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A Randomized Phase III Study of Patients With Advanced Gastric Adenocarcinoma Without Progression After Six Cycles of XELOX (Capecitabine Plus Oxaliplatin) Followed by Capecitabine Maintenance or Clinical Observation

  • Guk Jin Lee;Hyunho Kim;Sung Shim Cho;Hyung Soon Park;Ho Jung An;In Sook Woo;Jae Ho Byun;Ji Hyung Hong;Yoon Ho Ko;Der Sheng Sun;Hye Sung Won;Jong Youl Jin;Ji Chan Park ;In-Ho Kim;Sang Young Roh;Byoung Yong Shim
    • Journal of Gastric Cancer
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    • v.23 no.2
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    • pp.315-327
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    • 2023
  • Purpose: Oxaliplatin, a component of the capecitabine plus oxaliplatin (XELOX) regimen, has a more favorable toxicity profile than cisplatin in patients with advanced gastric cancer (GC). However, oxaliplatin can induce sensory neuropathy and cumulative, dose-related toxicities. Thus, the capecitabine maintenance regimen may achieve the maximum treatment effect while reducing the cumulative neurotoxicity of oxaliplatin. This study aimed to compare the survival of patients with advanced GC between capecitabine maintenance and observation after 1st line XELOX chemotherapy. Materials and Methods: Sixty-three patients treated with six cycles of XELOX for advanced GC in six hospitals of the Catholic University of Korea were randomized 1:1 to receive capecitabine maintenance or observation. The primary endpoint was progression-free survival (PFS), analyzed using a two-sided log-rank test stratified at a 5% significance level. Results: Between 2015 and 2020, 32 and 31 patients were randomized into the maintenance and observation groups, respectively. After randomization, the median number of capecitabine maintenance cycles was 6. The PFS was significantly higher in the maintenance group than the observation group (6.3 vs. 4.1 months, P=0.010). Overall survival was not significantly different between the 2 groups (18.2 vs. 16.5 months, P=0.624). Toxicities, such as hand-foot syndrome, were reported in some maintenance group patients. Maintenance treatment was a significant factor associated with PFS in multivariate analysis (hazard ratio, 0.472; 95% confidence interval, 0.250-0.890; P=0.020). Conclusions: After 6 cycles of XELOX chemotherapy, capecitabine maintenance significantly prolonged PFS compared with observation, and toxicity was manageable. Maintenance treatment was a significant prognostic factor associated with PFS.

Characterization of Bacillus amyloliquefaciens DA12 Showing Potent Antifungal Activity against Mycotoxigenic Fusarium Species

  • Lee, Theresa;Park, Dami;Kim, Kihyun;Lim, Seong Mi;Yu, Nan Hee;Kim, Sosoo;Kim, Hwang-Yong;Jung, Kyu Seok;Jang, Ja Yeong;Park, Jong-Chul;Ham, Hyeonheui;Lee, Soohyung;Hong, Sung Kee;Kim, Jin-Cheol
    • The Plant Pathology Journal
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    • v.33 no.5
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    • pp.499-507
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    • 2017
  • In an attempt to develop a biological control agent against mycotoxigenic Fusarium species, we isolated Bacillus amyloliquefaciens strain DA12 from soil and explored its antimicrobial activities. DA12 was active against the growth of mycotoxigenic F. asiaticum, F. graminearum, F. proliferatum, and F. verticillioides both in vitro and in planta (maize). Further screening using dual culture extended the activity range of strain DA12 against other fungal pathogens including Botrytis cinerea, Colletotrichum coccodes, Endothia parasitica, Fusarium oxysporum, Raffaelea quercus-mongolicae, and Rhizoctonia solani. The butanol extract of the culture filtrate of B. amyloliquefaciens DA12 highly inhibited the germination of F. graminearum macroconidia with inhibition rate 83% at a concentration of $31.3{\mu}g/ml$ and 100% at a concentration of $250{\mu}g/ml$. The antifungal metabolite from the butanol extract was identified as iturin A by thin layer chromatography-bioautography. In addition, volatile organic compounds produced by DA12 were able to inhibit mycelial growth of various phytopathogenic fungi. The volatile compounds were identified as 2-heptanone, 5-methyl heptanone and 6-methyl heptanone by gas chromatography-mass spectrometry (GC-MS) analysis. These results indicate that the antagonistic activity of Bacillus amyloliquefaciens DA12 was attributable to iturin A and volatile heptanones, and the strain could be used as a biocontrol agent to reduce the development of Fusarium diseases and mycotoxin contamination of crops.

