Supplementation with rumen-inert fat in the growing phase altered adipogenic gene expression and the size and number of adipocytes in Hanwoo steers.

We hypothesized that the provision of rumen-inert fat (RIF) to growing cattle (9 to 13 mo of age) would affect the expression of genes involved in lipid metabolism and thereby affect the size and number of adipocytes of steers slaughtered at 30 mo of age. Thirty steers with an average initial body weight (BW) of 239 ±â€…25 kg were allocated to six pens, balanced for BW and genetic merit for marbling, and assigned to one of two treatment groups: control (only basal diet) or test diet (basal diet with 200 g of RIF per day, on an as-fed basis) for 5 mo. Biopsy samples of longissimus lumborum (LM) muscle were then collected for analysis of fatty acid composition and gene expression. Both groups were then fed the same basal diets during the early and late fattening phases, without RIF, until slaughter (average shrunk BW = 759 kg). Supplementation with RIF increased the longissimus thoracis (LT) intramuscular fatty acid concentration at slaughter (P = 0.087) and numerically increased the quality grade score (P = 0.106). The LM intramuscular relative mRNA expression of genes such as PPARα, ZFP423 and SREBP1, FASN, SCD, FABP4, GPAT1, and DGAT2 were downregulated (P < 0.1) following RIF supplementation. Supplementation of RIF decreased (P < 0.1) diameter and concomitantly increased intramuscular adipocytes per viewing section at slaughter. This likely was caused by promotion of triacylglycerol hydrolysis during the growing phase. Another possible explanation is that the relative mRNA expression of gene ATGL was upregulated by RIF supplementation during the growing (P < 0.1) and the fattening phases (P < 0.05), while the genes associated with fatty acid uptake (FABP4) and esterification (DGAT2) were downregulated during the growing phase and upregulated (P < 0.1) during the fattening phase. This implies that the lipid turnover rate was higher for steers during the growing than fattening phase. This study demonstrated that RIF supplementation during the growing phase induced a carryover effect on the lipogenic transcriptional regulation involved in adipocyte lipid content of intramuscular adipose tissue; increased triacylglycerol hydrolysis during the growing phase subsequently was followed by increased lipid accumulation during the fattening phases.

Rumen inert fat (RIF) is a type of fat supplement that is used in the diets of beef cattle as early as 6 mo of age in calves and continues through the finishing period to improve the dietary energy density which can be used by the animal to deposit more lipid in the muscle tissue. However, for Hanwoo beef cattle, the precise time of RIF supplementation has not yet been determined. This study hypothesized that supplementing RIF at the growing phase (9 to 13 mo of age) would have a positive influence on the marbling characteristics of meat at slaughter. The growth rate and performance of steers were not improved by RIF supplementation, however, an increase in intramuscular fatty acid content was noted that was accompanied by the increased number of intramuscular adipocytes and decreased intramuscular adipocyte diameter. Supportively, upregulation of the genes associated with fatty acid uptake and esterification during the fattening phase of RIF-fed animals was noted. Overall, supplementing RIF at the growing stage could improve the lipid content of the meat which is supported by the increased lipid hydrolysis during the growing phase and followed by increased lipid accumulation during the fattening phases.

Effect of a Porous Suture Containing Transforming Growth Factor Beta 1 on Healing After Rotator Cuff Repair in a Rat Model.

