14 research outputs found
HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer
Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests that resistant clones exist within a larger drug-sensitive cell population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically derived, intrapatient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 downregulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of histone deacetylase (HDAC) 4, FOLR2, PIK3R1, or STAT1 (P <0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum-sensitive cells but not in HDAC4 overexpressing platinum-resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum-induced STAT1 activation, and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors [n = 7 of 16 (44%); P = 0.04]. Therefore, clinical selection of HDAC4-overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer
Minimum flexural reinforcement for T-beams made of higher strength concrete
Design codes specify minimum flexural reinforcement for reinforced concrete beams. With the extensive use of higher strength concrete, the empirical expressions of the past for minimum flexural reinforcement, in which the concrete strength is not considered, had to be revised. Six reinforced concrete T-beams, having small ratios of flexural reinforcement, were tested to study the behaviour at the positive moment region and to evaluate the code requirements on minimum flexural reinforcement. A criterion was set and evaluations of different minimum reinforcement requirements were made using this criterion and the test data.Key words: beams, crack control, ductility, flexural strength, high strength concrete, minimum flexural reinforcement, reserve strength. </jats:p
Assessment of toxic metals and phthalates in children's toys and clays
Toxic metals and phthalates are introduced in the manufacturing of plastic toys and modeling clays. In Lebanon, inexpensive plastic toys and modeling clays (sold in dollar stores) are affordable and popular, and there is no legislation to monitor or regulate such toys. This study aimed to assess the quality of inexpensive plastic toys and modeling clays imported in Lebanon. Metal concentrations in toys, namely, zinc [not detectable (ND) to 3,708 μg-g], copper (ND to 140), chromium (ND to 75 μg-g), tin (ND to 39 μg-g), and cadmium (Cd) (ND to 20 μg-g), were lower than the European Union (EU) Directive limits, whereas lead (ND to 258 μg-g) in 10 percent of samples and antimony (Sb) (ND to 195 μg-g) in 5 percent of samples were greater than the EU limits. In modeling clays, most of the metals were lower than the EU Directive limits except for Cd and arsenic (As). Cd was detected in 83 percent of samples, with a mean level of 9.1 μg-g, which is far greater than the EU Directive limit (1.9 μg-g). The As mean level of 4.5 μg-g was greater than the EU limit (4.0 μg-g) and was detected in 9 percent of samples. Phthalic acid esters (PAEs) were found in 60 percent of children's toys and 77 percent of modeling clays. Phthalic acid butyl ester had the highest-level PAE encountered and was ≤59.1 percent in one type of clay. However, among children's toys, di(4-octyl) ester terephthalic acid was the highest encountered phthalate at a concentration of 25.7 percent. The community survey indicated that 82 percent of households purchase their toys from inexpensive shops and that only 17 percent of parents were aware of the health hazard of such toys. Consequently, an intervention plan was proposed for the provision of safe toys to children. © Springer Science+Business Media New York 2013.ADELANTADO