villalba, Ariadna, and John Parratt. "108 Longitudinally extensive transverse myelitis as the sole manifestation of sarcoidosis." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 6 (May 24, 2018): A43.1—A43. http://dx.doi.org/10.1136/jnnp-2018-anzan.107.
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IntroductionNeurosarcoidosis is a rare disease with variable clinical and radiological manifestations. We report a case of longitudinally extensive transverse myelitis mimicking NMO that was pathologically confirmed to be sarcoidosis.Case a 50 year old Caucasian man presented with left arm paraesthesia, sensory and gait disturbance. Spinal MRI showed a swollen longitudinally extensive cord lesion (6 spinal segments) with peripheral enhancement. Brain MRI was normal. The CSF protein was 0.51 g/L and oligoclonal bands were restricted to the CSF. AQP-4 and MOG antibodies were negative. Serum ACE, vasculitis, and infectious screens were negative. The patient was administered a four day course of 1 g of iv methylprednisolone once daily, and improved clinically and radiologically. However, subsequent deterioration prompted treatment with plasma exchange (6 courses) and rituximab, which was ineffective. The peripheral nature of the enhancement pattern and steroid responsiveness prompted a whole body PET, showing FDG avid mediastinal lymph nodes, and a biopsy demonstrated non-necrotizing granulomas. Mycobacteria were absent. The diagnosis of sarcoidosis was made and the patient was initiated on intravenous infliximab (500 mg at 0, 2, 6 and 8 weeks). The patients gait and sensation improved.ConclusionNeurosarcoidosis should be included in the differential of longitudinally extensive transverse myelitis, particularly in AQP4-IgG seronegative patients.References1. Tavee JO, Stern BJ. Neurosarcoidosis. Continuum (Minneap Minn)2014Jun;20(3 Neurology of Systemic Disease):545–59.2. Sohn M, Culver DA, Judson MA, Scott TF, Tavee J, Nozaki K. Spinal cord neurosarcoidosis. Am J Med Sci2014Mar;347(3):195–8.3. Flanagan EP, Kaufmann TJ, Krecke KN, Aksamit AJ, Pittock SJ, Keegan BM, Giannini C, Weinshenker BG. Discriminating long myelitis of neuromyelitis optica from sarcoidosis. Ann Neurol2016Mar;79(3):437–47.
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Rücker, Nadine, Sandra Billig, René Bücker, Dieter Jahn, Christoph Wittmann, and Franz-Christoph Bange. "Acetate Dissimilation and Assimilation in Mycobacterium tuberculosis Depend on Carbon Availability." Journal of Bacteriology 197, no. 19 (July 27, 2015): 3182–90. http://dx.doi.org/10.1128/jb.00259-15.
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ABSTRACTMycobacterium tuberculosispersists inside granulomas in the human lung. Analysis of the metabolic composition of granulomas from guinea pigs revealed that one of the organic acids accumulating in the course of infection is acetate (B. S. Somashekar, A. G. Amin, C. D. Rithner, J. Troudt, R. Basaraba, A. Izzo, D. C. Crick, and D. Chatterjee, J Proteome Res 10:4186–4195, 2011, doi:http://dx.doi.org/10.1021/pr2003352), which might result either from metabolism of the pathogen or might be provided by the host itself. Our studies characterize a metabolic pathway by whichM. tuberculosisgenerates acetate in the cause of fatty acid catabolism. The acetate formation depends on the enzymatic activities of Pta and AckA. Using actyl coenzyme A (acetyl-CoA) as a substrate, acetyl-phosphate is generated and finally dephosphorylated to acetate, which is secreted into the medium. Knockout mutants lacking either theptaorackAgene showed significantly reduced acetate production when grown on fatty acids. This effect is even more pronounced when the glyoxylate shunt is blocked, resulting in higher acetate levels released to the medium. The secretion of acetate was followed by an assimilation of the metabolite when other carbon substrates became limiting. Our data indicate that during acetate assimilation, the Pta-AckA pathway acts in concert with another enzymatic reaction, namely, the acetyl-CoA synthetase (Acs) reaction. Thus, acetate metabolism might possess a dual function, mediating an overflow reaction to release excess carbon units and resumption of acetate as a carbon substrate.IMPORTANCEDuring infection, host-derived lipid components present the major carbon source at the infection site. β-Oxidation of fatty acids results in the formation of acetyl-CoA. In this study, we demonstrate that consumption of fatty acids byMycobacterium tuberculosisactivates an overflow mechanism, causing the pathogen to release excess carbon intermediates as acetate. The Pta-AckA pathway mediating acetate formation proved to be reversible, enablingM. tuberculosisto reutilize the previously secreted acetate as a carbon substrate for metabolism.
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Bui, Hoa Thi Hai, Tam Thi Pham, Hien Thi Thu Nguyen, Trung Minh Do, Vu Thi Nga, Nguyen Duy Bac, Vu Thi Bich Huyen, Hai Minh Le, and Quang Canh Tran. "Transformation Chlorophyll a of Spirulina platensis to Chlorin e6 Derivatives and Several Applications." Open Access Macedonian Journal of Medical Sciences 7, no. 24 (December 20, 2019): 4372–77. http://dx.doi.org/10.3889/oamjms.2019.838.
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BACKGROUND: Spirulina platensis contains a large amount of chlorophylls, chlorophyll a, that are starting materials to synthesize functionalized chlorins. Chlorin e6 (Ce6) as well as its derivatives are second generation sensitizers using in photodynamic therapy (PDT) of various cancers. In this study, we transfer chlorophyll a of S. platensis to Ce6derivatives and determine their several applications.
AIM: to evaluate the effects of Ce6 derivatives to treat cancer cells.
METHODS: Ce6 trimethylester was created from methyl pheophorbide a2 in S. platensis provided by the Hidumi Company, Nghe An province, Viet Nam. Hela cells were incubated with Ce6 trimethylester and the irradiated with the diode laser dose of 1.2 J/cm2/min through the system of filters £ 650 nm. MTT assay and clonogenic assay were used to determine survival rate and cloning efficiency of cells. Antimicrobial effect of Ce6 trimethylester with halogen light were studied with Propionibacterium acnes VTCC 0218 and Staphylococcus aureus VTCC 0173.
RESULTS: From dry biomass (700 g) of S. platensis, after extracting chlorophyll a and methanolysis, 4.2 g of methyl pheophorbide a was obtained. The reaction to give Ce6 trimethylester with 82% yield was performed with potassium hydroxide (KOH) in MeOH/THF/CHCl3. After irradiation with a 650 nm laser at 1.2 J, the cell viability in all samples decreased with Ce6 trimethylester treatment, the survival declining trend of Hela cells treated with Ce6 trimethylester were proportional when concentration of Ce6 trimethylester increased. The rate of colony formation was declined as the concentration of Ce6 trimethylester treated was increased. The growth of both S. aureus and P. acnes can be inactivated by Ce6 trimethylester PDT. The MIC99 value against P. acnes VTCC 0218 and S. aureus VTCC 0173 of Ce6 trimethylester with halogen light was 1.25 μg/ml.
CONCLUSION: The Ce6 trimethylester from S. platensis cultivated in Viet Nam could be used as a potential photosentizer for photodynamic therapy for treatment of cancer and acne.
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Platzbecker, Uwe, Ulrich Germing, Aristoteles Giagounidis, Katharina Goetze, Philipp Kiewe, Karin Mayer, Oliver Ottman, et al. "ACE-536 Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from a Phase 2 Study." Blood 124, no. 21 (December 6, 2014): 411. http://dx.doi.org/10.1182/blood.v124.21.411.411.