Hydrodesulfurization of Diesel for Molten Carbonate Fuel Cell Applications (용융탄산염 연료전지용 디젤의 수소첨가탈황)

  • Kim, Minsoo;Kim, Hyun Koo;Jang, Seong-Cheol;Kim, Yeongcheon;Choi, Sun Hee;Yoon, Sung Pil;Han, Jonghee;Nam, Suk Woo;Choi, Dae-Ki;Chul, Hyung
    • Transactions of the Korean hydrogen and new energy society
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    • v.26 no.1
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    • pp.21-27
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    • 2015
  • Hydrogen production from commercial diesel fuels is an attactive option for energy generation purpose due to the low cost and good availability of diesel fuels. However, in order to utilize commercial diesel fuels, the sulfur contents must be removed down to approximately 0.1 ppm level to protect the fuel cell catalysts from poisoning. Commercial catalysts $CoMo/Al_2O_3$ and $NiMo/Al_2O_3$ were tested for HDS (Hydrodesulfurization) of model diesel and commercial diesel. The experimental conditions were $250-400^{\circ}C$ and LHSV (Liquid Hourly Space Velocity) $0.27-2.12hr^{-1}$. $NiMo/Al_2O_3$ was found to be more effective than $CoMo/Al_2O_3$ in removing sulfur from model diesel. Based on the experimental results of model diesel, commercial diesel fuel purchased from a local petrol station was tested for HDS using $NiMo/Al_2O_3$. The GC-SCD (Gas Chromatography Sulfur Chemiluminescence Detector) results showed that the DMDBT (Dimethyldibenzothiophene) derivatives were fully removed from the commercial diesel fuel proving that HDS with $NiMo/Al_2O_3$ is technically feasible for industrial applications.

Purification and Characterization of Gibberellin $3Beta$-Hydroxylase from Immature Seeds of Phaseolus vulgaris (강낭콩미숙종자로부터 Gibberellin $3Beta$-Hydroxylase 정제 및 성질)

  • 곽상수
    • Proceedings of the Botanical Society of Korea Conference
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    • 1987.07a
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    • pp.133-148
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    • 1987
  • Gibberellin(GA) 3-$\beta$ hydroxylation is very important for the shoot elogation in the higher plants, since only 3$\beta$-hydryoxylated GAs promote shoot elogation in several plants. Fluctuation of 3$\beta$-hydryoxylase activity was examined during seed maturation using two cultivars of , P. vulgaris, Kentucky Wonder (normal) and Masterpiece (dwarf). Very immature seeds of both cultivars contain high level of 3$\beta$-hydroxylase activity (per mg protein). Both cultivars showed maximum of enzyme activity (per seed) in the middle of their maturation process. Gibberellin 3$\beta$-hydroxylase catalyzing the hydroxylation of GA20 to GA1 was purified 313-fold from very early immature seeds of P. vulgaris. Crude soluble enzyme extracts were purified by 15% methanol precipitation, hydrophobic interaction chromatogrphy, DEAE ion exchange column chromatography and gel filtration HPLC. The 3$\beta$-hydroxylase activity was unstable and lost much of its activity duting the purification. The molecular weight of purified enzyme was extimated to be 42, 000 by gel filtration HPLC and SDS-PAGE. The enzyme exhibited maximum activity at pH 7.7. The Km values for [2.3-3H] GA20 and [2.3-3H]GA9 were 0.29 $\mu$M and 0.33 $\mu$M, respectively. The enzyme requires 2-oxoglutarate as a cosubstrate; the Km value for 2-oxoglutarate was 250 $\mu$M using 3H GA20 as a substrate. Fe2+ and ascorbate significantly activated the enzyme at all purification steps, while catalase and BSA activated the purified enzyme only. The enzyme was inhibited by divalent cations Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+ and Hg2+. Effects of several GAs and GA anaogues on the putrified 3$\beta$-hydroxylase were examined using [3H]GA9 and GA20 as a substrates. Among them, GA5, GA9, GA15, GA20 and GA44 inhibited the enzyme activity. [13C, 3H] GA20 was converted by the partially purified enzyme preparation to [13C, 3H]GA1, GA5 and GA6, which were identified by GC-MS, GA9 was converted only GA4, GA15 and GA44 were converted to GA37 and GA38, respectively. GA5 was epoxidized to GA6 by the preparation. This suggests that 3$\beta$-hydroxylation of GA20 and epoxidation of GA5 are catalyzed by the same enzyme in P, vulgaris.

