Indian Monsoonal Variations During the Past 80 Kyr Recorded in NGHP-02 Hole 19B, Western Bay of Bengal: Implications From Chemical and Mineral Properties

金沢大学理工研究域地球社会基盤学系Detailed reconstruction of Indian summer monsoons is necessary to better understand the late Quaternary climate history of the Bay of Bengal and Indian peninsula. We established a chronostratigraphy for a sediment core from Hole 19B in the western Bay of Bengal, extending to approximately 80 kyr BP and examined major and trace element compositions and clay mineral components of the sediments. Higher δ 18 O values, lower TiO 2 contents, and weaker weathering in the sediment source area during marine isotope stages (MIS) 2 and 4 compared to MIS 1, 3, and 5 are explained by increased Indian summer monsoonal precipitation and river discharge around the western Bay of Bengal. Clay mineral and chemical components indicate a felsic sediment source, suggesting the Precambrian gneissic complex of the eastern Indian peninsula as the dominant sediment source at this site since 80 kyr. Trace element ratios (Cr/Th, Th/Sc, Th/Co, La/Cr, and Eu/Eu*) indicate increased sediment contributions from mafic rocks during MIS 2 and 4. We interpret these results as reflecting the changing influences of the eastern and western branches of the Indian summer monsoon and a greater decrease in rainfall in the eastern and northeastern parts of the Indian peninsula than in the western part during MIS 2 and 4. © 2018. American Geophysical Union. All Rights Reserved

17 beta-HSD Type 12-Like Is Responsible for MaturationInducing Hormone Synthesis During Oocyte Maturation in Masu Salmon

The maturation-inducing hormone 17(alpha), 20(beta)-dihydroxy-4-pregnen-3-one (DHP) was first identified in the amago salmon. Although carbonyl reductase-like 20 beta-hydroxysteroid dehydrogenase (CR/20b-HSD) was reported to convert 17 alpha-hydroxyprogesterone (17OHP) to DHP in rainbow trout, we previously found that CR/20 beta-HSD messenger RNA (mRNA) was not upregulated in stimulated granulosa cells from masu salmon, which suggested that DHP is synthesized by a different enzyme. Accordingly, the current study aimed to identify the specific 20 beta-hydroxysteroid dehydrogenase (20 beta-HSD) responsible for DHP production by granulosa cells during final oocyte maturation in masu salmon. RNA sequencing was performed on granulosa layers that were isolated from ovarian follicles at 1 month before ovulation and incubated with or without forskolin, which was used to mimic luteinizing hormone, and similar to 12 million reads were obtained, which yielded 71,062 contigs of > 100 bp. tBlastx analysis identified 1 contig (#f103496)as similar to 17 beta-hydroxysteroid dehydrogenase type 12 (hsd17 beta 12); however, because the full-length #f103496 sequence was different from hsd17 beta 12, it was termed hsd17 beta 12-like (hsd17 beta 12l). We found that mammalian cells transfected with full-length hsd171 beta 2l exhibited considerable 20b-HSD activity, as indicated by efficient conversion of exogenous 17OHP to DHP. In addition, we found that hsd17 beta 12l mRNA levels were consistently low in follicles during vitellogenic growth; however, the levels increased significantly during final oocytematuration. The levels of hsd17 beta 12lmRNA were also considerably increased in granulosa layers in which 20 beta-HSD activity was induced by salmon pituitary extract. Therefore, we suggest that hsd17 beta 12l, not CR/20 beta-HSD, is the 20 beta-HSD responsible for DHP production by granulosa cells in masu salmon during final oocytematuration

Integrated system for detection and molecular characterization of circulating tumor cells.

Circulating tumor cells (CTCs) invade blood vessels in solid tumors and promote metastases by circulating in the blood. CTCs are thus recognized as targets for liquid biopsy and can provide useful information for design of treatments. This diagnostic approach must consider not only the number of CTCs but also their molecular and genetic characteristics. For this purpose, use of devices that enrich CTCs independent of these characteristics and detectors that recognize various CTC characteristics is essential. In the present study, we developed a CTC detection system comprising ClearCell FX and ImageStream Mark II. We clarified the analytical performance of this system by evaluating recovery rate, lower limits of detection, and linearity. These parameters are critical for detecting rare cells, such as CTCs. We tested these parameters using three cell lines with different expression levels of the epithelial marker-epithelial cell adhesion molecule (EpCAM) and spiked these cells into whole-blood samples from healthy donors. The average recovery rate and lower limit of detection were approximately 40% and five cells/7.5 mL of whole blood, respectively. High linearity was observed for all evaluated samples. We also evaluated the ability of the system to distinguish between normal and abnormal cells based on protein expression levels and gene amplification and found that the system can identify abnormal cells using these characteristics. The CTC detection system thus displays the ability to distinguish specific characteristics of CTC, thereby providing valuable information for cancer treatment

Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2

BackgroundMetabolic reprogramming has emerged as a cancer hallmark, and one of the well-known cancer-associated metabolic alterations is the increase in the rate of glycolysis. Recent reports have shown that both the classical and alternative signaling pathways of nuclear factor κB (NF-κB) play important roles in controlling the metabolic profiles of normal cells and cancer cells. However, how these signaling pathways affect the metabolism of sarcomas, specifically rhabdomyosarcoma (RMS) and osteosarcoma (OS), has not been characterized.MethodsClassical NF-κB activity was inhibited through overexpression of the IκBα super repressor of NF-κB in RMS and OS cells. Global gene expression analysis was performed using Affymetrix GeneChip Human Transcriptome Array 2.0, and data were interpreted using gene set enrichment analysis. Seahorse Bioscience XFe24 was used to analyze oxygen consumption rate as a measure of aerobic respiration.ResultsInhibition of classical NF-κB activity in sarcoma cell lines restored alternative signaling as well as an increased oxidative respiratory metabolic phenotype in vitro. In addition, microarray analysis indicated that inhibition of NF-κB in sarcoma cells reduced glycolysis. We showed that a glycolytic gene, hexokinase (HK) 2, is a direct NF-κB transcriptional target. Knockdown of HK2 shifted the metabolic profile in sarcoma cells away from aerobic glycolysis, and re-expression of HK2 rescued the metabolic shift induced by inhibition of NF-κB activity in OS cells.ConclusionThese findings suggest that classical signaling of NF-κB plays a crucial role in the metabolic profile of pediatric sarcomas potentially through the regulation of HK2

NFκB signaling in alveolar rhabdomyosarcoma

Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFκB–YY1–miR-29 regulatory circuit is dysregulated, resulting in repression of miR-29 and loss of the associated tumor suppressor activity. To further elucidate the role of NFκB in aRMS, we first tested 55 unique sarcoma cell lines and primary cell cultures in a large-scale chemical screen targeting diverse molecular pathways. We found that pharmacological inhibition of NFκB activity resulted in decreased cell proliferation of many of the aRMS tumor cultures. Surprisingly, mice that were orthotopically allografted with aRMS tumor cells exhibited no difference in tumor growth when administered an NFκB inhibitor, compared to control. Furthermore, inhibition of NFκB by genetically ablating its activating kinase inhibitor, IKKβ, by conditional deletion in a mouse model harboring the Pax3:Foxo1 chimeric oncogene failed to abrogate spontaneous tumor growth. Genetically engineered mice with conditionally deleted IKKβ exhibited a paradoxical decrease in tumor latency compared with those with active NFκB. However, using a synthetic-lethal approach, primary cell cultures derived from tumors with inactivated NFκB showed sensitivity to the BCL-2 inhibitor navitoclax. When used in combination with an NFκB inhibitor, navitoclax was synergistic in decreasing the growth of both human and IKKβ wild-type mouse aRMS cells, indicating that inactivation of NFκB alone may not be sufficient for reducing tumor growth, but, when combined with another targeted therapeutic, may be clinically beneficial

Image_4.JPEG

Background<p>Metabolic reprogramming has emerged as a cancer hallmark, and one of the well-known cancer-associated metabolic alterations is the increase in the rate of glycolysis. Recent reports have shown that both the classical and alternative signaling pathways of nuclear factor κB (NF-κB) play important roles in controlling the metabolic profiles of normal cells and cancer cells. However, how these signaling pathways affect the metabolism of sarcomas, specifically rhabdomyosarcoma (RMS) and osteosarcoma (OS), has not been characterized.</p>Methods<p>Classical NF-κB activity was inhibited through overexpression of the IκBα super repressor of NF-κB in RMS and OS cells. Global gene expression analysis was performed using Affymetrix GeneChip Human Transcriptome Array 2.0, and data were interpreted using gene set enrichment analysis. Seahorse Bioscience XF^e24 was used to analyze oxygen consumption rate as a measure of aerobic respiration.</p>Results<p>Inhibition of classical NF-κB activity in sarcoma cell lines restored alternative signaling as well as an increased oxidative respiratory metabolic phenotype in vitro. In addition, microarray analysis indicated that inhibition of NF-κB in sarcoma cells reduced glycolysis. We showed that a glycolytic gene, hexokinase (HK) 2, is a direct NF-κB transcriptional target. Knockdown of HK2 shifted the metabolic profile in sarcoma cells away from aerobic glycolysis, and re-expression of HK2 rescued the metabolic shift induced by inhibition of NF-κB activity in OS cells.</p>Conclusion<p>These findings suggest that classical signaling of NF-κB plays a crucial role in the metabolic profile of pediatric sarcomas potentially through the regulation of HK2.</p

Image_1.JPEG

Background<p>Metabolic reprogramming has emerged as a cancer hallmark, and one of the well-known cancer-associated metabolic alterations is the increase in the rate of glycolysis. Recent reports have shown that both the classical and alternative signaling pathways of nuclear factor κB (NF-κB) play important roles in controlling the metabolic profiles of normal cells and cancer cells. However, how these signaling pathways affect the metabolism of sarcomas, specifically rhabdomyosarcoma (RMS) and osteosarcoma (OS), has not been characterized.</p>Methods<p>Classical NF-κB activity was inhibited through overexpression of the IκBα super repressor of NF-κB in RMS and OS cells. Global gene expression analysis was performed using Affymetrix GeneChip Human Transcriptome Array 2.0, and data were interpreted using gene set enrichment analysis. Seahorse Bioscience XF^e24 was used to analyze oxygen consumption rate as a measure of aerobic respiration.</p>Results<p>Inhibition of classical NF-κB activity in sarcoma cell lines restored alternative signaling as well as an increased oxidative respiratory metabolic phenotype in vitro. In addition, microarray analysis indicated that inhibition of NF-κB in sarcoma cells reduced glycolysis. We showed that a glycolytic gene, hexokinase (HK) 2, is a direct NF-κB transcriptional target. Knockdown of HK2 shifted the metabolic profile in sarcoma cells away from aerobic glycolysis, and re-expression of HK2 rescued the metabolic shift induced by inhibition of NF-κB activity in OS cells.</p>Conclusion<p>These findings suggest that classical signaling of NF-κB plays a crucial role in the metabolic profile of pediatric sarcomas potentially through the regulation of HK2.</p