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Abstract Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis, such as myelodysplastic syndromes (MDS). Patients with MDS often have elevated levels of erythropoietin (EPO) and may be non-responsive or refractory to erythropoiesis-stimulating agents (ESAs). MDS patients have also been shown to have increased serum GDF11 levels (Suragani R et al., Nature Medicine 2014) and increased Smad 2/3 signaling in the bone marrow (Zhou L et al., Blood 2008). ACE-536 binds to ligands in the TGF-ß superfamily, including GDF11, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. RAP-536 (murine version of ACE-536) reduced Smad 2 signaling, increased hemoglobin (Hb) levels and decreased bone marrow erythroid hyperplasia in a mouse model of MDS (Suragani R et al., Nature Medicine 2014). In a healthy volunteer study, ACE-536 was well-tolerated and increased Hb levels (Attie K et al., Am J Hematol 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 on anemia in patients with Low or Int-1 risk MDS who have either high transfusion burden (HTB, defined as ≥4 units RBCs/8 weeks prior to baseline) or low transfusion burden (LTB, defined as <4 units RBCs/8 weeks prior to baseline). Study outcomes include erythroid response (either Hb increase in LTB patients or reduced transfusion burden in HTB patients), safety, tolerability, PK, and PD biomarkers. Methods.Inclusion criteria included Low or Int-1 risk MDS, age ≥ 18 yr, anemia (defined as either being HTB patient or having baseline Hb < 10.0 g/dL in LTB patient), EPO >500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. In the dose escalation phase, ACE-536 was administered by subcutaneous (SC) injection once every 3 weeks in 7 sequential cohorts (n=3-6) at dose levels of 0.125, 0.25, 0.5, 0.75, 1.0, 1.33 and 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort (n=30) is planned, and all patients completing this study may enroll in a 12-month extension study. Results. Preliminary data were available for 26 patients (7 LTB/19 HTB) as of 18 Jul 2014. Median age was 71 yr (range: 27-88 yr), 50% were female, 54% had prior EPO therapy and 15% had prior lenalidomide. 69% were WHO subtype RCMD, and the remaining patients were del(5q), RARS, or RAEB-1. Mean (SD) baseline Hgb for the LTB patients (n=7) was 9.1 (0.4) g/dL. Mean (SD) units RBC transfused in the 8 weeks prior to treatment was 0.9 (1.1) units for the LTB patients and 6.3 (2.4) units for the HTB patients. Two of the 7 LTB patients had an increase in mean Hb ≥1.5 g/dL over 8 weeks compared to baseline. Mean maximum Hb increase in the LTB patients was 0.8, 1.0, 2.2, and 2.7 g/dL in the 0.125 (n=1), 0.25 (n=1), 0.75 (n=3), and 1.75 (n=2) mg/kg dose groups, respectively. Six of the 7 LTB patients achieved RBC transfusion independence (RBC-TI) for ≥8 weeks during the study. Six of the 19 HTB patients had a ≥4 unit or ≥50% reduction in RBC units transfused over an 8-week interval during the treatment period compared to the 8 weeks prior to treatment; five of these 6 patients achieved RBC-TI ≥ 8 weeks during the study (range 71-152 days). Increases in neutrophil count following study drug administration were observed in some patients. ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent adverse events regardless of causality were: diarrhea (n=4, grade 1/2), bone pain, fatigue, muscle spasms, myalgia, and nasopharyngitis (n=3 each, grade 1/2). Conclusions. Based on preliminary data in Low or Int-1 MDS patients, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels or decreased transfusion requirement, with a favorable safety profile. These data strongly support further evaluation of longer-term treatment with ACE-536 in patients with MDS. Disclosures Platzbecker: Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding. Goetze:Celgene Corp: Honoraria; Novartis Pharma: Honoraria. Radsak:Celgene: Research Funding. Hankin:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.
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Wang, Rongqi, Alex Zagariya, Olivia Ibarra-Sunga, Claudia Gidea, Edmund Ang, Sonali Deshmukh, Gaurav Chaudhary, John Baraboutis, Gerasimos Filippatos, and Bruce D. Uhal. "Angiotensin II induces apoptosis in human and rat alveolar epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 5 (May 1, 1999): L885—L889. http://dx.doi.org/10.1152/ajplung.1999.276.5.l885.
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Recent work from this laboratory demonstrated potent inhibition of apoptosis in human alveolar epithelial cells (AECs) by the angiotensin-converting enzyme inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 ( Lung Cell. Mol. Physiol. 19): L1013–L1017, 1998]. On this basis, we hypothesized that apoptosis in this cell type might be induced by angiotensin II (ANG II) through its interaction with the ANG II receptor. Purified ANG II induced dose-dependent apoptosis in both the human AEC-derived A549 cell line and in primary type II pneumocytes isolated from adult Wistar rats as detected by nuclear and chromatin morphology, caspase-3 activity, and increased binding of annexin V. Apoptosis also was induced in primary rat AECs by purified angiotensinogen. The nonselective ANG II-receptor antagonist saralasin completely abrogated both ANG II- and angiotensinogen-induced apoptosis at a concentration of 50 μg/ml. With RT-PCR, both cell types expressed the ANG II-receptor subtypes 1 and 2 and angiotensin-converting enzyme (ACE). The nonthiol ACE inhibitor lisinopril blocked apoptosis induced by angiotensinogen, but not apoptosis induced by purified ANG II. These data demonstrate the presence of a functional ANG II-dependent pathway for apoptosis in human and rat AECs and suggest a role for the ANG II receptor and ACE in the induction of AEC apoptosis in vivo.
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Piga, Antonio G., Silverio Perrotta, Angela Melpignano, Caterina Borgna-Pignatti, Ersi Voskaridou, Vincenzo Caruso, Aldo Filosa, et al. "ACE-536 Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study." Blood 124, no. 21 (December 6, 2014): 53. http://dx.doi.org/10.1182/blood.v124.21.53.53.
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Abstract Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis (IE), such as beta-thalassemia (β-thal). In β-thal, IE is due to intracellular α-globin aggregates causing premature death of late-stage erythroid precursors. Patients with β-thal often have elevated levels of EPO and are unresponsive to erythropoiesis-stimulating agents (ESAs). ACE-536 binds to ligands in the TGF-β superfamily, such as GDF11, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. In a healthy volunteer study, ACE-536 was well-tolerated and increased hemoglobin (Hb) levels (Attie K et al., Am J Hematol 2014). Murine ACE-536 (RAP-536) increased Hb levels and decreased RBC inclusion bodies and hemolysis in a mouse model of β-thal (Suragani R et al., Blood 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 in adults with transfusion-dependent (TD, defined as ≥4 units RBCs/8 weeks prior to baseline) or non-transfusion dependent (NTD, defined as <4 units RBCs/8 weeks prior to baseline) β-thalassemia. Study outcomes include erythroid response (either Hb increase in NTD patients or reduced RBC transfusion burden in TD patients), safety, tolerability, PK, and pharmacodynamic biomarkers. Methods. Inclusion criteria included age ≥ 18 yr and anemia, defined as either being TD patient or having baseline Hb <10.0 g/dL in NTD patient. Transfusion burden in TD patients for any 12 weeks on treatment was compared with the 12 weeks prior to treatment. ACE-536 was administered by subcutaneous injection once every 3 weeks for up to 5 doses with a 2-month follow-up. Study design includes sequential cohorts (n=6 patients/cohort) at dose levels of 0.2, 0.4, 0.6, 0.8, 1.0, 1.25 and 1.5 mg/kg. An expansion cohort (n=30) is planned, and all patients completing this study may be eligible to enroll in a 12-month extension study. Results. Preliminary data were available for the 30 patients (23 NTD/7 TD) enrolled in the first 5 cohorts as of 18 Jul 2014. Median age was 34.5 yr (range: 20-57 yr), 16 (53%) were male and 83% had prior splenectomy. Mean (SD) baseline Hb for the NTD patients was 8.3 (0.9) g/dL. Efficacy data for the NTD patients in the 0.6 to 1.0 mg/kg cohorts demonstrated a maximum increase from baseline in Hb ≥ 1.5 g/dL in 7 of 11 (64%) patients. Efficacy data for the 7 TD patients treated in the 0.6 to 1.0 mg/kg cohorts demonstrated a >50% reduction in transfusion burden for all 7 patients. This was accompanied by a maximum decrease from baseline in serum ferritin levels ranging from 12-60%. Reductions in liver iron concentration by MRI were observed in both NTD and TD patients. Two patients with long-standing leg ulcers at baseline (one NTD, one TD) healed within approximately 3 months of ACE-536 treatment. ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent related adverse events included bone pain, headache and myalgia. No notable changes in platelets or WBC were observed. Conclusions. Based on preliminary data, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels in NTD patients and decreased transfusion requirement and serum ferritin levels in TD patients with β-thalassemia via a novel mechanism of action, and demonstrated a favorable safety profile. These data strongly support further evaluation of ACE-536 in patients with β-thalassemia. Disclosures Piga: Acceleron Pharma: Research Funding; Celgene: Honoraria; Novartis: Research Funding; ApoPharma: Research Funding. Voskaridou:Celgene Coporation: Membership on an entity's Board of Directors or advisory committees. Condon:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.
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Smith, Francine G., Suzanne Chan, and Saskia N. De Wildt. "Effects of renal denervation on cardiovascular and renal responses to ACE inhibition in conscious lambs." Journal of Applied Physiology 83, no. 2 (August 1, 1997): 414–19. http://dx.doi.org/10.1152/jappl.1997.83.2.414.
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Smith, Francine G., Suzanne Chan, and Saskia N. De Wildt.Effects of renal denervation on cardiovascular and renal responses to ACE inhibition in conscious lambs. J. Appl. Physiol. 83(2): 414–419, 1997.—Cardiovascular and renal effects of either the angiotensin-converting enzyme inhibitor captopril or vehicle were measured in chronically instrumented lambs in the presence (intact; n = 6) and absence of renal sympathetic nerves (denervated; n = 5) to determine whether there was an interaction between the renin-angiotensin system and renal sympathetic nerves early in life. Captopril caused a similar decrease in mean arterial pressure ( P < 0.001) in intact and denervated lambs, predominantly through a decrease in diastolic pressure. Heart rate was increased from 177 ± 34 to 213 ± 22 (SD) beats/min during captopril compared with vehicle infusion in intact lambs. In denervated lambs, basal heart rates were elevated to 218 ± 33 beats/min; there was no further increase in heart rate during captopril compared with vehicle infusion. Captopril infusion caused a decrease in renal vascular resistance but only in the absence of renal nerves. These findings provide evidence to suggest that early in life there is an interaction between renal sympathetic nerves and the renin-angiotensin system in regulating renal hemodynamics and the baroreflex control of the heart.