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The Effect of 15% Carbamide Peroxide on the Surface Roughness and Staining of Esthetic Restoratives (15% Carbamide Peroxide가 심미수복재의 표면조도와 착색에 미치는 영향)

  • Kim, Soo-Hwa;Choi, Hye-Sook;Roh, Jj-Yeon;Kim, Kwang-Mahn
    • Journal of dental hygiene science
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    • v.13 no.2
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    • pp.165-173
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    • 2013
  • The purpose of this study was to evaluate the surface change after 15% carbamide peroxide home bleaching to various restorative materials (composite resin [CR], resin modified glass ionomer [RMGI] and glass ionomer [GI]) and to observe the effect of surface condition of the materials on re-staining. Three esthetic restorative materials (Filtek Z250, 3M, USA; Fuji II LC, GC, Japan; Fuji II, GC, Japan) were used in this study. Twenty specimens per material group were made and divided into two groups (bleached and control). The specimens were immersed in coffee after applying bleaching agent. The color change and surface roughness were measured before and after bleaching and after immersion in coffee. The data were analyzed with SPSS 18.0. The results were as follows: 1. The color of all experiment groups was significantly changed after bleaching (p<0.05). RMGI was the greatest value of ${\Delta}E^*$ and ${\Delta}L^*$. GI and CR groups were in ordering (p<0.05). The ${\Delta}a^*$ value was decreased GI, RMGI and CR. RMGI was only significantly decreased in ${\Delta}b^*$ value (p<0.05). 2. The surface roughness before and after bleaching was significantly different on CR, RMGI and GI (p<0.05). 3. After staining with coffee, the value of ${\Delta}E^*$ was increased in GI, RMGI and CR, furthermore GI and RMGI showed significant difference in the bleaching groups (p<0.05). The ${\Delta}L^*$ value of GI and RMGI was significantly decreased. 4. The change of surface roughness after staining was not significantly different in all groups (p>0.05). The maintenance of color stability in esthetic restorations is one of the most important properties. Tooth whitening is for the aesthetic. Therefore, dental professionals should notice to patients about re-staining after tooth whitening. They should give an instruction that how to prevent and which kinds of agents could be stained.

Germination-Induced Changes in Flavoring Compound Profiles and Phytonutrient Contents in Scented Rice (향미벼의 발아 전 후 향기 성분 및 기능성 지질성분 함량의 변화)

  • Mahmud, MM Chayan;Das, Animesh Chandra;Lee, Seul-Ki;Kim, Tae-Hyeong;Oh, Yejin;Cho, Yoo-Hyun;Lee, Young-Sang
    • KOREAN JOURNAL OF CROP SCIENCE
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    • v.61 no.4
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    • pp.242-250
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    • 2016
  • Although rice has been cultivated as a major food crop for approximately 5,000 years, the interest of customers in 'scented rice' is a recent trend in the Korean market. As a part of developing a germinated scented rice variety, the newly bred scented rice variety 'Cheonjihyang-1 se' was germinated for 24 h, and changes in profiles of flavor-related volatiles, lipophilic phytonutrients, and fatty acids were investigated. The profiling of volatile compounds by using a headspace-gas chromatography-mass spectrometry (HS-GC-MS) revealed a total of 56 odor-active flavoring compounds; 52 at the pre-germination stage, 51 at the post-germination stage, and 47 common at both stages. The major flavoring compounds were nonanol and benzene, which constituted 11.5% and 6.6%, respectively, of the total peak area in pre-germinated rice, and 19.4% and 6.5%, respectively, in post-germinated rice. Germination induced an increase in 13 flavoring compounds, including 3,3,5-trimethylheptane and 1-pentadecene, which increased by 763 and 513%, respectively by germination. However, we observed a germination-induced decrease in most of the other flavoring compounds. Especially, the most important scented rice-specific popcorn-flavoring compound, 2-acetyl-1-pyrroline, showed 89% decrease due to germination. Furthermore, the germination of scented rice induced a decrease in the content of various phytonutrients. For example, the total contents of phytosterols, squalene, and tocols decreased from 207.97, 31.74, and $25.32{\mu}g\;g^{-1}$ at pre-germination stage down to 136.66, 25.12, and $17.76{\mu}g\;g^{-1}$, respectively at post-germination stage. The fatty acid compositions were also affected by germination. The composition of three major fatty acids, linoleic, oleic, and palmitic acids, increased from 36.6, 34.2, and 24.4%, respectively, at the pre-germination stage to 37.9, 36.9, and 20.7%, respectively, at the post-germination stage. All these results suggested significant changes in the flavor-related compounds and phytonutrients of the scented rice variety 'Cheonjihyang-1 se' during the process of germination, and subsequently the need for developing a more precise process of germination to enhance the flavor and nutritional quality of the germinated scented rice products.

