Recurrence monitoring using ctDNA in patients with metastatic colorectal cancer: COSMOS-CRC-03 and AURORA studies
Eiji OkiRyota NakanishiKoji AndoIchiro TakemasaJun WatanabeNobuhisa MatsuhashiTakeshi KatoYoshinori KagawaMasahito KotakaKeiji HirataMasahiko SugiyamaTamon KusumotoYuji MiyamotoKayo ToyosakiJunji KishimotoYasue KimuraTomoharu YoshizumiYoshiaki Nakamura
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•Treatment guidelines recommend resection of oligometastatic CRC.•Optimal perioperative systemic therapy has not been fully defined.•The COSMOS-CRC-03 study evaluates the ctDNA's prognostic value for oligometastatic cancer.•The AURORA trial tests mFOLFOXIRI plus bevacizumab post-surgery.•We designed these studies to stratify patients based on a ctDNA assay. International treatment guidelines recommend tumor resection for patients with oligometastatic colorectal cancer (CRC). Despite this, recurrence occurs in ∼60% of patients post-surgery, indicating that the role and optimal type of perioperative systemic therapy has not been fully defined. In the COSMOS-oligo trials, comprising two studies, we are evaluating the potential role of circulating tumor DNA (ctDNA) analysis in clinical decision making and exploring adjuvant therapy strategies for patients with resectable metastatic CRC. The COSMOS-CRC-03 study aims to evaluate the prognostic value of post-operative minimal residual disease as detected by ctDNA and to explore the role of ctDNA in detecting disease recurrence. We plan to assess the predictive accuracy of ctDNA results for recurrence using blood collected 28 days post-surgery. We will additionally explore whether regular post-operative ctDNA test can detect recurrence earlier than standard imaging. Post-operative adjuvant therapy will not be administered to ctDNA-negative patients. The complementary AURORA trial is a randomized phase II study designed to test whether post-operative mFOLFOXIRI plus bevacizumab is superior to standard mFOLFOX6 for patients with metastatic CRC when the ctDNA status is positive after curative-intent surgery for patients enrolled in the COSMOS-CRC-03 study. Both studies will only include patients with resectable distant metastases of CRC. We designed these studies to stratify patients based on the results of a ctDNA assay and to determine the optimal treatment for patients at the highest risk for recurrence. International treatment guidelines recommend tumor resection for patients with oligometastatic colorectal cancer (CRC). Despite this, recurrence occurs in ∼60% of patients post-surgery, indicating that the role and optimal type of perioperative systemic therapy has not been fully defined. In the COSMOS-oligo trials, comprising two studies, we are evaluating the potential role of circulating tumor DNA (ctDNA) analysis in clinical decision making and exploring adjuvant therapy strategies for patients with resectable metastatic CRC. The COSMOS-CRC-03 study aims to evaluate the prognostic value of post-operative minimal residual disease as detected by ctDNA and to explore the role of ctDNA in detecting disease recurrence. We plan to assess the predictive accuracy of ctDNA results for recurrence using blood collected 28 days post-surgery. We will additionally explore whether regular post-operative ctDNA test can detect recurrence earlier than standard imaging. Post-operative adjuvant therapy will not be administered to ctDNA-negative patients. The complementary AURORA trial is a randomized phase II study designed to test whether post-operative mFOLFOXIRI plus bevacizumab is superior to standard mFOLFOX6 for patients with metastatic CRC when the ctDNA status is positive after curative-intent surgery for patients enrolled in the COSMOS-CRC-03 study. Both studies will only include patients with resectable distant metastases of CRC. We designed these studies to stratify patients based on the results of a ctDNA assay and to determine the optimal treatment for patients at the highest risk for recurrence.Keywords:
Cosmos (plant)
Corticosterone (CORT) and other glucocorticoids cause peripheral insulin resistance and compensatory increases in β-cell mass. A prolonged high-fat diet (HFD) induces insulin resistance and impairs β-cell insulin secretion. This study examined islet adaptive capacity in rats treated with CORT and a HFD. Male Sprague-Dawley rats (age ∼6 weeks) were given exogenous CORT (400 mg/rat) or wax (placebo) implants and placed on a HFD (60% calories from fat) or standard diet (SD) for 2 weeks (N = 10 per group). CORT-HFD rats developed fasting hyperglycemia (>11 mM) and hyperinsulinemia (∼5-fold higher than controls) and were 15-fold more insulin resistant than placebo-SD rats by the end of ∼2 weeks (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR] levels, 15.08 ± 1.64 vs 1.0 ± 0.12, P < .05). Pancreatic β-cell function, as measured by HOMA-β, was lower in the CORT-HFD group as compared to the CORT-SD group (1.64 ± 0.22 vs 3.72 ± 0.64, P < .001) as well as acute insulin response (0.25 ± 0.22 vs 1.68 ± 0.41, P < .05). Moreover, β- and α-cell mass were 2.6- and 1.6-fold higher, respectively, in CORT-HFD animals compared to controls (both P < .05). CORT treatment increased p-protein kinase C-α content in SD but not HFD-fed rats, suggesting that a HFD may lower insulin secretory capacity via impaired glucose sensing. Isolated islets from CORT-HFD animals secreted more insulin in both low and high glucose conditions; however, total insulin content was relatively depleted after glucose challenge. Thus, CORT and HFD, synergistically not independently, act to promote severe insulin resistance, which overwhelms islet adaptive capacity, thereby resulting in overt hyperglycemia.
Hyperinsulinemia
Corticosterone
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The effect of 48 h of fasting in C57B1/6J-ob/ob and +/+ mice on body weight (BW), blood glucose (BG), serum immunreactive insulin (IRI), plasma immunoreactive glucagon (IRG) and on tissue levels of cyclic adenosine monophosphate (cAMP) were studied. Both groups of mice lost weight and demonstrated a decrease in BG and IRI with fasting. However, the BG and IRI of the ob/ob animals were initially highter and remained higher than those of the 2% of their initial weight while the +/+ lost 14 %. The +/+ mice exhibited an increase in cAMP levels in skeletal muscle, fat and liver with fasting, while the ob/ob mice had increased levels of cAMP in fat, but not in muscle. They also had a paradoxical decrease in liver cAMP levels with fasting, and associated with this was the lack of stimulation of glycogenolysis. Glycogenolysis was significant in the livers of fasted +/+ mice. The plasma IRG levels of the fed ob/ob mice were significantly higher (1.8) times) than those of the fed +/+ mice. Islet cAMP levels were decreased with fasting in ob/ob mice. However, the levels were significantly higher in 48-h faster ob/ob mice compared to the fasted +/+ group. The apparent paradoxical response to fasting observed in the livers of the ob/ob mice remains unexplained.