BACKGROUND: The healing failure rate after rotator cuff repair is considerably high. PURPOSE: To evaluate the effect of a porous suture containing transforming growth factor beta 1 (TGF-ß1) on the sustained release of TGF-ß1 and rotator cuff healing in a rat model. STUDY DESIGN: Controlled laboratory study. METHODS: A porous suture was developed, and its tensile strength was measured. TGF-ß1 was delivered using the porous suture, and a TGF-ß1 release test and human fibroblast proliferation assay were performed. For the animal experiment, 30 rats were randomly allocated into 3 groups (n = 10 each). A bilateral supraspinatus tendon tear was made in all the rats, and repair was performed. Group 1 received repair only; group 2, repair and a single injection of TGF-ß1; and group 3, repair using the porous suture containing TGF-ß1. Eight weeks after repair, biomechanical and histological analyses were performed. RESULTS: The porous suture was successfully developed with mechanical properties compatible with the conventional suture, and the sustained release of TGF-ß1 from the porous suture was confirmed. In addition, the cell proliferation assay confirmed the biological safety of the porous suture. In the animal experiment, group 3 biomechanically exhibited the largest cross-sectional area and the highest ultimate failure load and ultimate stress (all P < .05). Histological examination revealed that group 3 showed significantly better collagen fiber density and tendon-to-bone maturation than did groups 1 and 2 (all P < .05). CONCLUSION: The porous suture containing TGF-ß1 could sustainedly and safely release TGF-ß1, and its use during rotator cuff repair could improve rotator cuff healing, as assessed on the basis of the biomechanical and histological changes in the rat model in this study. Considering the effectiveness, safety, and convenience of the porous suture without extra effort in surgery, the findings of the present study will have a far-reaching effect on the treatment of rotator cuff tears. CLINICAL RELEVANCE: The porous suture containing TGF-ß1 might improve healing after rotator cuff repair.

Psychosocial stress and ovarian function in adolescent and young adult cancer survivors.

STUDY QUESTION: Is psychosocial stress associated with ovarian function in reproductive-aged survivors of cancer diagnosed as adolescents and young adults (AYA survivors)? SUMMARY ANSWER: We observed no association between self-reported and biomarkers of psychosocial stress and ovarian function in AYA survivors. WHAT IS KNOWN ALREADY: Psychosocial stress suppresses hypothalamic-pituitary-ovarian axis, resulting in ovulatory dysfunction, decreased sex steroidogenesis and lower fertility in reproductive-aged women. Many cancer survivors experience high psychosocial stress and hypothalamic-pituitary-adrenal axis dysregulation. The menstrual pattern disturbances and infertility they experience have been attributed to ovarian follicle destruction, but the contribution of psychosocial stress to these phenotypes is unknown. STUDY DESIGN, SIZE, DURATION: A cross-sectional study was conducted estimating the association between perceived stress, measured by self-report and saliva cortisol, and ovarian function, measured by bleeding pattern, dried blood spot (DBS) FSH and LH, and saliva estradiol. We included 377 AYA survivor participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: AYA survivor participants were ages 15-35 at cancer diagnosis and ages 18-40 at study enrollment, had completed primary cancer treatment, had a uterus and at least one ovary, did not have uncontrolled endocrinopathy and were not on hormone therapy. Recruited from cancer registries, physician referrals and cancer advocacy groups, participants provided self-reported information on psychosocial stress (Perceived Stress Scale-10 (PSS-10)) and on cancer and reproductive (fertility, contraception, menstrual pattern) characteristics. DBS samples were collected timed to the early follicular phase (cycle Days 3-7) for menstruating individuals and on a random day for amenorrheic individuals; saliva samples were collected three time points within 1 day. FSH and LH were measured by DBS ELISAs, cortisol was measured by ELISA and estradiol was measured by liquid chromatography tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: The median age of participants was 34.0 years (range 19-41) at a median of 6.0 years since cancer diagnosis. The most common cancer was breast (32.1%). Median PSS-10 score was 15 (range 0-36), with 5.3% scoring ≥26, the cut point suggestive of severe stress. Cortisol levels followed a diurnal pattern and cortisol AUC was negatively correlated with PSS-10 scores (P = 0.03). Neither PSS-10 scores nor cortisol AUC were associated with FSH, LH, estradiol levels or menstrual pattern. Waking and evening cortisol and the cortisol awakening response also were not related to ovarian function measures. LIMITATIONS, REASONS FOR CAUTION: Our analysis is limited by its cross-sectional nature, heterogeneity of cancer diagnosis and treatments and low prevalence of severe stress. WIDER IMPLICATIONS OF THE FINDINGS: The lack of association between psychosocial stress and a variety of ovarian function measures in female AYA cancer survivors suggests that psychosocial stress does not have a significant impact on the reproductive axis of AYA survivors. This finding is important in counseling this population on their menstrual pattern and family building plans. STUDY FUNDING/COMPETING INTEREST(S): NIH HD080952, South Korea Health Industry Development Institute HI18C1837 (JK). Dr A.D. works for Bluebird Bio, Inc., Dr D.Z. works for ZRT Labs and Dr P.M.S. works for Ansh Labs, which did not sponsor, support or have oversight of this research. Other authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Relationship between fatty infiltration and gene expression in patients with medium rotator cuff tear.