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Yee, Andrew J., Jacob P. Laubach, Ajay K. Nooka, Elizabeth K. O'Donnell, Edie A. Weller, Nicole R. Couture, Ellen E. Wallace, et al. "Phase 1 Dose-Escalation Study of Sotatercept (ACE-011) in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma." Blood 126, no. 23 (December 3, 2015): 4241. http://dx.doi.org/10.1182/blood.v126.23.4241.4241.
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Abstract Introduction Anemia and bone disease are hallmarks of multiple myeloma (MM). Sotatercept (ACE-011) is a novel, first-in-class activin type IIA receptor fusion protein that binds with high affinity to activin A and GDF11, and it acts during late-stage erythropoiesis to increase the production of mature erythrocytes through a mechanism independent of erythropoietin. Sotatercept has shown promising activity in clinical trials for anemia in myelodysplastic syndromes (Komrokji et al., ASH 2014) and in thalassemia (Cappellini et al., EHA 2015). Additionally, we have shown that targeting activin A through an analog of sotatercept reverses osteoblast inhibition and improves MM bone disease in a mouse model (Vallet et al., PNAS 2010). Lenalidomide increases activin A secretion with consequent inhibition of osteoblastogeneis, and this can be abrogated by treatment with an activin A neutralizing antibody (Scullen et al., Leukemia 2013). Sotatercept has been previously studied with melphalan, prednisolone, and thalidomide in MM (Abdulkadyrov et al., Br J Haematol 2014). Based on these findings, we evaluated sotatercept in combination with lenalidomide and dexamethasone in MM (NCT01562405). Methods Patient with relapsed and/or refractory MM with at least one prior line of therapy, anemia with hemoglobin <13 g/dL, lytic bone disease, and otherwise adequate organ function were eligible to participate. Sotatercept 10, 15, 30, or 45 mg was given s.c. q28 days along with lenalidomide and weekly dexamethasone on a standard 28 day schedule, with dose escalation following a 3 + 3 design. Sotatercept was held for hemoglobin ≥13 g/dL or for ≥ grade 3 hypertension. Bone mineral density by DEXA was assessed after four cycles. Bisphosphonates were not permitted during the study; prior bisphosphonate therapy was allowed. Results Thirteen patients with a median age of 62 years (range 49-77) and a median of 2 prior lines (range 1-5) of therapy have been enrolled to date (July 31, 2015). Median duration of treatment is 8.1 months (range 0.5, 27 months); five patients continue on study. The MTD has not been reached, and the current dosing level is sotatercept 45 mg with lenalidomide 25 mg. Grade 3-4 adverse events included anemia (38%), diarrhea (15%), fatigue (15%), hypophosphatemia (15%), and thrombocytopenia (38%). Grade 3 hypertension occurred in one patient receiving sotatercept 15 mg (hemoglobin at the time, 11.5 g/dL). There was one death on study that was unrelated to treatment. In patients who completed at least two cycles of treatment, there was a significant mean increase in hemoglobin on study of 0.94 g/dL (N = 10, p = 0.0048) from a mean starting hemoglobin 10.27 g/dL (range 8.6, 12.2). Mean maximal increase in hemoglobin was 2.11 g/dL (range 1.1, 4). Bone density by DEXA was assessed after four cycles. In patients who received a cumulative dose of sotatercept over 45 mg (N = 6), total lumbar spine BMD increased by a mean of 2.0% after four cycles; 83% had increase in BMD. ORR for this combination was 60% (CR = 1, VGPR = 1, PR = 4, SD = 4) in patients evaluable for response. Conclusion Sotatercept in combination with lenalidomide and dexamethasone is well tolerated with expected toxicities related to lenalidomide in MM. Preliminary data from this ongoing study suggest that sotatercept leads to early increases in both hemoglobin and bone mineral density, and it is the first agent that may address both of these significant causes of morbidity in MM. Disclosures Laubach: Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Nooka:Onyx Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. O'Donnell:Millennium: Consultancy. Puccio-Pick:Celgene Corp.: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Raje:Acetylon: Research Funding; AstraZeneca: Research Funding; Onyx: Consultancy; Takeda: Consultancy; Eli Lilly: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy.
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Bir, J., MR Golder, SK Biswas, SS Islam, R. Kumar, and KA Huq. "Application of probiotics and prebiotics for promoting growth of Tiger shrimp (Penaeus monodon): an approach to eco-friendly shrimp aquaculture." International Journal of Agricultural Research, Innovation and Technology 10, no. 2 (January 21, 2021): 15–20. http://dx.doi.org/10.3329/ijarit.v10i2.51571.
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The current study has been conducted to evaluate the growth performance of shrimp (Penaeus monodon) by applying eco-friendly culture mechanism like prebiotics and probiotics. The experiment was carried out for 95 days in different shrimp farms at coastal district of Bagerhat, Bangladesh. Three different treatments viz., probiotic treated as T1, prebiotics treated as T2 and both probiotics and prebiotics as T3 with a control group were designed to conduct the experiment. The size of the experimental ponds was five acre and the stocking density was 4/m2 in each treatment. CP NASA shrimp feed (32% protein) was given thrice in a day during the study period. After 95 days of culture period, the maximum weight gain was observed at T3 (33.78±0.18 g) whereas the minimum weight gain was observed at control group (25.69±0.10 g). The survival rate was the highest in T3 (89.01%) followed by T2 (75.51%) and T1 (53.44%) and the lowest rate was observed in control group (50.88%). Overall production was higher in T3 (833.78 kg ha-1) compared to T2 (553.40 kg ha-1), T1 (447.84 kg ha-1) and Control group (310.57 kg ha-1). pH value was found to maximum in T3 (7.71±0.08) and it was minimum in T1 (7.41±0.10). In addition, the maximum TAN value was found to be 2.22±0.19 mg L-1 in C pond and it was minimum in T3 (0.32±0.06 mg L-1). Therefore, it could be concluded that combine application of probiotics and prebiotics might be the reliable media to enhance production of shrimp by maintaining eco-friendly environment in aquaculture.
Int. J. Agril. Res. Innov. Tech. 10(2): 15-20, December 2020
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Schubert, T. S., R. M. Leahy, D. A. Davison, A. J. Silagyi, and E. M. Killgore. "Gladiolus Rust Caused by Uromyces transversalis Makes First Nearctic Appearance in Florida." Plant Disease 91, no. 9 (September 2007): 1202. http://dx.doi.org/10.1094/pdis-91-9-1202b.
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The most serious rust pathogen of gladiolus (Gladiolus × hortulanus), Uromyces transversalis, has been listed as an exotic pathogen of concern for the United States for more than 80 years (4). Native to South Africa, the pathogen was reported in the Western Hemisphere for the first time in Brazil (2) and Argentina (1). Reports of gladiolus rust in several central Mexican states from 2004 to 2005 (3; http://www.pestalert.org/espanol/oprDetail.cfm?oprID=138 ) and interceptions at Mexican border stations and in Brazilian imports in 2005 at the port of Miami, FL collectively raised the alert level in the United States to high. In April 2006, the Hawaii Department of Agriculture notified the USDA of rust-infected gladiolus in a cut-flower shipment that was traced back to a 1,400-acre (565 ha) farm in Manatee County, FL. Inspection at the farm yielded samples that were quickly confirmed as U. transversalis by FDACS-DPI and USDA plant pathologists. The disease was identified in eight residential gardens near the commercial find and in another 700-acre (285 ha) farm in remote Hendry County, 100 miles to the southeast. In May 2006, gladiolus rust was detected in residential and commercial gladiolus in San Diego County, CA (see companion publication). On the advice of a USDA-assembled panel of experts, strict rust management guidelines and fallow host-free periods were implemented with the ultimate goal of eradication. Subsequent summer, fall, and now winter surveys in the infested commercial and residential areas have uncovered diminishing amounts of rust, with last traces detected on 9 September 2006. Commercial planting resumed at both farms in late summer, and crops remained rust free under weekly inspection until 15 February 2007 in Manatee County and 29 March 2007 in Hendry County. To insure a rust-free product, cut flowers are carefully inspected and foliage stripped at the packinghouse. Eradication will be attempted once more with a fallow host-free period before the 2007 season. U. transversalis is an autoecious rust that mainly infects Gladiolus spp., but has been known to infect other members of the Iridaceae: Anomatheca, Crocosmia, Melasphaerula, Tritonia, and Watsonia. Amphigenous uredinia form in transverse lines across gladiolus foliage and also on flower spikes under heavy disease pressure. The isolate present in Florida fits the literature description of U. transversalis in every respect (uredinia 0.5 to 1.5 mm in diameter, subglobose to ellipsoid verruculose yellow-amber urediniospores, 15 to 28 × 14 to 20 μm with wall 1.5 to 2.5 μm thick; telia also amphigenous, 0.5 to 1.3 μm in diameter, dark brown-black, subglobose to pyriform smooth amber teliospores, 20 to 30 × 15 to 20 μm with wall 1.5 to 2.0 μm thick, 4 to 6 μm thick at apex, pale brown to hyaline pedicel 30 to 40 μm long, yellow-brown paraphyses in pustule) ( http://nt.ars-grin.gov/fungaldatabases/new_allView.cfm?whichone=all&thisName=Uro myces%20transversalis&organismtype=Fungus ). Urediniospores initiated typical foliar lesions on transplanted gladiolus samples kept in the FDACS-DPI quarantine greenhouse during the diagnostic process. References: (1) J. R. Hernandez and J. F. Hennen. Sida 20:313, 2002. (2) G. P. B. Pitta et al. Biologica 47:323, 1981. (3) G. Rodriguez-Alvarado et al. Plant Dis. 90:687, 2006. (4) J. A. Stevenson. Page 82 in: Foreign Plant Diseases. USDA Fed. Hortic. Board Bureau Plant Ind. Government Printing Office, Washington DC, 1926.