JVG, 1993, ANAL CHIM ACTA, V276, P39; Biedermann-Brem S, 2008, CHROMATOGRAPHIA, V68, P227, DOI 10.1365-s10337-008-0672-9; Borling P, 2006, SURVEY MIGRATION HLT; Chen ML, 2008, ENVIRON INT, V34, P79, DOI 10.1016-j.envint.2007.07.004; Earls AO, 2003, J CHROMATOGR A, V983, P237, DOI 10.1016-S0021-9673(02)01736-3; EN (British Standards), 2006, 713 BS EN EUR COMM S; Guney M, 2011, ENVIRON SCI TECHNOL, V45, P3819, DOI 10.1021-es200810s; Guney M, 2012, ENVIRON SCI TECHNOL, V46, P4265, DOI 10.1021-es203470x; Heudorf U, 2007, INT J HYG ENVIR HEAL, V210, P623, DOI 10.1016-j.ijheh.2007.07.011; Kalnicky DJ, 2001, J HAZARD MATER, V83, P93, DOI 10.1016-S0304-3894(00)00330-7; Kawamura Y, 2009, J FOOD HYG SOC JPN, V50, P93; Kevin M, 2012, REGUL TOXICOL PHARM, V62, P248; Kumar A, 2007, CURR SCI INDIA, V93, P818; NTP-CERHR, 2000, NTP CERHR EXP PAN RE; Omolaoye JA, 2010, J ENV CHEM ECOTOXICO, V2, P126; RASTOGI SC, 1992, B ENVIRON CONTAM TOX, V48, P289; Rastogi SC, 1996, B ENVIRON CONTAM TOX, V56, P527; Soares EP, 2005, J RADIOANAL NUCL CH, V264, P9, DOI 10.1007-s10967-005-0667-z; Stanley MK, 2003, HDB ENV CHEM; United States Food and Drug Administration, 2002, SAF ASS DI 2 ETH PHT34
Colchicine Toxicity in End-Stage Renal Disease Patients: A Case-Control Study
Colchicine has been used in a number of disorders. Because colchicine is partially excreted from the kidney, there is a need for dose reduction in case of renal functional impairment. There are no data with regards to safe dosing schedule of colchicine in hemodialysis patients. We aimed to evaluate adverse effects of colchicine use in a hemodialysis cohort. We screened hemodialysis patients who were using colchicine for any reason. All patients were interviewed regarding possible toxicities of colchicine use and were examined with a special focus on neuromuscular system. Creatine kinase and myoglobin were used to detect any subclinical muscle injury or rhabdomyolysis, respectively. Twenty-two maintenance hemodialysis patients who were on colchicine for more than 6 months and 20 control hemodialysis patients not using colchicine were included in the study. Four of 22 patients were using 0.5 mg/day, 4 patients were using 1.5 mg/day, and 14 patients were using 1 mg/day colchicine. Mean duration for colchicine use was 8.9 +/- 8.2 years. There was no difference between the groups in terms of myoneuropathic signs and symptoms and blood counts except for white blood cell count, which was significantly higher in patients on colchicine. Serum creatine kinase (56.3 +/- 39.5 and 52.1 +/- 36.1 for colchicine and control groups, respectively, P = 0.72) and myoglobin (191.4 +/- 108.8 and 214.6+/-83.5 for colchicine and control groups, respectively, P = 0.44) levels were not different between the groups. We conclude that in a small number of haemodialysis patients who were apparently tolerating colchicine, detailed assessment revealed no evidence of sublinical toxicity when compared with controls.ERA-EDTA fellowship programThe author A. G. received grant support from the ERA-EDTA fellowship program. No sources of funding were used to conduct this study or prepare this article
Epithelial-stromal cell interactions and ECM mechanics drive the formation of airway-mimetic tubular morphology in lung organoids
Complex human airway cellular organisation where extracellular matrix (ECM), epithelial and stromal lineages interact present challenges for organ study in vitro. Current in vitro lung models, that focus on the lung epithelium do not represent complex airway morphology and cell-ECM interactions seen in vivo.