Glycogenolysis
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Bilateral destruction of the hypothalamic paraventricular nuclei (PVN) produced a profound depression of plasma TSH and the median eminence TRH concentration in hypothyroid rats. Anterior pituitary type II iodothyronine 5′- deiodinase (5′-D) activity was consistently lower but not significantly different in sham- and PVN-lesioned rats. Treatment with suboptimal replacement doses of 0.15 and 0.75 ng T4/100 g BW-day produced a graded depression of plasma TSH in the PVN (P < 0.02), but not in the sham (P > 0.8) groups. Adenohypophyseal 5′-D was depressed in both sham and PVN groups by the highest T4 dose. Plasma T4 was much lower in PVN than in sham rats given comparable doses of T4 (P < 0.001), but plasma T3 was not significantly different. This suggests that an increase in peripheral T4 metabolism was produced by PVN lesions. Our data indicate that changes in adenohypophyseal 5′- D activity are not responsible for the decrease in plasma TSH in PVN-lesioned rats and that neither the PVN nor endogenous TRH plays a significant role in the regulation of anterior pituitary 5′-D activity. (Endocrinology123: 1676–1681, 1988)
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Abstract Dysregulation of the adipoinsular axis in male obese Zucker diabetic fatty (ZDF; fa/fa) rats, a model of type 2 diabetes, results in chronic hyperinsulinemia and increased de novo lipogenesis in islets, leading to β-cell failure and diabetes. Diazoxide (DZ; 150 mg/kg·d), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 wk as a strategy for prevention of diabetes. DZ reduced food intake (P < 0.02) and rate of weight gain only in ZDF rats (P < 0.01). Plasma insulin response to glucose load was attenuated in DZ-Zucker lean rats (ZL; P < 0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P < 0.001). DZ improved hemoglobin A1c (P < 0.001) and glucose tolerance in ZDF (P < 0.001), but deteriorated hemoglobin A1c in ZL rats (P < 0.02) despite normal tolerance in the fasted state. DZ lowered plasma leptin (P < 0.001), free fatty acid, and triglyceride (P < 0.001) levels, but increased adiponectin levels (P < 0.02) only in ZDF rats. DZ enhanced β3-adrenoreceptor mRNA (P < 0.005) and adenylate cyclase activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet β3- adrenergic receptor mRNA (P < 0.005) but paradoxically decreased islet adenylate cyclase activity (P < 0.005) in these animals. Islet fatty acid synthase mRNA (P < 0.03), acyl coenzyme A carboxylase mRNA (P < 0.01), uncoupling protein-2 mRNA (P < 0.01), and triglyceride content (P < 0.005) were only decreased in DZ-ZDF rats, whereas islet insulin mRNA and insulin content were increased in DZ-ZDF (P < 0.01) and DZ-ZL rats (P < 0.03). DZ-induced β-cell rest improved the lipid profile, enhanced the metabolic efficiency of insulin, and prevented β-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing β-cell failure and progression to diabetes in humans.
Hyperinsulinemia
Lipogenesis
Diazoxide
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다수 사용자를 지원하는 프로그램에서 쓰레드의 중요성이 증가함에 따라 데이타베이스 관리 시스템의 하부구조인 객체 저장 시스템들도 쓰레드를 이용하도록 확장되고 있다. 기존의 프로세스/쓰레드 모델은 멀티프로세스/단일쓰레드 모델, 단일프로세스/멀티쓰레드 모델, 그리고 멀티프로세스/멀티쓰레드 모델로 분류할 수 있다. 이 중 멀티프로세스/멀티쓰레드 모델은 다른 모델들을 포괄할 수 있는 일반적인 형태의 구조이다. 본 논문에서는 멀티프로세스/단일쓰레드 모델로 개발된 객체 저장 시스템 COSMOS 를 멀티프로세스/멀티쓰레드 모델로 확장한 COSMOS/MT 를 설계하고 구현한다. 먼저 COSMOS 의 트랜잭션 컨텍스트를 분석하여 공유 트랜잭션 컨택스트와 비공유 트랜잭션 컨택스트로 분류한 후, 각 트랜잭션 컨텍스트의 유지방법을 제안한다. 그리고, 구현한 모델의 유용성을 보이기 위하여 TPC-A 벤치마크에 대해 성능 평가를 수행한다. 실험결과 1000 개의 클라이언트를 서비스하는 경우 COSMOS/MT 가 COSMOS 에 비하여 처리율이 최고 5배까지 향상됨을 보인다. 마지막으로, 멀티프로세스/멀티쓰래드 모델의 성능을 결정하는 중요 요소인 프로세스 당 쓰레드 개수에 따른 성능 변화에 대하여 고찰하고, 실험을 통하여 프로세스당 쓰레드 개수에 따른 시스템의 성능 변화를 보인다.