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Sachdev, Robert N. S., Shao-Ming Lu, Ron G. Wiley, and Ford F. Ebner. "Role of the Basal Forebrain Cholinergic Projection in Somatosensory Cortical Plasticity." Journal of Neurophysiology 79, no. 6 (June 1, 1998): 3216–28. http://dx.doi.org/10.1152/jn.1998.79.6.3216.
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Sachdev, Robert N. S., Shao-Ming Lu, Ron G. Wiley, and Ford F. Ebner. Role of the basal forebrain cholinergic projection in somatosensory cortical plasticity. J. Neurophysiol. 79: 3216–3228, 1998. Trimming all but two whiskers in adult rats produces a predictable change in cortical cell-evoked responses characterized by increased responsiveness to the two intact whiskers and decreased responsiveness to the trimmed whiskers. This type of synaptic plasticity in rat somatic sensory cortex, called “whisker pairing plasticity,” first appears in cells above and below the layer IV barrels. These are also the cortical layers that receive the densest cholinergic inputs from the nucleus basalis. The present study assesses whether the cholinergic inputs to cortex have a role in regulating whisker pairing plasticity. To do this, cholinergic basal forebrain fibers were eliminated using an immunotoxin specific for these fibers. A monoclonal antibody to the low-affinity nerve growth factor receptor 192 IgG, conjugated to the cytotoxin saporin, was injected into cortex to eliminate cholinergic fibers in the barrel field. The immunotoxin reduces acetylcholine esterase (AChE)-positive fibers in S1 cortex by >90% by 3 wk after injection. Sham-depleted animals in which either saporin alone or saporin unconjugated to 192 IgG is injected into the cortex produces no decrease in AChE-positive fibers in cortex. Sham-depleted animals show the expected plasticity in barrel column neurons. In contrast, no plasticity develops in the ACh-depleted, 7-day whisker-paired animals. These results support the conclusion that the basal forebrain cholinergic projection to cortex is an important facilitator of synaptic plasticity in mature cortex.
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Lopes, Kelvin Saldanha, Francisco Willyego Holanda Maciel, Roque Soares Martins Neto, Vilana Maria Adriano Araújo, Juscelino de Freitas Jardim, and Mardonio Rodrigues Pinto. "Aplicações e possibilidades terapêuticas do uso do biomaterial quitosana para a odontologia: revisão de literatura." ARCHIVES OF HEALTH INVESTIGATION 9, no. 6 (April 20, 2020): 587–91. http://dx.doi.org/10.21270/archi.v9i6.4782.
Full textAbstract:
A quitosana, polissacarídeo linear obtido a partir do exoesqueleto de crustáceos e artrópodes, tem sido pesquisada em Odontologia por suas diversas propriedades terapêuticas. O objetivo do presente estudo foi realizar uma revisão da literatura sobre as aplicações atuais e as possibilidades terapêuticas da quitosana na odontologia. A busca foi realizada através do banco de dados eletrônico do Pubmed, utilizando os descritores Quitosana, Odontologia e Biomateriais. Foram incluídas pesquisas científicas utilizando quitosana em diversas áreas da odontologia e excluídas revisões de literatura e estudos não odontológicos, sendo selecionados 13 artigos. A quitosana induz resposta transcricional e anti-inflamatória em fibroblastos gengivais sobre citocinas inflamatórias, fatores transformadores do crescimento (TGF -β) e fatores de crescimento tumoral (TNF-α) que estão diretamente relacionados à atividade patológica periodontal. Nas infecções endodônticas persistentes, a substância atua criando ligações de hidrogênio e liberação de íons cálcio, o que potencializa a ação dos irrigadores intracanal, além de causar menos estresse oxidativo. Para a odontologia restauradora, a quitosana demonstrou eficácia como auxiliar no condicionamento da dentina e mostrou potencial para induzir a migração de odontoblastos na proteção do complexo dentino-pulpar. A substância atua como uma cura de feridas orais devido à sua capacidade de estimular a formação de fibroblastos e novos vasos sanguíneos, além de células anti-inflamatórias.
Descritores: Biopolímeros; Biomateriais; Biotecnologia.
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Piga, Antonio G., Immacolata Tartaglione, Rita Gamberini, Ersi Voskaridou, Angela Melpignano, Paolo Ricchi, Vincenzo Caruso, et al. "Luspatercept Increases Hemoglobin, Decreases Transfusion Burden and Improves Iron Overload in Adults with Beta-Thalassemia." Blood 128, no. 22 (December 2, 2016): 851. http://dx.doi.org/10.1182/blood.v128.22.851.851.
Full textAbstract:
Abstract Background.Luspatercept (ACE-536) is a modified activin receptor type IIB fusion protein that promotes late-stage erythroid differentiation. In beta-thalassemia, imbalanced production of alpha and beta globin chains in erythroid precursors causes ineffective erythropoiesis (IE) leading to anemia and dysregulated iron homeostasis. In a mouse model of beta-thalassemia, luspatercept corrected the effects of ineffective erythropoiesis and in a phase 1 clinical study with healthy volunteers, was well tolerated and increased hemoglobin (Suragani R, Nat Med, 2014; Suragani R, Blood, 2014; Attie K, Am J Hematol, 2014). Aims.This is an ongoing, phase 2, multicenter, open-label, dose-finding study followed by a long-term extension study to evaluate the effects of luspatercept in patients (pts) with either transfusion-dependent (TD) or non-transfusion dependent (NTD) beta-thalassemia with the following key endpoints: erythroid response (including Hgb increase) and patient-reported quality-of-life (QoL) measures in NTD patients, and reductions in RBC transfusion burden in TD patients. Methods.Inclusion criteria included age ≥ 18 yr and either TD (defined as ≥ 4 RBC units transfused in the 8 weeks prior to first dose, confirmed over 6 months) or NTD (defined as < 4 RBC units transfused in the 8 weeks prior to first dose with baseline Hgb < 10.0 g/dL). Luspatercept was administered subcutaneously every 3 weeks for up to 5 doses over 12 weeks with an 8 week follow-up (20 weeks total). Six cohorts (n=35) were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort (n=29) and all pts who rolled over to the extension study (n=51) were treated at ≥ 0.8 mg/kg with escalation up to 1.25 mg/kg. Results. A total of 30 TD pts enrolled in the base study and, of those, 24 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 38 yr (range 22-55 yr), 67% had prior splenectomy. At baseline, median transfusion burden was 8 units/12 weeks (range 4-15 units) and mean (SD) liver iron concentration (LIC) was 5.1 (5.3) mg/g dw. A total of 20/24 (83%) and 16/24 (67%) TD pts achieved a ≥ 33% and ≥ 50% decrease in transfusion burden over any 12-week period compared to baseline, respectively. Duration of response ranged from 12 to 48+ weeks. A total of 34 NTD pts enrolled in the base study and, of those, 27 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 37 yr (range 23-62 yr); 67% had prior splenectomy. At baseline, median Hgb was 8.7 g/dL (range 7.6-9.8 g/dL) and mean (SD) LIC was 4.9 (3.4) mg/g dw. A total of 21/27 (78%) and 15/27 (56%) NTD pts achieved ≥ 1.0 g/dL and ≥ 1.5 g/dL increases, respectively, in mean Hgb over any 12-week period compared to baseline. Duration of response ranged from 16 to 72+ weeks, with no trend for lower Hgb response over time. Increases in mean hemoglobin over a 12-week period correlated with increases in a pt-reported QoL questionnaire, FACIT-F (r=0.67, p=0.001). 3/5 (60%) pts with baseline LIC ≥ 5 mg/g dw had a decrease in LIC ≥ 2 mg/g dw after at least 6 months of treatment; 8/9 (89%) patients with baseline LIC < 5 mg/g dw maintained LIC < 5 mg/g dw. Luspatercept was generally well tolerated, with no related SAEs. AEs were mostly mild-moderate. The most frequent related AEs (≥ 10% in base + extension studies) in TD pts were bone pain, myalgia, arthralgia, headache, asthenia, and musculoskeletal pain. The most frequent related AEs (≥ 10% in base + extension studies) in NTD pts were bone pain, headache, musculoskeletal pain, and arthralgia. Conclusions: Luspatercept treatment in pts with beta-thalassemia had a favorable safety profile. Efficacy was clinically relevant in both NTD pts (increased Hgb levels, decreased LIC, and improved quality of life) and TD pts (decreased RBC transfusions). A Phase 3, double-blind, placebo-controlled study of luspatercept in regularly transfused adults with beta-thalassemia is ongoing (NCT02604433). Disclosures Zhang: Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Leneus:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership.