BACKGROUND: Fatty infiltration (FI) is a key prognostic factor that affects outcomes after rotator cuff repair and is radiologically evaluated using the Goutallier classification. The purpose of this study was to assess alterations in gene and protein expression according to the Goutallier classification in the supraspinatus muscle and any relationships among various gene expression profiles. METHODS: Twenty-four samples of the supraspinatus muscle from 12 patients with a high FI grade (grade 3 or 4) and 12 patients with a low FI grade (grade 1 or 2) with medium-sized tears were acquired during arthroscopic surgery. Alterations in the expression of genes and proteins associated with adipogenesis, fibrosis, inflammation, and muscle atrophy were compared between the high- and low-FI groups using reverse-transcription quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. RESULTS: mRNA expression of not only the adipogenic genes (peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α; P < .001 and P = .020) but also the fibrosis-related gene (α-smooth muscle actin; P < .001), inflammation-related genes (interleukin [IL]-1ß and tumor necrosis factor α; P = .041 and P = .039), and muscle atrophy-related genes (atrogin 1 and myostatin; P = .006 and P < .001) was higher in the high-FI group compared with that in the low-FI group. In addition, adipogenic gene expression was significantly correlated with the expression of other categories of genes (all P < .05, except atrogin 1). A correlation of gene and protein expression was observed for IL-1ß (P = .027) and myostatin (P = .029). CONCLUSIONS: The radiologic grading of FI was associated with the expression of various genes, including adipogenic, fibrotic, inflammatory, and atrophy-related genes, and these genes were closely correlated with each other in terms of expression. This information could be helpful in patient counseling.

Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities.

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.

High-risk human papillomavirus testing as a primary screening for cervical cancer: position statement by the Korean Society of Obstetrics and Gynecology and the Korean Society of Gynecologic Oncology.

Based on emerging data and current knowledge regarding high-risk human papillomavirus (hrHPV) testing as a primary screening for cervical cancer, the Korean Society of Obstetrics and Gynecology and the Korean Society of Gynecologic Oncology support the following scientific facts: • Compared to cytology, hrHPV screening has higher sensitivity and detects more cases of high-grade cervical intraepithelial neoplasia. • Qualified hrHPV testing can be considered as an alternative primary screening for cervical cancer to the current cytology method. • The starting age of primary hrHPV screening should not be before 25 years because of possible overtreatment in this age, which has a high human papillomavirus (HPV) prevalence but rarely progresses to cancer. The screening interval should be no sooner than every 3 years and no longer than every 5 years. • Before the introduction of hrHPV screening in Korea, research into comparative effectiveness of primary hrHPV screening for cervical cancer should be conducted to determine the appropriate HPV assay, starting age, and screening interval.

High-risk human papillomavirus testing as a primary screening for cervical cancer: position statement by the Korean Society of Obstetrics and Gynecology and the Korean Society of Gynecologic Oncology.

Based on emerging data and current knowledge regarding high-risk human papillomavirus (hrHPV) testing as a primary screening for cervical cancer, the Korean Society of Obstetrics and Gynecology and the Korean Society of Gynecologic Oncology support the following scientific facts: • Compared to cytology, hrHPV screening has higher sensitivity and detects more cases of high-grade cervical intraepithelial neoplasia. • Qualified hrHPV testing can be considered as an alternative primary screening for cervical cancer to the current cytology method. • The starting age of primary hrHPV screening should not be before 25 years because of possible overtreatment in this age, which has a high human papillomavirus (HPV) prevalence but rarely progresses to cancer. The screening interval should be no sooner than every 3 years and no longer than every 5 years. • Before the introduction of hrHPV screening in Korea, research into comparative effectiveness of primary hrHPV screening for cervical cancer should be conducted to determine the appropriate HPV assay, starting age, and screening interval.