A Safety Survey of Pesticide Residues on Agricultural Products Marketed in Incheon from 2019 to 2021 (인천광역시 유통 농산물의 잔류농약 안전성 조사)

  • Park, Byung-Kyu;Kwon, Sung-Hee;Yeom, Mi-Sook;Han, Se-Youn;Kang, Min-Jung;Joo, Kwang-Sig;Heo, Myung-Je;Kwon, Mun-Ju
    • Journal of Food Hygiene and Safety
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    • v.37 no.4
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    • pp.249-259
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    • 2022
  • This study investigated pesticide residues in 7,069 agricultural products distributed in the city of Incheon from 2019 to 2021. Ingestion of pesticides can cause serious carcinogenic, endocrine, neurological, and reproductive problems. Pesticide residues in the samples were analyzed using various multi-residue methods (GC-MS/MS, GC-ECD/NPD, LC-MS/MS, and HPLC-UVD) on the Korean Food Code. The violation rate of the samples exceeding the maximum residue level (MRL) of pesticide residues for the years 2019, 2020, and 2021 was 1.0%, 1.4%, and 1.1%, respectively. Diazinon, flubendiamide, procymidone, fluxametamide, and fluquinconazole were the most frequently reported violative pesticide residues. Most commonly encountered agricultural products exceeding MRLs were coriander leaves, chamnamul, chwinamul, welsh onion, and crown daisy. Agricultural products and pesticides frequently exceeding MRLs should be continuously inspected for food safety. Continuous monitoring of pesticide residues in agricultural products is indispensable to improve consumer safety by preventing the distribution of agricultural products exceeding MRLs.

Study of Surfactant Enhanced Remediation Methods for Organic Pollutant(NAPL) Distributed over the Heterogeneous Medium (계면활성제를 이용한 불균질 매질에서 유기오염물(NAPL)의 정화효율에 관한 실험)

  • 서형기;이민희;정상용
    • Journal of Soil and Groundwater Environment
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    • v.6 no.4
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    • pp.51-59
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    • 2001
  • Column and box tests were performed to investigate the removal efficiency of NAPL using the surfactant enhanced flushing In heterogeneous medium. Homogeneous Ottawa sand and heterogeneous soil were used to verify the increase of remediation efficiency for the surfactant enhanced flushing in column test. Box tests with two different heterogeneous sub-structure were performed to quantify the capability of the surfactant enhanced flushing as a remediation method to remove NAPL from the heterogeneous medium. Two different grain size sand layers were repeated in the box to simulate the heterogeneous layer formation and the modified fault structure was built to simulate the fault system in the box. O-xylene as a LNAPL and PCE as a DNAPL were used and oleamide as a non-ionic surfactant. The maximum NAPL effluent concentration with 1% oleamide flushing in the homogeneous column test increased about 460 times compared to that with only water flushing and about 250 times increased in the real soil column test. In heterogeneous medium, the maximum effluent concentration increased about 150 times in 1% oleamide flushing and most of NAPL were removed from the box within 8 pore volume flushing, suggesting that the removal efficiency increased very much compared to in only water flushing. Results investigated the capability of the surfactant enhanced remediation method to remove NAPL even in heterogeneous medium.

