382 research outputs found
Different Effects of Maternal Low-Isoflavone Soy Protein and Genistein Consumption on Hepatic Lipid Metabolism of 21-Day-Old Male Rat Offspring.
Amino acid composition and isoflavone are alleged contributors to the beneficial effects of soy protein isolate (SPI) on lipid metabolism. Therefore, we investigated the contributing component(s) of SPI in a maternal diet to the regulation of lipid metabolism in offspring. We also determined serum parameters in dams to investigate specific maternal cues that might be responsible for this regulation. Female rats were fed either a casein (CAS), a low-isoflavone SPI, or a casein plus genistein (GEN, 250 mg/kg) diet for two weeks before mating, as well as during pregnancy and lactation. Male offspring (CAS, SPI and GEN groups) were studied 21 days after birth. The SPI group had lower serum triglyceride levels than the other groups. Serum cholesterol was reduced in both the SPI and GEN groups compared with the CAS group. Expressions of target genes of peroxisome proliferator-activated receptor α were altered in the SPI group. Serum aromatic amino acid levels in dams were associated with serum triglyceride in offspring. In conclusion, the maternal consumption of a low-isoflavone SPI diet or a casein diet containing genistein has different effects on the lipid metabolism of their offspring; however, more profound effects were observed in the SPI group. Therefore, the altered lipid metabolism of offspring may be attributed to amino acid composition in maternal dietary protein sources
Lapatinib, a Dual EGFR and HER2 Tyrosine Kinase Inhibitor, Downregulates Thymidylate Synthase by Inhibiting the Nuclear Translocation of EGFR and HER2
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been shown to exert a synergistic antitumor effect when combined with fluoropyrimidine. This synergy may be attributable to the downregulation of thymidylate synthase (TS), which is frequently overexpressed in fluoropyrimidine-resistant cancer cells. However, the molecular mechanism underlying the downregulation of TS has yet to be clearly elucidated.In this study, we demonstrate that lapatinib, a dual TKI of EGFR and HER2 downregulates TS via inhibition of the nuclear translocation of EGFR and HER2. From our cDNA microarray experiments, we determined that a variety of nucleotide synthesis-related genes, including TS, were downregulated with lapatinib, and this was apparent in HER2-amplified cells. Targeted and pharmacologic inhibition assays confirmed that the dual inhibition of EGFR and HER2 is required for the more effective reduction of TS as compared to what was observed with gefitinib or trasutuzumab alone. Additionally, we determined that co-transfected EGFR and HER2 activate the TS gene promoter more profoundly than do either EGFR or HER2 alone. The translocation of EGFR and HER2 into the nucleus and the subsequent activation of the TS promoter were inhibited by lapatinib.These results demonstrate that lapatinib inhibits the nuclear translocation of EGFR and HER2 and downregulates TS, thus sensitizing cancer cells to fluoropyrimidine
Association of pathway mutation with survival after recurrence in colorectal cancer patients treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy
Background
Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR.
Methods
Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-β, and PI3K).
Results
Mutation of genes within the WNT, P53, RTK-RAS, TGF-β, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-β pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-β pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p < 0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-β pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-β pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation.