Cosmos (plant)
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In normal rats, females have higher circulating GH-binding protein (GHBP) levels than males, whereas in the GH-deficient dwarf (Dw) rat, there is no sexual dimorphism in plasma GHBP, suggesting that GH secretion may be involved in this difference. In order to study the relationship between gonadal steroids and GH on GHBP and GH receptor regulation, the levels of plasma GHBP, hepatic bovine GH, and human GH (hGH) binding as well as GHBP and GH receptor messenger RNA (mRNA) have now been studied in normal, Dw, hypophysectomized (Hx), or ovariectomized (Ovx) rats, subjected to different GH and gonadal steroid exposure. In normal male rats, estradiol (E2, 12.5-25 micrograms/day for 1 or 2 weeks) markedly increased plasma GHBP and hepatic hGH, and bGH binding. These effects of E2 were diminished in Dw rats, absent in Hx rats, but restored in Hx rats given exogenous hGH. Plasma GHBP rose in female rats given E2, and fell in females given the anti-estrogen tamoxifen. Ovx animals had lower plasma GHBP and hepatic GH binding which was reversed by E2, but not testosterone treatment. Continuous hGH infusions in Ovx rats restored hepatic GH binding, and increased plasma GHBP. In Dw males, hGH increased plasma GHBP and hepatic GH binding, whereas testosterone had no effect on GHBP or GH receptors and did not affect their up-regulation by hGH. Hepatic levels of GHBP-, and GH receptor mRNA transcripts showed the same trends in response to steroid or GH treatment, but the differences were rarely significant, except in Ovx animals which had higher GHBP mRNA transcripts after GH or E2 treatment. Thus E2 and GH increase both plasma GHBP and hepatic GH receptor binding. GH up-regulates GHBP in the absence of E2, whereas E2 treatment does not raise GHBP in the absence of GH. Whereas some of the effects of estrogen could be mediated via alterations in GH secretion, estrogen may also directly influence GHBP production at the liver, but only in the presence of GH.
Growth hormone-binding protein
Sexual dimorphism
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Plasma glucose, insulin, and FFA concentrations were determined in 15 normal subjects and 15 patients with noninsulin-dependent diabetes mellitus (NIDDM) from 0800 to 1600 h. Breakfast and lunch were consumed at 0800 and 1200 h, respectively, and plasma concentrations were measured at hourly intervals from 0800-1600 h. Plasma glucose concentrations between 0800 and 1600 h were significantly elevated in patients with NIDDM, and the higher the fasting glucose level, the greater the postprandial hyperglycemia. Hyperglycemia in patients with NIDDM was associated with plasma insulin levels that were significantly higher (P less than 0.001) than those in normal subjects, and substantial hyperinsulinemia occurred between 0800 and 1600 h in patients with mild NIDDM (fasting plasma glucose concentrations, less than 140 mg/dl). Both fasting and postprandial FFA levels were also increased in patients with NIDDM (P less than 0.001), and the greater the plasma glucose response, the higher the FFA response (r = 0.70; P less than 0.001). However, there was no significant correlation between plasma insulin and FFA concentrations. More specifically, hyperinsulinemic patients with mild diabetes (fasting plasma glucose, less than 140 mg/dl) maintained normal ambient FFA levels, while FFA concentrations were significantly elevated in patients with severe NIDDM (fasting plasma glucose, greater than 250 mg/dl), with insulin concentrations comparable to those in normal subjects. These results demonstrate that patients with NIDDM are not capable of maintaining normal plasma FFA concentrations. This defect in FFA metabolism is proportionate to the magnitude of hyperglycemia and occurs despite the presence of elevated levels of plasma insulin. These results are consistent with the view that insulin resistance in NIDDM also involves the ability of insulin to regulate FFA metabolism.