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Chang, K. F., R. J. Howard, B. D. Gossen, and S. F. Hwang. "Stem Smut (Ustilago hypodytes) on Intermediate Wheatgrass in Canada." Plant Disease 85, no. 1 (January 2001): 96. http://dx.doi.org/10.1094/pdis.2001.85.1.96b.
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Intermediate wheatgrass (Thinopyrum intermedium [Host] Barkworth & D.R. Dewey) (syn. Agropyron intermedium [Host] Beauv.) is becoming an important forage grass species in Alberta, Canada. Severe losses in seed yield due to stem smut (Ustilago hypodytes [Schlecht.] Fr.) were noted in a 70-acre field near Warner, AB, in 1999. The crop had been established in 1993 and harvested for seed each year. Smut symptoms (5% incidence) were noted initially in 1997. Incidence, determined by counting the number of symptomatic stems, increased to 10% in 1998 and 50% in 1999. The symptoms usually appeared in the first week of June. Brown sori developed on infected stems, especially between the uppermost node and the leaf below the flag leaf, and gradually became black during the period of seed filling, which is characteristic of stem smut (1). Teliospores were smooth, spherical to oval, light to dark brown, and 4.5 to 5.0 × 5.0 to 6.8 μm in dimension, which is also consistent with previous descriptions of U. hypodytes. Infected stems occasionally flowered, but did not set seed, so seed yield losses were proportional to disease incidence. Plants infected with stem smut were often stunted. Tissues in the smutty stem often became sunken and stems became twisted and thinner than normal due to the propagation of sori in the stem over time. Stem smut has been reported on crested wheatgrass and slender wheatgrass in other parts of Canada (2) and on T. intermedium in the United States (3). This is the first report of stem smut affecting commercial grass seed production in Alberta, Canada. This disease could also have a significant impact on the seed production of intermediate wheatgrass elsewhere. References: (1) G. W. Fischer. 1953. Manual of the North American Smut Fungi. Ronald Press, New York. (2) B. D. Gossen and D. Regnier. Can. Plant Dis. Surv. 71:88–89, 1991. (3) J. F. Karn and J. M. Krupinsky. Phytopathology 73:1152–1155, 1983.
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Cappellini, Maria-Domenica, John Porter, Raffaella Origa, Gian Luca Forni, Adberrahmane Laadem, Frédéric Galacteros, Dimana Miteva, et al. "A Phase 2a, Open-Label, Dose-Finding Study To Determine The Safety and Tolerability Of Sotatercept (ACE-011) In Adults With Beta (β)-Thalassemia: Interim Results." Blood 122, no. 21 (November 15, 2013): 3448. http://dx.doi.org/10.1182/blood.v122.21.3448.3448.
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Abstract Background Beta (β)-thalassemia is characterized by ineffective erythropoiesis leading to anemia, bone marrow erythroid hyperplasia, iron overload, and organ failure. Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor (ActRIIA) fusion protein that increases the release of mature erythrocytes into circulation by acting mainly on late-stage erythropoiesis (Carrancio S, et al. Blood. 2012;120:abstract 372). Clinical data in healthy volunteers have shown that treatment with sotatercept results in increased red blood cell (RBC) parameters, including hemoglobin level (Ruckle J, et al. J Bone Miner Res. 2009;24:744-52). RAP-011, a murine ortholog of sotatercept, was efficacious in a mouse model of β-thalassemia intermedia, reducing ineffective erythropoiesis as well as significantly improving anemia and decreasing bilirubin levels, supporting the clinical development of sotatercept (Dussiot M et al. Blood 2012;120:abstract 247). Methods This is an ongoing phase 2a, multicenter, open-label, dose-finding study to determine a safe and active dose level of sotatercept in adult patients with RBC-transfusion dependent (TD) β-thalassemia major or patients with β-thalassemia intermedia who are either TD or non-transfusion dependent (NTD). The dose levels of sotatercept studied to date are 0.1, 0.3, and 0.5 mg/kg, given subcutaneously once every 3 weeks. Safety is assessed according to NCI-CTC grading. Efficacy is assessed by hemoglobin increase from baseline and/or reduction in transfusion burden. Secondary endpoints include assessment of biomarkers for erythropoiesis, hemolysis, iron metabolism, and bone metabolism, as well as in vitro dyserythropoiesis. Dose escalation to higher dose levels is planned contingent on data review and favorable safety profile as determined by the Steering Committee. Results Patient demographics. A total of 25 patients have been enrolled as of July 26, 2013; 8 in the 0.1 mg/kg cohort, 9 in the 0.3 mg/kg cohort, and 8 in the 0.5 mg/kg cohort. Treatment and analysis for the 0.5 mg/kg cohort is underway and will be updated and presented. In the 0.1 and 0.3 mg/kg cohorts, 3 (18%) patients had β-thalassemia major and 14 (82%) had β-thalassemia intermedia (12 of whom were NTD and 2 of whom were TD). Of the 12 NTD β-thalassemia intermedia patients, 6 were treated at the 0.1 mg/kg dose level and 6 at the 0.3 mg/kg dose level. Median baseline hemoglobin for these NTD patients was 8.6 g/dL (range 5.8 to 10.7 g/dL). Median number of sotatercept doses administered was 4 (range 2 to 7) in the 0.1 mg/kg cohort and 8 (range 3 to 9) in the 0.3 mg/kg cohort; 13/17 (76%) patients remained on treatment. Safety.Sotatercept was generally well tolerated. There were no dose-limiting toxicities reported. Two serious adverse events were reported in the 0.1 mg/kg cohort: a grade 2 phlebitis in an NTD patient with a history of high D-dimer at baseline, and a worsening grade 3 bone pain in a TD β-thalassemia major patient with a history of osteoporosis; both were considered possibly study drug-related. Hemoglobin levels/transfusion requirements. Among NTD patients, preliminary data showed that 1 (17%) patient in the 0.1 mg/kg cohort and all 6 (100%) patients in the 0.3 mg/kg cohort had at least a 1 g/dL increase in hemoglobin level from baseline; among these, 1 patient treated with sotatercept 0.3 mg/kg showed a 2 g/dL hemoglobin level increase from baseline as well as a decrease in total bilirubin level from 2.7 × upper limit of normal (ULN) at baseline to 1.8 × ULN. No other relevant decrease in total bilirubin level was reported at the lower dose levels (0.1 mg/kg or 0.3 mg/kg). Three TD patients were still receiving treatment (2 β-thalassemia intermedia and 1 β-thalassemia major). There had been no appreciable reduction in transfusion burden in the 0.1 and 0.3 mg/kg cohorts to date; however further follow up is warranted and an update will be presented. Conclusion Based on these preliminary data, sotatercept administered subcutaneously every 3 weeks may improve anemia via a novel mechanism of action with a favorable safety profile, thereby addressing a significant unmet medical need for patients with NTD β-thalassemia intermedia. The current data suggest a dose-dependent response that supports further evaluation of the exposure–effect relationship of sotatercept in patients with NTD β-thalassemia intermedia. The first, second, and last authors contributed equally to this abstract. Disclosures: Cappellini: Genzyme: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Off Label Use: Sotatercept is an investigational agent that is being assessed for efficacy and safety in beta-thalassemia. Porter:Novartis: Consultancy, Research Funding; Shire: Consultancy; Celgene: Honoraria. Forni:Celgene: Research Funding; Shire: Research Funding; Novartis Pharma: Research Funding. Laadem:Celgene Corp.: Employment, Equity Ownership. Galacteros:Celgene: Consultancy. Miteva:Celgene Corp.: Employment. Sung:Celgene Corp.: Employment, Equity Ownership. Chopra:Celgene Corp.: Employment, Equity Ownership. Klesczewski:Celgene Corp.: Employment. Attie:Acceleron Pharma: Employment. Hermine:Celgene Corporation: Consultancy, Research Funding.
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Bose, Prithviraj, Naval Daver, Elias J. Jabbour, Allison Pike, Kate J. Newberry, Lingsha Zhou, Sherry Pierce, Xuemei Wang, Hagop M. Kantarjian, and Srdan Verstovsek. "Phase-2 Study of Sotatercept (ACE-011) in Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia." Blood 128, no. 22 (December 2, 2016): 478. http://dx.doi.org/10.1182/blood.v128.22.478.478.