Influence of Smoking on the Expression of Genes and Proteins Related to Fat Infiltration, Inflammation, and Fibrosis in the Rotator Cuff Muscles of Patients With Chronic Rotator Cuff Tears: A Pilot Study.

PURPOSE: To evaluate the altered gene and protein expression patterns in the rotator cuff muscles of smokers and non-smokers with rotator cuff tears and to identify the smoking-associated key genetic factor(s) involved in rotator cuff muscle physiology. METHODS: Twenty-four samples of rotator cuff muscle from 12 current heavy smokers (mean age 61.8 ± 5.1 years) and age- and sex-matched 12 non-smokers (mean age 61.8 ± 6.9 years) with medium-sized tears were acquired during arthroscopic surgery. As a statistical method, the propensity score matching technique was used to select control group by 1:1 matching for age and sex. Inclusion criteria were patients who underwent arthroscopic repair for medium-sized full-thickness rotator cuff tears and those that were current smokers with a smoking history >20 packs/year. Patients lacking medium-sized tears, those with recent steroid injection history, isolated subscapularis tear, preoperative stiff shoulder, acute traumatic tear, or previous surgery on the same shoulder, or those that declined to participate were excluded. Alterations in the expression of genes and proteins associated with myogenesis, inflammation, adipogenesis, and muscle fibrosis were compared between smokers and non-smokers with reverse-transcription quantitative polymerase chain reaction, western blotting, and immunohistochemistry. RESULTS: Histologic analysis revealed increased inflammation and remarkable fat accumulation and fibrogenesis in the rotator cuff muscle from smokers compared with that from non-smokers. The mRNA expression levels of inflammatory high mobility group box 1 (HMGB1; P = .043), adipogenic CCAAT/enhancer-binding protein alpha (P = .046) and peroxisome proliferator-activated receptor gamma (PPARγ; P = .048), myogenic differentiation 1 (P = .032), fibrogenic alpha-smooth muscle actin (α-SMA; P = .033), and metalloproteinase 9 (P = .036) were significantly greater in samples from smokers than from non-smokers. A correlation was observed between gene and protein expression of HMGB1 (P = .034), PPARγ (P = .021), and α-SMA (P = .021). CONCLUSIONS: Smokers with rotator cuff tears showed high inflammation, large fat infiltration, and fibrosis in rotator cuff muscle that is associated with the increased expression of HMGB1, PPARγ, and α-SMA, respectively. LEVEL OF EVIDENCE: Case control study (Prognostic level III).

Effect of Fatty Acid-Binding Protein 4 Inhibition on Rotator Cuff Muscle Quality: Histological, Biomechanical, and Biomolecular Analysis.

BACKGROUND: A rotator cuff tear (RCT) induces fatty acid-binding protein 4 (FABP4) expression, resulting in ectopic fat accumulation in the rotator cuff muscle. PURPOSE: To evaluate whether FABP4 inhibition reduces fatty infiltration and improves muscle physiology after RCT in a rat model. STUDY DESIGN: Controlled laboratory study. METHODS: Human supraspinatus muscle and deltoid muscle tissues were acquired from patients with RCTs during arthroscopic surgery, and FABP4 expression in the supraspinatus muscle was evaluated as compared with the intact deltoid muscle. A rat RCT model was established by detaching the supraspinatus tendon, after which a specific FABP4 inhibitor was locally injected into the supraspinatus muscle 4 times at 3-day intervals starting 2 weeks after the surgery. Body weight and blood glucose levels were measured at 2 and 4 weeks after the RCT, and the mRNA and protein expressions of various target molecules (including FABP4), histological changes, and biomechanical tensile strength were assessed in the supraspinatus muscles at 4 weeks after the RCT. RESULTS: The expression of human FABP4 was significantly increased in the torn rotator cuff muscle as compared with the intact deltoid muscle. In the rat model, the mRNA and protein expressions of FABP4 and HIF1α were significantly increased by the RCT as compared with the control. The FABP4 inhibitor treatment significantly decreased FABP4 expression when compared with the vehicle treatment; however, HIF1α expression was not significantly decreased versus the vehicle treatment. Histologically, RCT induced noticeable muscle fatty infiltration, which was remarkably reduced by the local injection of the FABP4 inhibitor. Biomechanically, the tensile strength of the rotator cuff muscle after the RCT was significantly improved by the FABP4 inhibitor in terms of load to failure and total energy to failure. CONCLUSION: RCT induces FABP4 expression in human and rat rotator cuff muscles. The FABP4 inhibitor drastically decreased the histological fatty infiltration caused by RCT and improved the tensile strength of the rotator cuff muscle. CLINICAL RELEVANCE: FABP4 inhibitor may have a beneficial effect on the muscle quality after RCT.