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Brief Introduction of Research Progresses in Control and Biocontrol of Clubroot Disease in China

  • He, Yueqiu;Wu, Yixin;He, Pengfei;Li, Xinyu
    • 한국균학회소식:학술대회논문집
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    • 2015.05a
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    • pp.45-46
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    • 2015
  • Clubroot disease of crucifers has occurred since 1957. It has spread to the whole China, especially in the southwest and nourtheast where it causes 30-80% loss in some fields. The disease has being expanded in the recent years as seeds are imported and the floating seedling system practices. For its effective control, the Ministry of Agriculture of China set up a program in 2010 and a research team led by Dr. Yueqiu HE, Yunnan Agricultural University. The team includes 20 main reseachers of 11 universities and 5 institutions. After 5 years, the team has made a lot of progresses in disease occurrence regulation, resources collection, resistance identification and breeding, biological agent exploration, formulation, chemicals evaluation, and control strategy. About 1200 collections of local and commercial crucifers were identified in the field and by artificiall inoculation in the laboratories, 10 resistant cultivars were breeded including 7 Chinese cabbages and 3 cabbages. More than 800 antagostic strains were isolated including bacteria, stretomyces and fungi. Around 100 chemicals were evaluated in the field and greenhouse based on its control effect, among them, 6 showed high control effect, especially fluazinam and cyazofamid could control about 80% the disease. However, fluzinam has negative effect on soil microbes. Clubroot disease could not be controlled by bioagents and chemicals once when the pathogen Plasmodiophora brassicae infected its hosts and set up the parasitic relationship. We found the earlier the pathogent infected its host, the severer the disease was. Therefore, early control was the most effective. For Chinese cabbage, all controlling measures should be taken in the early 30 days because the new infection could not cause severe symptom after 30 days of seeding. For example, a biocontrol agent, Bacillus subtilis Strain XF-1 could control the disease 70%-85% averagely when it mixed with seedling substrate and was drenching 3 times after transplanting, i.e. immediately, 7 days, 14 days. XF-1 has been deeply researched in control mechanisms, its genome, and development and application of biocontrol formulate. It could produce antagonistic protein, enzyme, antibiotics and IAA, which promoted rhizogenesis and growth. Its The genome was sequenced by Illumina/Solexa Genome Analyzer to assembled into 20 scaffolds then the gaps between scaffolds were filled by long fragment PCR amplification to obtain complet genmone with 4,061,186 bp in size. The whole genome was found to have 43.8% GC, 108 tandem repeats with an average of 2.65 copies and 84 transposons. The CDSs were predicted as 3,853 in which 112 CDSs were predicted to secondary metabolite biosynthesis, transport and catabolism. Among those, five NRPS/PKS giant gene clusters being responsible for the biosynthesis of polyketide (pksABCDEFHJLMNRS in size 72.9 kb), surfactin(srfABCD, 26.148 kb, bacilysin(bacABCDE 5.903 kb), bacillibactin(dhbABCEF, 11.774 kb) and fengycin(ppsABCDE, 37.799 kb) have high homolgous to fuction confirmed biosynthesis gene in other strain. Moreover, there are many of key regulatory genes for secondary metabolites from XF-1, such as comABPQKX Z, degQ, sfp, yczE, degU, ycxABCD and ywfG. were also predicted. Therefore, XF-1 has potential of biosynthesis for secondary metabolites surfactin, fengycin, bacillibactin, bacilysin and Bacillaene. Thirty two compounds were detected from cell extracts of XF-1 by MALDI-TOF-MS, including one Macrolactin (m/z 441.06), two fusaricidin (m/z 850.493 and 968.515), one circulocin (m/z 852.509), nine surfactin (m/z 1044.656~1102.652), five iturin (m/z 1096.631~1150.57) and forty fengycin (m/z 1449.79~1543.805). The top three compositions types (contening 56.67% of total extract) are surfactin, iturin and fengycin, in which the most abundant is the surfactin type composition 30.37% of total extract and in second place is the fengycin with 23.28% content with rich diversity of chemical structure, and the smallest one is the iturin with 3.02% content. Moreover, the same main compositions were detected in Bacillus sp.355 which is also a good effects biocontol bacterial for controlling the clubroot of crucifer. Wherefore those compounds surfactin, iturin and fengycin maybe the main active compositions of XF-1 against P. brassicae. Twenty one fengycin type compounds were evaluate by LC-ESI-MS/MS with antifungal activities, including fengycin A $C_{16{\sim}C19}$, fengycin B $C_{14{\sim}C17}$, fengycin C $C_{15{\sim}C18}$, fengycin D $C_{15{\sim}C18}$ and fengycin S $C_{15{\sim}C18}$. Furthermore, one novel compound was identified as Dehydroxyfengycin $C_{17}$ according its MS, 1D and 2D NMR spectral data, which molecular weight is 1488.8480 Da and formula $C_{75}H_{116}N_{12}O_{19}$. The fengycin type compounds (FTCPs $250{\mu}g/mL$) were used to treat the resting spores of P. brassicae ($10^7/mL$) by detecting leakage of the cytoplasm components and cell destruction. After 12 h treatment, the absorbencies at 260 nm (A260) and at 280 nm (A280) increased gradually to approaching the maximum of absorbance, accompanying the collapse of P. brassicae resting spores, and nearly no complete cells were observed at 24 h treatment. The results suggested that the cells could be lyzed by the FTCPs of XF-1, and the diversity of FTCPs was mainly attributed to a mechanism of clubroot disease biocontrol. In the five selected medium MOLP, PSA, LB, Landy and LD, the most suitable for growth of strain medium is MOLP, and the least for strains longevity is the Landy sucrose medium. However, the lipopeptide highest yield is in Landy sucrose medium. The lipopeptides in five medium were analyzed with HPLC, and the results showed that lipopeptides component were same, while their contents from B. subtilis XF-1 fermented in five medium were different. We found that it is the lipopeptides content but ingredients of XF-1 could be impacted by medium and lacking of nutrition seems promoting lipopeptides secretion from XF-1. The volatile components with inhibition fungal Cylindrocarpon spp. activity which were collect in sealed vesel were detected with metheds of HS-SPME-GC-MS in eight biocontrol Bacillus species and four positive mutant strains of XF-1 mutagenized with chemical mutagens, respectively. They have same main volatile components including pyrazine, aldehydes, oxazolidinone and sulfide which are composed of 91.62% in XF-1, in which, the most abundant is the pyrazine type composition with 47.03%, and in second place is the aldehydes with 23.84%, and the third place is oxazolidinone with 15.68%, and the smallest ones is the sulfide with 5.07%.

