Abstract
The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (
IDH
) wild-type glioblastoma (GBM) is currently limited due to high ...molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of
IDH
wild-type GBM tumors derived from a quantitative proteomic analysis of 39
IDH
wild-type GBMs as well as
IDH
mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (
FKBP9
). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (
PHGDH
). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.
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Among linear α-olefins, 1-octene is widely used as a starting material in the industrial production of plastics, oils, waxes, and surfactants. The adsorption separation of gaseous ...olefin/paraffin using various adsorbents has been extensively studied; however, detailed studies on the adsorption separation of liquid-phase olefin/paraffin are scant. In this study, we systematically investigated the selective adsorption of 3A, 4A, 5A, and 13X bead-shaped zeolites from 1-octene/n-octane liquid binary mixture as a function of type and weight of the zeolites. Batch-type adsorption experiments were performed in the 1-octene volume fraction range of 10–90 %. The results show that 5A and 13X zeolites are promising adsorbents for selective 1-octene adsorption owing to the preferential adsorption of 1-octene on the cation sites in the micropore. Contrastingly, both 1-octene and n-octane cannot enter 3A and 4A micropores, resulting in negligible preferential adsorption of 1-octene over n-octane. The Langmuir constant of 5A is higher than that of 13X due to the stronger polarization effect of Ca2+ compared to that of Na+, resulting in additional attractive interaction between the adsorbent and 1-octene. The experimental analysis presented in this study provides a solid basis for the development of selective adsorbents for the liquid–liquid separation.
OBJECTIVE: To evaluate predictors of undergoing fertility preservation treatment (FPT) in women with breast cancer. DESIGN: Secondary analysis of a clinical database. SETTING: Three academic ...fertility preservation centers. PATIENT(S): One hundred eight patients with breast cancer undergoing FPT and 77 patients with breast cancer not undergoing FPT from 2005 to 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients’ demographic and medical information. RESULT(S): Women who had FPT were older, wealthier, and had lower cancer stage compared with women who did not have FPT. The rate of the administration of neoadjuvant chemotherapy (NAC) was significantly lower in women who underwent FPT. After adjusting for age, body mass index (BMI), income, cancer stage, and center, a negative correlation persisted between NAC and FPT (odds ratio 0.091, 95% confidence interval 0.009–0.904). When we stratified the women by center, women at center 1 had a significantly lower FPT rate, lower parity, higher BMI, more advanced cancer stage, and lower income compared with centers 2 and 3. The rates of NAC were significantly higher in center 1. CONCLUSION(S): Although age, BMI, income, cancer stage, center, and NAC seem to be associated with undergoing FPT, NAC is the only modifiable variable. Because NAC restricts the time available for FPT, oncologists may consider offering adjuvant chemotherapy, except in cases in which NAC clearly improves survival, in women who are interested in FPT.
We had previously demonstrated that vitrification reduces the levels of certain phospholipid classes, and that oocytes from aged mice show a similar lipidome alteration, even without vitrification. ...In the current investigation, we examined if vitrification-warming of mouse oocytes from young and aged mice causes any changes in molecular aspects of lipid-associated features.
Metaphase II (MII) stage oocytes were harvested from young (10-14-week-old) and aged (45-54-week-old) mice by a superovulation regime with PMSG followed by hCG. We examined the status of the intracellular lipid pool and the integrity of the plasma membrane by staining oocytes with BODIPY 500/510 and CellMask live dyes. Expression of lipid uptake- and necroptosis-associated genes was assessed by quantitative PCR analyses, in oocytes from young and old mice, before and after vitrification. Localization patterns of two crucial necroptosis proteins, phosphorylated MLKL (pMLKL) and phosphorylated RIPK1 (pRIPK1) were examined in mouse oocytes by immunofluorescence staining. Necrostain-1 (Nec1), an inhibitor of RIPK1, was used to examine if RIPK1 activity is required to maintain oocyte quality during vitrification.