Obstetrical, neonatal, and long-term outcomes of children conceived from in vitro matured oocytes.

OBJECTIVE: To investigate the obstetrical, neonatal, and long-term outcomes of in vitro maturation (IVM) compared with conventional in vitro fertilization (IVF) in women with polycystic ovarian syndrome (PCOS). DESIGN: Matched retrospective case-control study. SETTING: University fertility clinic. PATIENT(S): One hundred eighty-four patients undergoing IVM were compared with 366 patients undergoing conventional IVF. All had PCOS and were matched for patient age, gestational age at birth, and the number of fetuses. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Obstetrics, neonatal outcomes, and childhood medical problems and development. RESULT(S): Women's mean age at oocytes retrieval was 32.6 ± 2.9 years. Children's mean age was 7.5 ± 2.3 years. There were no differences in the frequency of obstetrical and neonatal outcomes between the two groups. No difference was found in birth weights between the two groups. The incidence of congenital anomalies was similar between the groups (4.3% in IVM group vs. 4.1% in IVF group). No significant difference was observed between the two groups in the frequency and duration of hospitalization during childhood. Growth developmental status of both groups was within normal range. CONCLUSION(S): In a matched setting between IVM and IVF babies born from women with PCOS, no significant increased risk associated with IVM was been identified after a mean follow-up of 7.5 years.

Changes in Perianchor Cyst Formation Over Time After Rotator Cuff Repair: Influential Factors and Outcomes.

BACKGROUND: There is a lack of knowledge about the changes in perianchor cysts over time and the factors related to perianchor cysts. PURPOSE: To evaluate the changes in perianchor cyst formation and anchor absorption over time after arthroscopic rotator cuff repair with a biocomposite suture anchor and to evaluate the factors affecting perianchor cyst persistence and their relationship with patient outcomes. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Forty consecutive patients (mean age, 61.10 ± 5.79 years) who underwent arthroscopic repair for medium- to large-sized rotator cuff tears using a single type of biocomposite (poly-L-lactic acid/polyglycolic acid-beta tricalcium phosphate) medial-row anchor were prospectively enrolled. Postoperative magnetic resonance imaging (MRI) at 2 different time points (6 and 18 months) was performed, and perianchor cyst formation, anchor absorption, and healing failures were evaluated using postoperative MRI. Demographic and clinical data were collected, and functional outcomes at a minimum of 18 months after surgery were assessed. RESULTS: Perianchor cysts were observed in 24 patients (60.0% total; grade 1: 35.0%; grade 2: 10.0%; grade 3: 7.5%; grade 4: 7.5%) at 6 months, and 7 patients (18.4% total; grade 1: 7.9%; grade 2: 5.3%; grade 3: 2.6%; grade 4: 2.6%) had a persistent perianchor cyst at 18 months after surgery. No anchors were absorbed at 6 months, but 73.7% of patients revealed complete or near-full absorption at 18 months. Patients with persistent perianchor cysts showed a significantly larger tear size in the anteroposterior dimension ( P = .002) and greater retraction ( P < .001). There were no differences in healing failures and functional outcomes between patients with and without persisting perianchor cysts (all P > .05). No differences were found in perianchor cyst formation and anchor absorption between anchors inserted in the greater tuberosity and the lesser tuberosity (all P > .05). CONCLUSION: The incidence and severity of perianchor cysts decreased with time, and most biocomposite suture anchors were absorbed at 18 months after surgery. Persisting perianchor cysts correlated with a larger tear size in the anteroposterior dimension and greater retraction.