Models including stromal populations often separate them via a semipermeable barrier precluding cell-cell interaction or the effect of ECM mechanics. We investigated the effect of stromal cells on basal epithelial cell-derived bronchosphere structure and function through a triple culture of human bronchial epithelial, lung fibroblast and airway smooth muscle cells. Epithelial-stromal cross-talk resulted in epithelial cell-driven branching tubules with stromal cells surrounding epithelial cells termed bronchotubules. Agarose-matrigel scaffold (Agrigel) formed a mechanically tuneable ECM, with adjustable viscoelasticity and stiffness enabling long-term tubule survival. Bronchotubule models may enable research into how epithelial-stromal cell and cell-ECM communication drive tissue patterning, repair and development of disease
Clinical evaluation of DIAGNOVIR SARS-CoV-2 ultra-rapid antigen test performance compared to PCR-based testing
Coronavirus Disease-19 (COVID-19) is a highly contagious infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The development of rapid antigen tests has contributed to easing the burden on healthcare and lifting restrictions by detecting infected individuals to help prevent further transmission of the virus. We developed a state-of-art rapid antigen testing system, named DIAGNOVIR, based on immune-fluorescence analysis, which can process and give the results in a minute. In our study, we assessed the performance of the DIAGNOVIR and compared the results with those of the qRT-PCR test. Our results demonstrated that the sensitivity and specificity of the DIAGNOVIR were 94% and 99.2%, respectively, with a 100% sensitivity and 96.97% specificity, among asymptomatic patients. In addition, DIAGNOVIR can detect SARS‑CoV‑2 with 100% sensitivity up to 5 days after symptom onset. We observed that the DIAGNOVIR Rapid Antigen Test’s limit of detection (LoD) was not significantly affected by the SARS‑CoV‑2 variants including Wuhan, alpha (B1.1.7), beta (B.1.351), delta (B.1.617.2) and omicron (B.1.1.529) variants, and LoD was calculated as 8 × 102, 6.81 × 101.5, 3.2 × 101.5, 1 × 103, and 1 × 103.5 TCID50/mL, respectively. Our results indicated that DIAGNOVIR can detect all SARS-CoV-2 variants in just seconds with higher sensitivity and specificity lower testing costs and decreased turnover time. © 2023, The Author(s).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Effect of solution heat treatment on the microstructure and crystallographic texture of IN939 fabricated by powder bed fusion-laser beam
The effect of various solution heat treatment temperatures (i.e., 1120, 1160, 1200 and 1240 ; DEG;C) on the microstructure, grain morphology and crystallographic texture of IN939 fabricated by powder bed fusion-laser beam (PBF-LB) was investigated. Microstructural analyses showed that the high-temperature gradient and rapid solidification of the PBF-LB processing caused different resulting microstructures compared to conventionally pro-duced counterparts. The melt pool morphologies and laser scanning paths were examined in the as-fabricated samples in the XZ-and XY-planes, respectively. After the application of solution heat treatment at 1120 ; DEG;C, the as-fabricated PBF-LB initial microstructure was still apparent. For solution heat treatments of 1200 ; DEG;C and above, the melt pool and scanning path morphologies disappeared and converted into a mixture of columnar grains in the XZ-plane and equiaxed grains in the XY-plane. On the other hand, large equiaxed grains were observed when the samples were solutionized at 1240 ; DEG;C. Additionally, g' phase precipitated within the matrix after all solution heat treatment conditions, which led to increase in the microhardness values. According to electron backscatter diffraction (EBSD) analyses, both as-fabricated and solution heat-treated samples had intense texture with {001} plane normal parallel to the building direction. The first recrystallized grains began to appear when the samples were subjected to the solution heat treatment at 1160 ; DEG;C and the fraction of the recrystallized grains increased with increasing temperature, as supported by kernel average misorientation (KAM) and grain spread orientation (GOS) analyses.; COPY; 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Bone and mineral metabolism in patients undergoing Roux-en-Y gastric bypass