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Abstract Introduction: Anemia is common in MPN-associated myelofibrosis (MF), and current therapies (e.g., erythropoiesis stimulating agents, androgens, danazol, immune modulatory drugs and corticosteroids) are unsatisfactory. Furthermore, anemia is not improved and initially worsened by ruxolitinib, an important MF therapy. New drugs with novel mechanisms of action are needed. Sotatercept is a first-in-class activin receptor type IIA (ActRIIA) ligand trap consisting of the extracellular domain of ActIIRA linked to the human IgG1 Fc domain. Sotatercept binds to and sequesters ligands of the transforming growth factor beta (TGF-ß) superfamily, thus relieving their blockade of terminal erythroid differentiation. Pre-clinically, sotatercept corrects ineffective erythropoiesis in ß-thalassemia (Dussiot, M. et al. Nat Med 2014) and its murine ortholog RAP-011 improves erythropoiesis in Diamond Blackfan anemia (Ear, J. et al. Blood 2015). Clinical trials in persons with lower risk myelodysplastic syndromes (Komrokji, R. et al. ASH 2014) and chemotherapy-induced anemia (Raftopoulos, H. et al. Support Care Cancer 2016) have shown promising results. Methods: This is an ongoing phase-2 study of sotatercept, 0.75 or 1 mg/kg subcutaneously every 3 weeks (1 cycle), in subjects with MF, whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). Subjects must be RBC-transfusion-dependent (Gale, R.P. et al. Leuk Res 2011), have hemoglobin <10 g/dL on every determination during the 84 days preceding study entry without RBC transfusions, or have hemoglobin <10 g/dL despite intermittent RBC transfusions without fulfilling the criteria for transfusion dependence. Primary endpoints include anemia response and safety. Secondary endpoints include time to and duration of anemia response. Anemia response is a composite of RBC-transfusion-independence and hemoglobin response (increase of ≥1.5 g/dL from baseline on every determination consecutively over ≥84 days without RBC transfusions). Subjects must have received ≥5 cycles of sotatercept to be evaluable for response. Results: 18 subjects are enrolled to date. 1 subject received 6 cycles at a sub-therapeutic dose of 0.3 mg/kg and was not considered for efficacy evaluation, but was evaluable for safety. Of the remaining 17 subjects, 11 received 0.75 mg/kg and 6, 1 mg/kg. Median age was 67 years (range, 47-84 years); 10 were male and 7 female. 14 had PMF and 3, post-ET MF. 12 subjects had JAK2 V617F, 1 had MPLW515L and 2 had CALR exon 9 mutations. 1 subject was triple negative and 1 subject had no JAK2 or MPL mutation but was not tested for CALR mutations. All 17 subjects had intermediate-2 or high risk disease by the Dynamic International Prognostic Scoring System. Table 1 summarizes baseline variables for these 17 subjects. Median number of cycles of sotatercept received is 5 (range, 1-13). 14 of the 17 subjects received ≥5 cycles and were evaluable for response. The 3 other subjects received 1, 2 and 2 cycles and discontinued due to unrelated medical problems, hypertension and stem cell transplant (SCT), respectively. 5 of 14 (36%) evaluable subjects have responded; 4 of whom continue on study in ongoing response. All responders are female and all female subjects evaluable for response responded. Responses occurred across phenotypic driver mutation categories and in both transfusion-dependent (n=3) and -independent (n=2) subjects. 40% and 25% of evaluable patients responded in the 0.75 mg/kg and 1 mg/kg dose cohorts, respectively. Most adverse events (AEs) were grades 1 or 2. The only AEs possibly attributable to sotatercept include grade 3 hypertension leading to discontinuation, and grade 1 myalgia, bone pain, pain in extremity and injection site reaction. 5 subjects remain on study. 12 have discontinued because of no response (5), SCT (2), unrelated medical problems (1), hypertension (1), disease progression (1), transformation to AML (1) and withdrawal of consent (1). Conclusion: Sotatercept improves anemia and RBC-transfusion-dependence in persons with MF and is well-tolerated. Enrollment to the trial is ongoing; updated results will be presented. A separate cohort of subjects receiving ruxolitinib has been added and will also be discussed. Based on the preponderance of responses at the 0.75 mg/kg dose, this dose has been selected for the combination cohort. Disclosures Daver: Incyte: Consultancy, Other: Advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.
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Kolesnikova, I. A. "Post-pedagogical Syndrome of the Digimodernism Age." Vysshee Obrazovanie v Rossii = Higher Education in Russia 28, no. 8-9 (September 20, 2019): 67–82. http://dx.doi.org/10.31992/0869-3617-2019-28-8-9-67-82.
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The article discusses the influence of Metamodern culture and digitalization of education on the transformation of the pedagogical understanding of learning process. The author relies on the post-postmodern age interpretations presented in the works of S. Abramson, M. Epstein, R. Eschelman, A. Kirby, J. Mensch, P. Samuels, L. Turner, T. Vermeulen and R. Van den Acker; the transdisciplinary (B. Nicholescu) and connectivist (D. Cormier, G. Siemens) approaches and international documents about the education development in a complex society. In the Metamodern epoch under the influence of the universal digitalization there have been signs indicating that the theory and practice of learning has gone beyond the enduring some pedagogical meanings. This is being manifested at the level of the spontaneous transformation of the main components of learning process; changes in the pedagogical thesaurus, the emergence of “hybrid” didactic theories. The author defines this phenomenon as the post-pedagogical syndrome of the digital age which is capable to disrupt the historical continuity of educational culture. The article talks about the lack of resources in modern pedagogical science to explain the realities of lifelong education as a part of the Digimodernism culture and to develop the truly innovative ways of teaching. The author has suggested that the creation of effective methods of teaching and self-education in the digital age is possible only in the case of rethinking and reassessment of basic didactic categories and concepts on a transdisciplinary basis, taking into account the pedagogical experience of the analogical era and preserving the continuity of humanitarian values and meanings. The author’s arguments and conclusions are addressed to supporters of the study of education on an interdisciplinary and transdisciplinary basis.
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Ruiz, Jonatan R., David Arteta, Amaya Buxens, Marta Artieda, Félix Gómez-Gallego, Catalina Santiago, Thomas Yvert, María Morán, and Alejandro Lucia. "Can we identify a power-oriented polygenic profile?" Journal of Applied Physiology 108, no. 3 (March 2010): 561–66. http://dx.doi.org/10.1152/japplphysiol.01242.2009.
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Using the model originally developed by Williams and Folland ( J Physiol 586: 113–121, 2008), we determined 1) a “total genotype score” (TGS, from the accumulated combination of the 6 polymorphisms, with a maximum value of “100” for the theoretically optimal polygenic score) in a group of elite power athletes, endurance athletes, and nonathletic controls, and 2) the probability for the occurrence of Spanish individuals with the “perfect” power-oriented profile (i.e., TGS = 100). We analyzed six polymorphism that are candidates to explain individual variations in elite power athletic status or power phenotypes ( ACE I/D, ACTN3 R577X, AGT Met235Thr, GDF-8 K153R, IL6 −174 G/C, and NOS3 −786T>C) in 53 elite track and field power athletes (jumpers, sprinters), 100 nonathletic controls, and 100 elite endurance athletes (distance runners and road cyclists) (all Spanish Caucasian males). The mean TGS was significantly higher in power athletes (70.8 ± 17.3) compared with endurance athletes (60.4 ± 15.9; P < 0.001) and controls (63.3 ± 13.2; P = 0.012), whereas it did not differ between the latter two groups ( P = 0.366). A total of five power athletes (9.4%, all sprinters) had a theoretically “optimal” TGS of 100 vs. 0 subjects in the other two groups. The probability of a Spanish individual possessing a theoretically optimal polygenic profile for up to the six candidate polymorphisms we studied was very small, i.e., ∼0.2% (or 1 in 500 Spanish individuals). We have identified a polygenic profile that allows us, at least partly, to distinguish elite power athletes from both endurance athletes and nonathletic population.
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Komrokji, Rami S., Guillermo Garcia-Manero, Lionel Ades, Abderrahmane Laadem, Bond Vo, Thomas Prebet, Aspasia Stamatoullas, et al. "An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients with Low or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion." Blood 124, no. 21 (December 6, 2014): 3251. http://dx.doi.org/10.1182/blood.v124.21.3251.3251.