Conclusions
Mutation in genes within TGF-β pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.This research was supported by the Seoul National University Hospital (SNUH) Research Fund (03–2014-0440) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1277 and HI13C2163). The funding bodies had no influence on the design of the study and collection, analysis, and interpretation of data and in writing the manuscript
The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer
Background: Triple-negative (TN) breast cancer, which is defined as being negative for the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), represents a subset of breast cancer with different biologic behaviour. We investigated the clinicopathologic characteristics and prognostic indicators of lymph node-negative TN breast cancer. Methods: Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Seoul National University Hospital between Jan. 2000 and Jun. 2003. Clinicopathologic variables and clinical outcomes were evaluated. Results: Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (< 35 y, p = 0.003), and higher histologic and nuclear grade (p < 0.001). It also correlated with a molecular profile associated with biological aggressiveness: negative for bcl-2 expression (p < 0.001), positive for the epidermal growth factor receptor (p = 0.003), and a high level of p53 (p < 0.001) and Ki67 expression (p < 0.00). The relapse rates during the follow-up period (median, 56.8 months) were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (p = 0.004). Relapse free survival (RFS) was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer (4-year RFS rate 85.5% vs. 94.2%, respectively; p = 0.001). On multivariate analysis, young age, close resection margin, and triple-negativity were independent predictors of shorter RFS. Conclusion: TN breast cancer had higher relapse rate and more aggressive clinicopathologic characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into the risk factor analysis for node-negative breast cancer
Reduced Dose Intensity FOLFOX-4 as First Line Palliative Chemotherapy in Elderly Patients with Advanced Colorectal Cancer
To evaluate the toxicity and efficacy of a reduced dose intensity (mini-) FOLFOX-4 regimen as a first-line palliative chemotherapy in elderly patients (≥70 yr of age) with advanced colorectal cancer, data from prospective databases at Seoul National University Bundang Hospital and Seoul Municipal Boramae Hospital were analyzed. A total of 20 patients were enrolled between January 2001 and August 2004, and were treated with oxaliplatin 65 mg/m2 on day 1, and with 2-hr infusions of leucovorin 150 mg/m2 followed by a 5-FU bolus (300 mg/m2) and 22-hr continuous infusions (450 mg/m2) for 2 consecutive days every 2 weeks until progression, unacceptable toxicity or patient refusal. Sixteen patients were evaluable for response with an overall response rate of 43.8%. Median progression-free survival was 4.8 months (95% CI: 3.0-6.7) and overall survival was 13.5 months (95% CI: 11.1-16.0). The main side effects were anemia and neutropenia, which were observed in 20.8% and 17.7%, respectively, of the total cycles administered. There were no grade 4 toxicities and only one patient suffered from febrile neutropenia. No grade 3 toxicities occurred except for anemia (5.2%) and vomiting (1.0%). In conclusion, the mini-FOLFOX-4 regimen was found to be well tolerated with acceptable toxicity, and to provide a benefit for elderly patients with colorectal cancer
Factors associated with neurodevelopment in preterm infants with systematic inflammation
Background
Several studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. We aimed to investigate whether preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment.
Methods
This prospective cohort study enrolled infants born before 30 weeks of gestation or with birth weight < 1250 g. Infants were grouped according to the presence of systemic inflammation: Control (no inflammation, n = 49), I (systemic inflammation, n = 45). Blood and cerebrospinal fluid samples for markers of brain injury and inflammation were collected and amplitude-integrated electroencephalography (aEEG) was performed within 4 h of septic workup. We evaluated aEEG at 35 weeks postmenstrual age (PMA), head circumference at 36 weeks PMA, and brain MRI at discharge. The Bayley Scales of Infant and Toddler Development III (Bayley-III) was performed at a corrected age (CA) of 18 months.
Results
The I group had more white matter injuries (2 vs. 26.7%, Control vs. I, respectively) at the time of discharge, lower brain functional maturation (9.5 vs. 8), and smaller head size (z-score − 1.45 vs. -2.12) at near-term age and poorer neurodevelopment at a CA of 18 months than the control (p < 0.05). Among the I group, the proportion of immature neutrophils (I/T ratios) and IL-1 beta levels in the CSF were associated with aEEG measures at the day of symptom onset (D0). Seizure spike on aEEG at D0 was significantly correlated with motor and social-emotional domains of Bayley-III (p < 0.05). The I/T ratio and CRP and TNF-α levels of blood at D0, white matter injury on MRI at discharge, head circumference and seizure spikes on aEEG at near-term age were associated with Bayley-III scores at a CA of 18 months.