Summary: Despite effective weight reduction, the impact of bariatric surgery on bone is a major concern. Mechanisms include decreased mechanical loading, calcium and vitamin D malabsorption, deficiency in other nutrients, and alterations in fat- and gut-derived hormones. The evidence to support clinical care pathways to prevent bone loss and fractures is at this point weak. Introduction: There is a growing concern regarding the potential deleterious impact of bariatric surgery on bone metabolism. This comprehensive review addresses this controversial topic. Methods: We reviewed and analyzed articles evaluating bone metabolism and mechanisms for the ensuing putative bone loss in adult patients exclusively undergoing Roux-en-Y gastric bypass (RYGB) surgery, for the period spanning 1942 till September 2012. Results: Mechanisms identified to contribute to alterations in bone metabolism after bypass surgery include: decreased mechanical loading, calcium and vitamin D malabsorption with secondary hyperparathyroidism, deficiency in other nutrients, in addition to alterations in adipokines, gonadal steroids, and gut-derived hormones favoring bone loss, with the exception of serotonin and glucagon-like peptide-1. The relative contribution of each of these hormones to changes in bone homeostasis after bypass surgery remains undefined. Bone loss reflected by a decline in bone mineral density (BMD) and an increase in bone turnover markers have been reported in many studies, limited for the most part by the exclusive use of dual energy X-ray absorptiometry. Well-designed long-term prospective trials with fractures as an outcome, and studies investigating the magnitude, reversibility, and impact of the observed metabolic changes on fracture outcomes are lacking. Conclusion: Robust conclusions regarding bone loss and fracture outcome after RYGB surgery cannot be drawn at this time. Although not evidence based, baseline evaluation and sequential monitoring with measurement of BMD and calciotropic hormones seem appropriate, with adequate calcium and vitamin D replacement. 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Grylloblatta rothi Gurney 1953
<i>Grylloblatta rothi</i> Gurney 1953 <p>(Figs. 1 A–F)</p> <p> <b>Material examined.</b> Neotype male, OSAC #0000583177, “ OR: Deschutes Co., Cultus Mtn. on/near summit 6720’ 10T590843, 4852390; Lytle & Marshall, 21 June 2011 ” with code number “7048” written in pencil on label margin; right metathoracic leg detached, left metathoracic leg missing (removed for sequencing). The UTM coordinates on the label correspond to 43.8190°N, - 121.8703°W. Specimen in ethanol, to be deposited at USNM. Extracted genomic DNA deposited at Oregon State Arthropod Collection, Corvallis, OR, OSAC #00000583177: DNA:01. Thirteen specimens (3 males, 7 females, 3 juveniles), same collection data as neotype, deposited in OSAC (OSAC _AC_ 2012-12-12 -001). All specimens were collected on snow fields at night near the summit, except a single juvenile found beneath a rock. Numerous carabid beetles and spiders were active on the snowfields as well.</p> <p> <b>Description:</b> Neotype body length 12.2 mm (measurements taken on ethanol-preserved specimen). Antenna with 24 segments on left and 25 on right [Gurney (1953): 29 on left, 16 on broken right antenna]. Abdominal sternites finely pubescent, with relatively few larger porect setae distributed across the surface. Abdominal tergites finely pubescent, with several erect setae along posterior margins. Cerci with 9 articulated segments, right cercus length 2.2 mm; first two basal segments appear to be comprised of two fused segments (indicated by two rings of trichobothria, which generally occur at the apex of an articulated segment, and faint vestiges of articulation); cerci shorter than the abdomen proper. Head width 2.4 mm, length 2.2 mm. Pronotum length 2.5 mm, width 2.1 mm. Interocular distance 1.8 mm, eye width 0.5 mm. Left hind femur length 3.3 mm, width 0.8 mm. Left hind tibia length 3.3 mm.</p> <p> Male supranal plate strongly asymmetrical; left finger-like lobe approaching the longitudinal midline of the abdomen; right finger-like posterior lobe less developed, at an approximate 60° angle. Male gonocoxae (Fig 1 B,C; <i>gcx-l, gcx-r</i>) asymmetrical, covered in fine setae with a few larger ones basomedially. Gonostyli (Fig 1 B,C <i>gst-l</i>, <i>gst-r</i>) articulate medially (not basally), appearing ‘hammerhead-like’ when viewed laterally. Right gonocoxa more elongate than left; bearing a distinct dorsal finger that projects medially and opposes the beak-like apex of the primary copulatory sclerite.</p> <p> Primary copulatory sclerite (main phallic sclerite in Gurney 1953) with dorsolateral lobe about half as long as lateral margin below the dorsal cap (Fig 1 E, <i>pcs</i>). Secondary accessory sclerite (apical lobe of accessory sclerite of right phallomere in Gurney 1953) (Fig 1 D,E, <i>sas</i>) rounded and lobe-like. Apex (terminus) of primary male copulatory sclerite expanded along apico-dorsal edge into noticeable flange (Fig. 1 F, <i>pcs</i> —arrow).</p> <p> <b>Distribution.