Hyperinsulinemia
Carbohydrate Metabolism
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Glucagon-like peptide-1 augments nutrient-stimulated insulin secretion. Chow-fed mice lacking the glucagon-like peptide-1 receptor (Glp1r) exhibit enhanced insulin-stimulated muscle glucose uptake but impaired suppression of endogenous glucose appearance (endoRa). This proposes a novel role for the Glp1r to regulate the balance of glucose disposal in muscle and liver by modulating insulin action. Whether this is maintained in an insulin-resistant state is unknown. The present studies tested the hypothesis that disruption of Glp1r expression overcomes high-fat (HF) diet-induced muscle insulin resistance and exacerbates HF diet-induced hepatic insulin resistance. Mice with a functional disruption of the Glp1r (Glp1r−/−) were compared with wild-type littermates (Glp1r+/+) after12 wk on a regular chow diet or a HF diet. Arterial and venous catheters were implanted for sampling and infusions. Hyperinsulinemic-euglycemic clamps were performed on weight-matched male mice. [3-3H]glucose was used to determine glucose turnover, and 2[14C]deoxyglucose was used to measure the glucose metabolic index, an indicator of glucose uptake. Glp1r−/− mice exhibited increased glucose disappearance and muscle glucose metabolic index on either diet. This was associated with enhanced activation of muscle Akt and AMP-activated protein kinase and reduced muscle triglycerides in HF-fed Glp1r−/− mice. Chow-fed Glp1r−/− mice exhibited impaired suppression of endoRa and hepatic insulin signaling. In contrast, HF-fed Glp1r−/− mice exhibited improved suppression of endoRa and hepatic Akt activation. This was associated with decreased hepatic triglycerides and impaired activation of sterol regulatory element-binding protein-1. These results show that mice lacking the Glp1r are protected from HF diet-induced muscle and hepatic insulin resistance independent of effects on total fat mass.
Glucose clamp technique
Carbohydrate Metabolism
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The role of the hypothalamic paraventricular nucleus (PVN) in thyroid hormone regulation of TSH synthesis during hypothyroidism was studied in adult male rats that were normal (n = 10), had primary hypothyroidism with sham lesions in the hypothalamus (n = 17), and had primary hypothyroidism with PVN lesions (n = 14). Two and 4 weeks after initiation of treatment, plasma levels of thyroid hormones (TSH, corticosterone and PRL) and pituitary content of TSH beta and alpha-subunit mRNA were measured. TRH mRNA levels in the PVN were determined by in situ hybridization histochemistry. At 2 weeks, despite a decrease in plasma free T4 in both hypothyroid groups, plasma TSH levels increased, but to a lesser degree, in the hypothyroid PVN lesioned compared to hypothyroid sham-lesioned group (7.8 +/- 1.3 vs. 20.5 +/- 1.1 ng/dl; P less than 0.05). Similarly, at 4 weeks, the hypothyroid PVN-lesioned group demonstrated a blunted TSH response compared to the hypothyroid sham-lesioned group (6.8 +/- 0.7 vs. 24.0 +/- 1.3 ng/dl; P less than 0.05). Plasma corticosterone and PRL did not significantly differ between sham-lesioned and PVN-lesioned groups. TSH beta mRNA levels markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls at 2 weeks (476 +/- 21% vs. 100 +/- 39%; P less than 0.05) and 4 weeks (1680 +/- 270% vs. 100 +/- 35%; P less than 0.05). In contrast, TSH beta mRNA levels did not increase with hypothyroidism in the PVN-lesioned group compared to those in euthyroid controls at 2 weeks (140 +/- 16%, P = NS) and only partially increased at 4 weeks (507 +/- 135; P less than 0.05). alpha mRNA levels at 4 weeks markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls (1121 +/- 226% vs. 100 +/- 48%; P less than 0.05), but did not increase in the hypothyroid PVN-lesioned rats (61 +/- 15%; P = NS). TRH mRNA in the PVN increased in the hypothyroid sham-lesioned rats compared to those in euthyroid controls (16.6 +/- 1.3 vs. 4.8 +/- 1.2 arbitrary densitometric units; P less than 0.05), and TRH mRNA was not detectable in the PVN of hypothyroid-lesioned rats at 2 weeks. In summary, lesions in rat PVN prevented the full increase in plasma TSH, pituitary TSH beta mRNA, and alpha mRNA levels in response to hypothyroidism. Thus, factors in the PVN are important in thyroid hormone feedback regulation of both TSH synthesis and secretion.
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