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Abstract Introduction: Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs). Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation (Carrancio et al. Br J Haematol 2014;165:870-82). Treatment with sotatercept stimulated erythropoiesis and significantly increased hemoglobin (Hb) levels in healthy volunteers (Sherman et al. J Clin Pharmacol 2013;53:1121-30), supporting its clinical development for the treatment of anemia in patients (pts) with lower-risk MDS. Methods: The primary objective of this phase 2, open-label, dose-finding study is to determine a safe, tolerable, and effective dose of sotatercept resulting in erythroid hematological improvement (HI-E; modified IWG 2006 criteria) in pts with anemia and IPSS-defined Low or Int-1-risk MDS or non-proliferative CMML (white blood cells < 13,000/µL). Secondary objectives include rate of RBC-transfusion independence (RBC-TI) ≥ 8 weeks. Eligible pts had anemia (≥ 2 RBC units transfusion requirement in the 12 weeks prior to enrollment for Hb ≤ 9.0 g/dL) with no response, loss of response, or low chance of response to ESAs (serum erythropoietin [EPO] > 500 mIU/mL). Pts received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks. ClinicalTrials.gov identifier: NCT01736683. Results: As of May 22, 2014, a total of 54 MDS pts were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Median age was 71 years (range 56–86) and median time from diagnosis was 4 years (range 0–31); most pts were male (70%). Pts received a median of 6 RBC units (range 0–18) in the 8 weeks prior to treatment start. Forty-five pts (83%) received ≥ 4 RBC units in the 8 weeks prior to treatment start (high transfusion burden; HTB), and 9 pts (17%) received < 4 units in the 8 weeks prior to treatment start (low transfusion burden; LTB). Nineteen pts (35%) had IPSS Low and 34 pts (63%) had IPSS Int-1-risk MDS; IPSS risk data were missing for 1 pt. Fifty-one pts (94%) had prior treatment with ESAs, 30 (56%) with hypomethylating agents, 26 (48%) with lenalidomide, and 26 (48%) with other MDS treatments; 15 pts (28%) had serum EPO > 500 mIU/mL. Of the 53 pts evaluable for efficacy, HI-E was observed in 21 pts (40%) overall: 0, 4 (67%), 8 (40%), and 9 pts (45%) in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Nineteen of 44 HTB pts responded with a ≥ 4 RBC units/8 weeks transfusion burden reduction; duration of transfusion response appeared to be dose-dependent. Five HTB pts achieved RBC-TI ≥ 8 weeks, with RBC-TI duration ranging from 59–345+ days. Eight of 9 LTB pts showed Hb increases, not influenced by transfusion, ranging from 1.3–3.8 g/dL. Of these, 2 pts had a Hb increase ≥ 1.5 g/dL sustained for ≥ 8 weeks. Pts with Hb > 11.0 g/dL were subject to dose delay per protocol, which may have impacted Hb increase sustainability. RBC-TI ≥ 8 weeks was achieved in 6 LTB pts. Increases in platelet and neutrophil levels were seen in pts with baseline thrombocytopenia and pts with baseline neutropenia, respectively. Sotatercept was generally well tolerated. Twenty pts (37%) reported ≥ 1 suspected treatment-related adverse event (AE); fatigue (11%), headache (9.3%), decreased appetite (7.4%), and nausea (7.4%) were the most common. Of 35 pts (65%) who discontinued treatment, 28 discontinued due to lack of therapeutic effect and 4 due to AEs. Of those AEs leading to discontinuation, 3 were suspected to be treatment-related: 1 pt with grade 2 hemolytic anemia, 1 pt with grade 3 hypertension, and 1 pt with grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Other reasons for discontinuation were withdrawal of consent (n = 2; 4%) and pt decision (n = 1; 2%). Conclusions: Sotatercept was well tolerated in lower-risk MDS pts at the dose levels tested, with promising evidence of clinical activity in this largely HTB cohort of ESA-refractory, anemic, lower-risk MDS pts. Further exploration of higher sotatercept dose levels and longer-term treatment is planned. PF and AFL contributed equally to this abstract as senior co-authors. Disclosures Komrokji: Celgene Corporation: Consultancy, Research Funding. Off Label Use: Sotatercept (ACE-011) is an investigational agent that is being assessed for efficacy and safety in myelodysplastic syndromes.. Garcia-Manero:Celgene Corporation: Research Funding. Ades:Novartis: Research Funding; Celgene Corporation: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Vo:Celgene Corporation: Employment. Prebet:Celgene Corporation: Honoraria. Boyd:US Oncology: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corporation: Membership on an entity's Board of Directors or advisory committees. Beyne-Rauzy:Novartis: Research Funding; Celgene: Research Funding. Zou:Celgene: Employment. Attie:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. List:Celgene: Consultancy.
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Traub, Hartmut. "J. G. Fichte." Fichte-Studien 7 (1995): 199–212. http://dx.doi.org/10.5840/fichte1995710.
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Traub, Hartmut. "J. G. Fichte." Fichte-Studien 40 (2012): 9–28. http://dx.doi.org/10.5840/fichte20124020.
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Vrebos, Jacques, and Christian Dupuis. "J. G. Hierzel." Plastic and Reconstructive Surgery 93, no. 1 (January 1994): 201–4. http://dx.doi.org/10.1097/00006534-199401000-00034.
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Barash, Galia, Lior Drach, Larisa Naugolni, Tamar Yacoel, Tzvi Tzvi Bistritzer, and Marianna Rachmiel. "Are Current Normal Values of 11DOC Useful for Diagnosis of Non Classical Congenital Adrenal Hyperplasia Due to 11β- Hydroxylase Deficiency?" Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A709. http://dx.doi.org/10.1210/jendso/bvab048.1444.
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Abstract Background: A non-classic form of 11β-hydroxylase deficiency (NC 11β-OHD) has been reported to cause mild androgen excess, with a clinical presentation of precocious puberty, menstrual cycle abnormalities, or hirsutism during adolescence. Since genetic diagnosis of NC 11βOHD is yet not routinely available, the current gold standard for biochemical diagnosis is elevated 11 DOC levels after corticotropin stimulation test (ACTHstimT). However, there are no clear hormone level cutoffs. One of the accepted references for basal and stimulated levels for the pediatric population was published in 1991 by Lashansky et al1. Aim: To determine the correlation between 11DOC levels measured during ACTHstimT, clinical symptoms attributed to NC11βOHD and androgen levels at presentation, and long-term follow-up among children and adolescents with hyperandrogenism. Methods: a retrospective study including all patients who underwent ACTHstimT between 20072015, in one center, during which 11 DOC levels were routinely measured as part of the test. Clinical data was collected from the patients’ medical files and, by telephone calls for complete long-term follow-up. 11DOC levels before and after ACTHstimT were categorized as elevated according to both pre-defined cut-offs; greater than 1.5 times the 95th percentile according to Lashansky1 normal level for sex and age, and greater than 1.5 times the upper limit of the normal level of the commercial kit. Results: Data were complete at presentation for 136 patients, 92 females, and for long for 98 patients, 68 females, mean follow up duration of 3.1 years (1.37,5.09). There was no statistically significant difference in the number of cases with elevated 11DOC according to both cut-offs, among patients with precocious and early puberty, premature adrenarche nor acne. Higher baseline and stimulated 11 DOC levels were demonstrated in females who presented with mild hirsutism and regular menses. Long term data demonstrated no statistically significant difference in the number of cases with elevated 11DOC levels among patients with compromised final adult height, PCOS or hyperandrogenism. There was negative correlation between stimulated 11 DOC levels and basal levels of testosterone, androstenedione and DHEAS levels. Conclusions: This report demonstrates that the current interpretation of 11DOC levels, basal and ACTHstimulated in children, according to 1.5 times the highest range, of both, the Lashansky1 acceptable norms for children, and some of the laboratory’s kit, are not clinically applicable.1Lashansky G, Saenger P, Fishman K, Gautier T, Mayes D, Berg G and Reiter E. Normative data for adrenal steroidogenesis in a healthy pediatric population: Age- and sex-related changes after adrenocorticotropin stimulation. J. Clin. Endocrinol. Metab. 1991; 73(3): 674-686.
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Pratiwi, Hardiyanti, Ikta Yarliani, Murniyanti Ismail, Rizki Noor Haida, and Noer Asmayanti. "Assessing the Toxic Levels in Parenting Behavior and Coping Strategies Implemented During the COVID-19 Pandemic." JPUD - Jurnal Pendidikan Usia Dini 14, no. 2 (November 30, 2020): 231–46. http://dx.doi.org/10.21009/jpud.142.03.
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The COVID-19 pandemics have caused a lot of stressors for parents. Apart from doing daily activities, parents also have to take care of their children and accompany them to study. The number of stressors can lead to toxic behavior in parenting. This study aims to measure the level of toxicity in parenting behavior and coping strategies adopted by parents. This study uses quantitative descriptive methods to measure toxic levels in parenting behavior during the COVID-19 pandemic. A total of 568 parents from Banjarmasin and Yogyakarta participated in this study. The survey results show that several factors can trigger parenting stress during the COVID-19 pandemic, namely worsening economic conditions, delinquent children, excessive anxiety, accumulated daily hassles, growing family demands, and disputes with spouses. However, some of these stressors do not lead to toxic parenting. The results showed that 97.79% of respondents from Banjarmasin and 95.29% from Yogyakarta showed a low toxic level. The remaining 2.21% of respondents in Banjarmasin and 4.71% of respondents in Yogyakarta indicated a moderate toxic level. Coping strategies are crucial for neutralizing stress. There are several strategies applied, namely trying to consider a problem is God's test, and there is a positive side to every problem; trying to address the source of stress and solving it; Withdrawing and finding individual time; looking for social support from the family and others; crying and releasing it by doing favorite things and capitulate and get back the problem. This Research is expected to be a reference for parents in choosing coping strategies to manage the stress they feel in parenting during the pandemic.
Keywords: Toxic parenting; stress trigger, coping strategy; COVID-19
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Deahl, K. L., R. Jones, L. A. Wanner, and A. Plant. "Late Blight Caused by Phytophthora infestans on Solanum sarrachoides in Northeastern Maine." Plant Disease 89, no. 4 (April 2005): 435. http://dx.doi.org/10.1094/pd-89-0435a.