</b> Kamp (1973) placed <i>G. ro t h i</i> within an assemblage of species inhabiting the high Cascades of Central Oregon, specifically Broken Top and Belknap Crater. Cultus Mountain is within this area, a region largely defined by the peaks of the Three Sisters. In the original description, Gurney also described an allotype, a single female specimen known from Crater Lake. He united these two specimens (the only specimens in the <i>rothi</i> assemblage known to Gurney) based on their relatively short cerci. Later researchers, including the present authors, expressed doubt that these two specimens were actually conspecific. Kamp, who was likely the last person to view the original type material, and who had in his possession specimens from throughout Oregon, believed the population at Crater Lake to be a distinct species (Kamp 1973). Our own research into populations in the vicinity of Crater Lake confirm his suspicions and we do not believe <i>Grylloblatta rothi</i> to be distributed this far south of the central Cascades.</p> <p> <b>Remarks.</b> Gurney (1953) described the holotype male as generally pale ‘antimony yellow’ with a ‘dark yellow ochre’ dorsum. The neotype and other specimens in our possession are consistent with this general yellowishbrown description and to our eyes their overall color approximates yellow ochre. As in Gurney’s original description, <i>G. ro t h i</i> we have examined are generally small for the genus, with alcohol-preserved male specimens ranging from 11.9 to 12.5 mm and females from 14.3 to 15.0 mm in length. The number of antennal segments in adult <i>Grylloblatta</i> is commonly used in identification keys to species, despite that it is a notoriously variable character between, and even within, individuals in a single population. The neotype differs in its antennal segment count from that reported for the left antenna in Gurney’s holotype. However it must be noted that specimens from the same population as the neotype show a range in antennal counts, ranging from 19 to 29 antennal segments and even display intra-individual discrepancies between right and left antenna as great as 10 segments. Thus, we do not feel that the precise number of antennal segments (in either the holotype or neotype) is of great importance for understanding the species.</p> <p> The male copulatory sclerites were not described in great detail by Gurney (1953) but he does note that the male dorsolateral lobe of the primary copulatory sclerite is about ‘about half as long as lateral margin below the dorsal cap’—a description that is consistent with the dorsolateral lobe of seen in male <i>Grylloblatta</i> from the Cultus Mountain population (dll, Fig. 1 E). Gurney did not mention that the primary male copulatory sclerite is expanded apicodorsally into a flange, a trait that is shared with <i>G. newberryensis</i>. However, this flange is only visible when viewed from a specific angle (notably an anterior facing view, as shown in the illustrations herein (Fig. 1 F), which was not depicted in Guney’s illustrations of the holotype. Gurney did describe and illustrate the secondary accessory sclerite (referred to as the ‘apical lobe of the accessory sclerite of the right phallomere’) as being rounded and lobe like, consistent with the males from Cultus Mountain (Fig 1 D,E, <i>sas</i>).</p> <p> Lastly, the cerci of this species are noticeable short in comparison to many other <i>Grylloblatta</i> species, a trait noted by Gurney in 1953, “The shortness of the cercal segments separates <i>rothi</i> from all other species except possibly <i>barberi,</i> and the character is so distinctive that the association of sexes [holotype and allotype] is believed correct.” However, both species described below share this trait as well as several other traits found in <i>G. rothi</i> and a more detailed, comparative study of the species allied to <i>G. ro t h i</i>, is currently being conducted by the authors. Female cerci are only slightly longer than the ovipositor. The ovipositor is ventrally covered in short setae, which is denser at the base and apex than they are medially. The dorsal valvula is slightly longer than the ventral valvula (Fig 1 A).</p> <p>Paratypes (including the allotype) of a species have no special significance in the determination of a neotype. Still, they may provide information to help clarify the species concept being employed by the original author. Unfortunately, in this particular case, the species concept was based on only two specimens (the holotype and allotype) that Gurney treated as conspecific based solely on the short cerci. We searched for the allotype along with the holotype unsuccessfully and we presume they were lost at the same time.</p>Published as part of <i>Marshall, Christopher J. & Lytle, David A., 2015, Two new species of Grylloblatta Walker, 1914 (Grylloblattodea: Grylloblattidae) from western North America, and a neotype designation for G. rothi Gurney 1953, pp. 408-418 in Zootaxa 3949 (3)</i> on pages 410-412, DOI: 10.11646/zootaxa.3949.3.6, <a href="http://zenodo.org/record/234609">http://zenodo.org/record/234609</a>