Bilateral salpingectomy to reduce the risk of ovarian/fallopian/peritoneal cancer in women at average risk: a position statement of the Korean Society of Obstetrics and Gynecology (KSOG).

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.

Decision making processes of women who seek elective oocyte cryopreservation.

PURPOSE: The aim of this study is to analyze women's opinions and their decision making processes regarding elective oocyte cryopreservation (OC). METHODS: One hundred twenty-four women who had elective OC counseling at the CHA Seoul Fertility Center were asked to complete a survey after their first visit. Data collection regarding age, marital status, monthly income, occupation, religion, reproductive history, questions about the participant's view on their own fecundity, and future parenthood were included. The modified Reproductive Concerns After Cancer scale and the Decisional Conflict Scale were used for analysis. RESULTS: The participants' mean age was 37.1 ± 4.8 years old. Eighty-six percent of the participants had regular periods. Ninety-two percent thought it was important to have their own biological offspring, and 86% were willing to pursue OC. Forty-nine percent appeared to have high DCS scores regarding making a decision of OC. Sixty-eight percent pursued OC, and the mean number of oocytes cryopreserved per patient was 10.5 ± 8.3. Multivariate analysis revealed that age was the only factor associated with high DCS scores (P = 0.002). Feeling less fertile than other women of same age and low DCS scores were the factors associated with pursuing OC (P = 0.02 and 0.004, respectively) after adjusting for possible confounding factors, including age. CONCLUSIONS: Older women had more difficulties in making decisions about OC. Adjusting for age, women who thought that they were less fertile than other women of same age and those with lower decisional conflict were more likely to pursue OC. Further studies should focus on the validation of older women's decisional conflicts regarding OC.

Oestrogen-induced expression of decay accelerating factor is spatiotemporally antagonised by progesterone-progesterone receptor signalling in mouse uterus.

Decay accelerating factor (DAF) is upregulated in the fetoplacental trophoblast, which protects the fetus from maternal complement injury. DAF was found to be downregulated in the endometrium of patients with repeated implantation failure. Thus, we examined the molecular mechanisms of DAF expression regulation by ovarian steroid hormones in the mouse uterus. Immunofluorescence staining demonstrated its exclusive localisation in the apical region of the epithelium in the uterus. Oestrogen (E2) significantly induced Daf mRNA in a time-dependent manner. Progesterone (P4) did not have any significant effect on Daf expression; however, it negatively modulated E2-induced DAF expression and RU486 effectively interfered with the inhibitory action of P4 in the uterus. During early pregnancy DAF was higher on Day 1 of pregnancy, but significantly decreased from Day 3, which is consistent with its E2-dependent regulation. Interestingly, DAF expression seemed to be influenced by the implanting blastocyst on Day 5 and it was gradually increased during preimplantation embryo development with peak levels at blastocyst stages. We demonstrated that E2-dependent DAF expression is antagonised by P4-progesterone receptor signalling in the uterine epithelium. Spatiotemporal regulation of DAF in the uterus and preimplantation embryos suggest that DAF functions as an immune modulator for embryo implantation and early pregnancy in mice.

Effect of Nitric Oxide on Human Corneal Epithelial Cell Viability and Corneal Wound Healing.