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Changes of Serum Fatty Acid and Carnitine Levels after Administration of L-carnitine in Rats (흰쥐에서 L-carnitine 투여 후에 혈청 지방산과 Carnitine의 농도 변화)

  • Lee, Jae Won;Hong, Young Mi
    • Clinical and Experimental Pediatrics
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    • v.45 no.9
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    • pp.1075-1082
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    • 2002
  • Purpose : Obesity is known to be associated with hypertension, dyslipidemia, and fatty liver and is thought to be associated with increased levels of free fatty acids. One of the strategies for decreasing free fatty acid levels is stimulation of hepatic lipid oxidation with L-carnitine. Carnitine is an essential cofactor for transport of long-chain fatty acid into mitochondria for oxidation. This study was designed to evaluate the changes of serum fatty acids and carnitine levels after exogenous injection of L-carnitine. Methods : Sprague Dawley rats were divided into two groups. Group A was control. Group B was given intraperitoneal injection with L-carnitine(200 mg/kg) daily for two weeks. Serum lipid (total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol) and fatty acid levels were analyzed on the first day of the first and second weeks after injection of L-carnitine. Total, free, and acyl carnitine levels also were performed by a enzymatic cycling techniques at the same day intervals. Results : There was no significant difference between the two groups in total cholesterol, HDL-cholesterol, LDL-cholesterol levels before and after the administration of L-carnitine. But triglyceride levels were significantly decreased at the first week in group B compared with group A. Among free fatty acids, linoleic acid showed significant decrement(A group : $131.3{\pm}31.3mg/dL$ vs B group : $90.0{\pm}7.0mg/dL$) at the first week. Total, free, and acyl carnitine levels showed significant increments at all days intervals, but only free carnitine showed significant increments according to cumulative doses of carnitine. Conclusion : Plasma linoleic acid, a long-chain fatty acid, showed significant decrement after administration of L-carnitine in the first week. This may suggest that L-carnitine can be used as an antilipidemic agent for obese patients. A prospective study will investigate obese children in the future.