We confirmed that vitrified-warmed oocytes from aged mice showed noticeable decrease in both CellMask and BODIPY 500/510 dyes. Among the lipid uptake-associated genes, Cd36 expression was higher in oocytes from aged mice. Necroptosis is a type of programmed cell death that involves damage to the plasma membrane, eventually resulting in cell rupture. The expression of necroptosis-associated genes did not significantly differ among groups. We observed that localization patterns of pMLKL and pRIPK1 were unique in mouse oocytes, showing association with microtubule organizing centers (MTOCs) and spindle poles. pMLKL was also localized on kinetochores of MII chromosomes. Oocytes treated with Nec1 during vitrification showed a decreased survival rate, indicating the importance of RIPK1 activity in oocyte vitrification.
We report that oocytes from aged mice show differential expression of CD36, which suggests that CD36-mediated lipid uptake may be influenced by age. We also show for the first time that pMLKL and pRIPK1 exhibit unique localization pattern in mouse oocytes and this may suggest role(s) for these factors in non-necroptosis-associated cellular processes.
Context and Objective:
There has been increased attention to the issue of fertility preservation (FP). We aimed to investigate the long-term safety of FP via controlled ovarian stimulation with ...letrozole supplementation (COSTLES) prior to breast cancer treatment.
Design, Setting, and Participants:
This is a prospective, nonrandomized, controlled study conducted between the years 2002 and 2014. A total of 337 women diagnosed with stage 3 or less invasive breast cancer were enrolled during a FP consultation before chemotherapy. Of those, 120 elected to undergo COSTLES for FP prior to chemotherapy (FP group). The remaining 217 patients did not undergo any FP procedure and served as the controls.
Main Outcome Measure:
The primary end point was cancer recurrence defined as the detection of locoregional tumor (chest wall, regional nodal disease), distant metastases, or contralateral invasive breast cancer.
Results:
The baseline characteristics at enrollment were similar between the FP and control groups except for the less frequent lymph node involvement (P = .02) in the former. The mean follow-up after diagnosis was 5.0 years in the FP group and 6.9 years in the control group. In the FP group, the hazard ratio for recurrence after ovarian stimulation was 0.77 (95% confidence interval 0.28–2.13), and the survival was not compromised compared with controls (P = .61). Neither BRCA gene mutation status (P = .57) nor undergoing FP before or after breast surgery (P = .44) affected survival outcomes in the FP group. Likewise, none of the tumor characteristics including the estrogen receptor status affected the survival rates after the COSTLES.
Conclusion:
COSTLES is unlikely to cause a substantially increased recurrence risk in breast cancer during the 5 years after diagnosis.
This prospective non-randomized controlled study showed no increased recurrence risk in breast cancer patients who pursued fertility preservation via controlled ovarian stimulation with letrozole during the 5 years after diagnosis.
Advanced maternal age (AMA) is known to be related to the decrease in the quality and quantity of oocytes. Oocyte vitrification is now considered an established assisted reproductive technology for ...fertility preservation. However, it remains unclear whether the oocytes in older women are more sensitive to various insults during vitrification. Thus, we evaluated whether AMA affects cellular and molecular features and developmental outcomes of oocytes after vitrification in mice. The oocytes were grouped as young fresh (YF), young vitrified/warmed (YV), aged fresh (AF), and aged vitrified/warmed (AV). The survival rate of AV oocytes was significantly lower than that of YV oocytes. The rates of fertilization, cleavage, and blastocyst formation of AV oocytes were significantly lower than those of other groups. AV oocytes were represented as aberrations in mitochondria distribution, microvacuole size, and autophagosome formation, leading to delayed embryo development in mice. This delay was associated with a reduced number of total cells and trophectoderm in the blastocyst developed from AV oocytes. Collectively, AMA exaggerates the vulnerability of oocytes to cryo-damage that occurs during vitrification in mice, suggesting that the current vitrification protocols optimized for oocytes from young females should be modified for oocytes from aged women.