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The area bordering three 110-ha (270-acre) fields of blighted potatoes (Solanum tuberosum L.) in three northeastern Maine locations was surveyed during the summer of 2004 for the occurrence of late blight on cultivated and noncultivated host plants. Special attention was directed to solanaceous weed species. Hundreds of Solanum sarrachoides Sendt. ex. Mart. (hairy nightshade) plants with numerous leaf lesions and moderate defoliation were seen. The frequency of blighted hairy nightshade approximated the frequency of late blight in the adjoining potato fields. Lesions typically contained extensive, white, superficial mycelia colonizing the abaxial and adaxial leaf surfaces. Samples placed in a moist chamber produced lemon-shaped sporangia. On the basis of morphological characteristics, the pathogen was tentatively identified as Phytophthora infestans (Mont.) de Bary. Isolates were obtained by surface-disinfecting leaf sections collected from two locations for 2 to 3 min in 0.5% NaOCl and placing the sections on rye grain medium amended with antibiotics (100 ppm each of penicillin G, pimaricin, and polymyxin). P. infestans was confirmed after reisolating onto rye-lima bean medium. Pathogenicity was tested on detached potato, tomato, and hairy nightshade leaves; the undersides of all leaflets from replicate plants were inoculated with droplets of swimming zoospores (≥500 zoospores per droplet), the leaves were kept at 17°C and 100% humidity, and the extent of sporulation was evaluated after 4, 6, and 7 days. With eight isolates obtained from S. sarrachoides, Koch's postulates were completed on potato and hairy nightshade. Radial growth responses of these strains on rye grain agar amended with 1, 10, or 100 μg per ml of metalaxyl (Ridomil 2E) yielded 50% effective dose values greater than 100 μg per ml, since percentage growth at the highest fungicide concentration exceeded 50% of the no metalaxyl control. These resistance levels are typical of the metalaxyl-insensitive strains of P. infestans isolated from potatoes in this area in recent years, which were previously found to correlate with metalaxyl resistance in bioassays using potato tissues (1). Eight single-sporangial isolates were homozygous for glucose-6-phosphate isomerase and peptidase (Gpi 100/111/122, Pep 100/100). All eight were A2-mating type and mitochondrial haplotype Ia, characteristics common to the US-8 clonal lineage of P. infestans from potato (2), which may infect a wider host range than the old US-1 clonal lineage. When evaluated on differential hosts, three isolates were tomato race PH-1 and complex potato race R 0,1,2,3,4,9,11. DNA fingerprint analysis with probe RG57 further established that the eight hairy nightshade isolates were identical to each other and to local P. infestans isolates from potato. To our knowledge, this is the first report of infection of S. sarrachoides by P. infestans in Maine. The pathogen was previously isolated from this host during field surveys in southern California in the 1980s in connection with late blight of tomato (4). Hairy nightshade has been shown to be a host for US-1, US-8, and US-11 isolates of P. infestans in a laboratory setting (3). The epidemiological significance of S. sarrachoides as an alternative or overwintering host of P. infestans is currently being assessed. References: (1) K. L. Deahl et al. Am. Potato J. 70:779, 1993. (2) S. B. Goodwin et al. Phytopathology 88:939, 1998. (3) H. W. Platt. Can. J. Plant Pathol. 21:301, 1999. (4) V. G. Vartanian and R. M. Endo Plant Dis. 69:516, 1985.
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Platzbecker, Uwe, Ulrich Germing, Katharina Götze, Philipp Kiewe, Thomas Wolff, Karin Mayer, Joerg Chromik, et al. "Luspatercept Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low-Intermediate Risk Myelodysplastic Syndromes (MDS): Long-Term Results from Phase 2 PACE-MDS Study." Blood 128, no. 22 (December 2, 2016): 3168. http://dx.doi.org/10.1182/blood.v128.22.3168.3168.
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Abstract Background: Management of anemia is a common therapeutic challenge in patients with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label, long-term extension study to evaluate the effects of luspatercept in patients (pts) with low-intermediate risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, and pt-reported QoL. Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), ESA refractory or EPO > 500 U/L, no prior HMA, and no current lenalidomide or ESA. Luspatercept was administered SC every 3 wks for up to 5 doses in the base study (NCT01749514), including 7 dose escalation cohorts (n=27 total, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, starting dose 1.0 mg/kg, max 1.75 mg/kg). A 2-year extension study (n=32) is ongoing (NCT02268383). Results: Data (as of 4 Mar 2016) were available for the 32 extension study pts. Of these, 13 pts received < 4U RBC/8 weeks pretreatment (low transfusion burden, LTB) and 19 pts received ≥ 4U RBC/8 weeks (high transfusion burden, HTB). Median age was 72 yr (range 29-90 yr), 59% had prior ESA. Median Hgb for LTB pts was 8.5 g/dL (range 6.4-10.1 g/dL) and median RBC transfusion burden for HTB pts was 6 U/8 weeks (range 4-14 units). 91% pts were RS+ (≥ 15% RS in bone marrow). IWG HI-E was achieved in 11/13 (85%) LTB pts and 15/19 (79%) HTB pts. 11/22 (50%) pts with at least 2 units transfused in 8 weeks prior to dosing with luspatercept achieved RBC transfusion independence for at least 8 weeks. The range of transfusion independence was 9 to 80+ weeks, with most responders still receiving treatment. IWG HI-E response rates were 83% for RS+ pts, 90% for EPO < 200 U/L, 86% for EPO 200-500 U/L, and 50% for EPO > 500 U/L; 85% for ESA-naïve and 79% for those who had prior ESA treatment. RBC transfusion independence was achieved in 58% for EPO < 200 U/L, 50% for EPO 200-500 U/L, and 33% for EPO > 500 U/L. Luspatercept was well tolerated, with 3 related grade 3 adverse events of myalgia, worsening of general condition, and blast cell count increase. The most common related AEs (≥ 2 pts in both base and extension studies) were fatigue, bone pain, diarrhea, myalgia, headache, hypertension, and injection site erythema. Conclusions: Long-term treatment with luspatercept was well tolerated and led to erythroid response in 81% of low-intermediate risk MDS pts who enrolled into the extension study. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). Disclosures Platzbecker: Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Donovan:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.
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Hassan Nelson, Lauren Juliette, and Sarika Rao. "Post Menopausal Hyperandrogenism: A Case of a Steroid Cell Tumor of the Ovary." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A783. http://dx.doi.org/10.1210/jendso/bvab048.1593.
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Abstract Introduction: Postmenopausal hyperandrogenism is a rare condition that causes hirsutism, virilization, and clitoromegaly that should be carefully evaluated in order to avoid overlooking an androgen secreting tumor (1). Case: A 48 year old African American female with a prior history of polycystic ovarian syndrome (PCOS) presented for evaluation of hirsutism. Of note, she also underwent menopause at age 41 after receiving chemotherapy for a history of multiple myeloma, and she has been on steroids since the time of her diagnosis. On exam, she had thick, dark hair growth on her chin, upper lip, and chest, as well as male-patterned baldness, acne, easy bruising, proximal muscle weakness, deep voice, and elevated blood pressure. Prior to endocrinology evaluation, she was started on spironolactone 25 mg BID. Lab work up included dehydroepiandrosterone sulfate (DHEAS) 73 mcg/dL (27-240 mcg/dL), 17-hydroxyprogesterone 74 ng/dL (31-455 ng/dL), androstenedione 271 ng/dL (30-200 ng/dL), total testosterone 763 ng/dL (8-60 ng/dL), bioavailable testosterone 244 ng/dL (0.8-10 ng/dL), hemoglobin A1c 4.3%, follicle stimulating hormone 30 IU/L, luteinizing hormone 23.9 IU/L, insulin 11 mcIU/mL (2.6-24.9 mcIU/mL), glucose 71, insulin-like growth factor 1 236 ng/mL (44-227 ng/mL) with subsequent normal glucose suppression test. While transvaginal ultrasound did not note any abnormal findings, a computed tomography of the abdomen/pelvis showed a new hyperdense focus in the left ovary as well as a tiny right adrenal nodule, most likely an adenoma. Follow up magnetic resonance imaging confirmed a 1.6 cm enhancing solid left ovarian mass; it also confirmed a right adrenal adenoma and left adrenal thickening versus a tiny adenoma. Urine metanephrines and catecholamines were normal. Patient had total hysterectomy and bilateral oophorectomy; pathology showed a steroid cell tumor. Conclusion: Postmenopausal hyperandrogenism has several causes: insulin resistance, PCOS, non-classic congenital adrenal hyperplasia, medications, and tumors of the ovaries or adrenals. Severe hyperandrogenemia should raise the suspicion of an ovarian or adrenal neoplasm, necessitating prompt imaging (1). Certain imaging may not reveal smaller masses, and additional imaging or ovarian/adrenal vein sampling may be needed. Typically, an elevated DHEAS with a high testosterone suggests an adrenal source, while androstenedione can be elevated in both glands. Once identified, the involved gland is surgically resected. This patient was found to have a steroid cell tumor, which has malignant potential. They make up less than 0.1% of all ovarian tumors (2). Initial treatment is surgical resection and may necessitate chemotherapy if malignant. 1) Markopoulos MC, Kassi E, Alexandraki KI, Mastorakos G, Kaltsas G. Hyperandrogenism after menopause. Eur J Endocrinol. 2015 Feb;172(2):R79-91. doi: 10.1530/EJE-14-0468. Epub 2014 Sep 15. PMID: 25225480.2) Hayes, Mary C. M.D.; Scully, Robert E. M.D. Ovarian Steroid Cell Tumors (Not Otherwise Specified), The American Journal of Surgical Pathology: November 1987 - Volume 11 - Issue 11 - p 835-845
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Clark, Mary J., and John R. Traynor. "Mediation of adenylyl cyclase sensitization by PTX-insensitive G?oA, G?i1, G?i2or G?i3." Journal of Neurochemistry 99, no. 6 (December 2006): 1494–504. http://dx.doi.org/10.1111/j.1471-4159.2006.04176.x.
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Schottky, Richard. "J. G. Fichte im Gesprach." Fichte-Studien 5 (1993): 219–24. http://dx.doi.org/10.5840/fichte1993517.
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