Conclusions
Systemic inflammation induced by clinical infection and NEC are associated with neurodevelopmental impairment in preterm infants. The seizure spike on aEEG, elevated I/T ratio, CRP, and plasma TNF-alpha during inflammatory episodes are associated with poor neurodevelopment.This research was supported by the Basic Science Research Programme through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2012R1A1A2044109, 2017R1D1A1B03036383, and 2017R1D1A1B04030931) and supported by grant no 0420160450 from the SNUH Research Fun
Prognostic influence of body mass index and body weight gain during adjuvant FOLFOX chemotherapy in Korean colorectal cancer patients
This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.Background: Asian population has different body mass index (BMI) profile compared to Caucasian population. However, the effect of obesity and body weight gain in Asian colorectal cancer patients treated with adjuvant chemotherapy has not been studied thus far. Methods: We have analyzed the association between disease-free survival (DFS) and obesity/body weight change during treatment in Korean stage III or high-risk stage II colorectal cancer patients treated with adjuvant 5-fluorouracil/leucovorin/oxaliplatin. BMI was classified according to WHO Asia-Pacific classification. Weight change was calculated by comparing body weights measured at the last chemotherapy cycle and before surgery. Results: Among a total of 522 patients, 35.7 % of patients were obese (BMI >= 25 kg/m(2)) and 29.1 % were overweight (BMI, 23-24.9 kg/m(2)) before surgery. 18.0 % of patients gained = 5 kg and 26.1 % gained 2-4.9 kg during the adjuvant chemotherapy period. Baseline BMI or body weight change was not associated with DFS in the overall study population. However, body weight gain (>= 5 kg) was associated with inferior DFS (adjusted hazard ratio 2.04, 95 % confidence interval 1.02-4.08, p = 0.043) in overweight and obese patients (BMI >= 23.0 kg/m(2)). Conclusion: In Korean colorectal cancer patients treated with adjuvant FOLFOX chemotherapy, body weight gain during the treatment period has a negative prognostic influence in overweight and obese patients
Central Pontine Myelinolysis in a Patient with Acute Lymphoblastic Leukemia after Hematopoietic Stem Cell Transplantation: A Case Report
We describe a 37-yr-old man who developed central pontine myelinolysis (CPM) after allogeneic hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia. After HSCT, desquamation developed on the whole body accompanied by hyperbilirubinemia. The liver biopsy of the patient indicated graft-versus-host disease-related liver disease, and the dose of methylprednisolone was increased. Then, the patient developed altered mentality with eye ball deviation to the left, for which electroencephalogram and magnetic resonance imaging (MRI) scans were done. Brain MRI scan demonstrated the imaging findings consistent with central pontine myelinolysis and extrapontine myelinolysis. He did not have any hyponatremia episode during hospitalization prior to the MRI scan. To the best of our knowledge, presentation of CPM after allogeneic HSCT is extremely rare in cases where patients have not exhibited any episodes of significant hyponatremia. We report a rare case in which hepatic dysfunction due to graft-versus-host disease has a strong association with CPM after HSCT
Prognostic impact of AJCC response criteria for neoadjuvant chemotherapy in stage II/III breast cancer patients: breast cancer subtype analyses
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background
Neoadjuvant chemotherapy (NAC) is a standard treatment for stage II/III breast cancer patients, and response to NAC is a useful prognostic marker. Since its introduction, 6–8 cycles of NAC has become the standard regimen to improve the outcome of these patients. The purpose of this study is to evaluate the prognostic impact of the American Joint Committee on Cancer (AJCC) response criteria and this tools usefulness in four different breast cancer subtypes.
Methods
We conducted a retrospective cohort study of clinical stage II/III breast cancer patients who received NAC of more than 6 cycles. Response after NAC and the clinicopathological factors were reviewed. AJCC response criteria for NAC were adopted from the AJCC Manual, 7th edition: complete response (CR), partial response (PR), and no response (NR).
Results
A total of 183 patients were enrolled; 22 (12.0 %), 123 (67.2 %), and 38 (20.8 %) patients showed CR, PR, and NR, respectively. The AJCC response was significantly associated with relapse-free survival (RFS) (P < 0.001), whereas pathologic CR (pCR), the current gold standard for response evaluation for NAC, was not (P = 0.140). AJCC response was a significant prognostic factor for RFS in all four breast cancer subtypes, namely luminal A (P = 0.006), luminal B (P = 0.001), HER-2 enriched (P = 0.039), and triple-negative breast cancer (P = 0.035).
Conclusions
The AJCC response criteria represent a simple and easily reproducible tool for response evaluation of NAC patients and a useful clinical prognostic marker for RFS. These criteria also have a prognostic impact in all four breast cancer subtypes, including luminal A in which pCR has a limited role
- …