The open carrier system (OC) is used for vitrification due to its high efficiency in preserving female fertility, but concerns remain that it bears possible risks of cross-contamination. Closed ...carrier systems (CC) could be an alternative to the OC to increase safety. However, the viability and developmental competence of vitrified/warmed (VW) oocytes using the CC were significantly lower than with OC. We aimed to improve the efficiency of the CC. Metaphase II oocytes were collected from mice after superovulation and subjected to in vitro fertilization after vitrification/warming. Increasing the cooling/warming rate and exposure time to cryoprotectants as key parameters for the CC effectively improved the survival rate and developmental competence of VW oocytes. When all the conditions that improved the outcomes were applied to the conventional CC, hereafter named the modified vitrification/warming procedure using CC (mVW-CC), the viability and developmental competence of VW oocytes were significantly improved as compared to those of VW oocytes in the CC. Furthermore, mVW-CC increased the spindle normality of VW oocytes, as well as the cell number of blastocysts developed from VW oocytes. Collectively, our mVW-CC optimized for mouse oocytes can be utilized for humans without concerns regarding possible cross-contamination during vitrification in the future.
Purpose: BRCA gene mutations and elevated serum estradiol (E₂) are well-known risk factors for breast cancer. The aim of this study was to investigate the association between BRCA gene mutations and ...serum E₂ level. Methods: We measured baseline (menstrual cycle day 2–3) E₂ levels of 96 women with breast cancer who underwent BRCA testing. Results: The mean age, parity, and age at menarche did not differ between women with and without BRCA1/2 mutations. Basal serum E₂ level was significantly higher in women with BRCA2 mutations compared to women with BRCA1 mutations or without BRCA mutations (71.7 ± 41.6 vs. 45.5 ± 20.7 vs. 38.5 ± 12.6 pg/ml in BRCA2 mutation carriers, BRCA1 mutation carriers, and non-carriers, respectively, p value = 0.03). Women with BRCA2 mutations had 3.1 times as great risk for high basal E₂ level (>48 pg/ml) as women without BRCA mutations after adjusting for age and BMI (95 % confidence interval: 1.3, 7.6). BRCA mutation carriers with high serum E₂ level were significantly younger than the carriers with low serum E₂ level (31.4 ± 3.1 vs. 34.7 ± 4.9 years, p = 0.04). Conclusions: In this pilot study, we found an association between high basal serum E₂ levels and BRCA2 mutations. Our results suggest that increased production of E₂ may have a role in the pathogenesis of BRCA2-mutation-related breast cancer.
Over 150,000 reproductive age individuals face fertility-threatening cancer treatments each year. Improved detection and treatment of cancer in reproductive-age patients have greatly increased the ...long-term survival and made it possible for these individuals to consider their long-term quality-of-life after cancer including having biologic offspring. Various methods of fertility preservation (FP) are now available for both males and females. In order to maximize FP options available to patients facing imminent gonadotoxic therapies, it is crucial that women have quick access to FP care and that providers expedite FP strategies. The overarching goal of a clinical FP program is to help patients and their physicians consider the impact of treatment on future fertility and facilitate FP efforts in what is often a limited time period before cancer treatment begins.
Based on the current understanding of a preventive effect of bilateral salpingectomy on ovarian/fallopian/peritoneal cancers, the Korean Society of Obstetrics and Gynecology, Korean Society of ...Gynecologic Endocrinology, Korean Society of Gynecologic Oncology, Korean Society of Maternal Fetal Medicine, and Korean Society for Reproductive Medicine support the following recommendations: • Women scheduled for hysterectomy for benign gynecologic disease should be informed that bilateral salpingectomy reduces the risk of ovarian/fallopian/peritoneal cancer, and they should be counseled regarding this procedure at the time of hysterectomy. • Although salpingectomy is generally considered as a safe procedure in terms of preserving ovarian reserve, there is a lack of evidences representing its long-term outcomes. Therefore, patients should be informed about the minimal potential of this procedure for decreasing ovarian reserve. • Prophylactic salpingectomy during vaginal hysterectomy is favorable in terms of prevention of ovarian/fallopian/peritoneal cancer, although operation-related complications minimally increase with this procedure, compared to the complications associated with vaginal hysterectomy alone. Conversion to open or laparoscopic approach from vaginal approach to perform prophylactic salpingectomy is not recommended. • Women who desire permanent sterilization at the time of cesarean delivery could be counseled for prophylactic salpingectomy before surgery on an individual basis.
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