Although the wound healing effects of nitric oxide (NO) are known, the mechanism by which NO modulates corneal wound healing remains unclear. In this study, we investigated the effect of exogenous NO donor (NaNO2) on corneal wound healing. We found that NaNO2 (0.1 µM to 100 µM) increased human corneal epithelial cell (HCEC) viability and migration. It also modulated the phosphorylation of mitogen-activated protein kinases (MAPKs) in a time- dependent manner in those HCECs. Further, p38 MAPK phosphorylation increased at 6 h and normalized at 24 h, while the phosphorylation of extracellular signal regulated kinase (ERK) was increased both at 6 h and 24 h. Topical treatment with NaNO2 (10 µM) enhanced corneal epithelial healing and decreased corneal opacity in murine corneal alkali burn model by modulating inflammatory cytokines. Our findings suggest that NO increased HCEC proliferation and migration via time-dependent MAPK activation and eventually enhanced corneal recovery from the alkali burn.

Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in mice.

BACKGROUND: Fatty infiltration in skeletal muscle is directly linked to loss of muscle strength and is associated with various adverse physical outcomes such as muscle atrophy, inflammation, insulin resistance, mobility impairments, and even mortality in the elderly. Aging, mechanical unloading, muscle injury, and hormonal imbalance are main causes of muscle fat accumulation, and the fat cells are derived from muscle stem cells via adipogenic differentiation. However, the pathogenesis and molecular mechanisms of fatty infiltration in muscles are still not fully defined. Fatty acid-binding protein 4 (FABP4) is a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism. Rotator cuff tear (RCT) usually occurs in the elderly and is closely related with fatty infiltration in injured muscle. To investigate potential mechanisms for fatty infiltration other than adipogenic differentiation of muscle stem cells, we examined the role of FABP4 in muscle fatty infiltration in an RCT mouse model. METHODS: In the RCT model, we evaluated the expression of FABP4 by qRT-PCR, western blotting, and immunohistochemical analyses. Histological changes such as inflammation and fat accumulation in the injured muscles were examined immunohistochemically. To evaluate whether hypoxia induces FABP4 expression, the levels of FABP4 mRNA and protein in C3H10T1/2 cells after hypoxia were examined. Using a transient transfection assay in 293T cells, we assessed the promoter activity of FABP4 by hypoxia-inducible factors (HIFs). Additionally, we evaluated the reduction in FABP4 expression and fat accumulation using specific inhibitors for HIF1 and FABP4, respectively. RESULTS: FABP4 expression was significantly increased after RCT in mice, and its expression was localized in the intramuscular fatty region. Rotator cuff tear-induced FABP4 expression was up-regulated by hypoxia. HIF1α, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1ß. Hypoxia-induced FABP4 expression was significantly decreased by HIF1 inhibitor treatment. Furthermore, in RCT model mice, fat accumulation was remarkably reduced by FABP4 inhibitor treatment. CONCLUSIONS: This study shows that RCT induces FABP4 expression, leading to fat accumulation in injured muscle. FABP4 transcription is regulated by the direct binding of HIF1 to the FABP4 promoter in the hypoxic condition induced by RCT. Fat accumulation in injured muscle was reduced by the inhibition of FABP4. Ultimately, in the RCT model, we identified a novel mechanism for fatty infiltration by FABP4, which differs from adipogenic differentiation of muscle stem cells, and we found that fatty infiltration might be regulated by inhibition of HIF1 or FABP4.

Fertility preservation during cancer treatment: The Korean Society for Fertility Preservation clinical guidelines.

While many fertility preservation (FP) options now exist for reproductive-aged cancer patients, access to these services continues to be limited. A comprehensive FP program should be organized to serve oncofertility patients effectively. Also, much effort is needed from various individuals-patients, specialists from various fields, and consultants-to facilitate FP in a timely manner. Various challenges still exist in improving access to FP programs. To improve access to FP treatment, it is important to educate oncologists and patients via electronic tools and to actively navigate patients through the system. Reproductive endocrinology practices that receive oncofertility referrals must be equipped to provide a full range of options on short notice. A multidisciplinary team approach is required, involving physicians, nurses, mental health professionals, office staff, and laboratory personnel. The bottom line of FP patient care is to understand the true nature of each patient's specific situation and to develop a patient flow system that will help build a successful FP program. Expanding the patient flow system to all comprehensive cancer centers will ensure that all patients are provided with adequate information regarding their fertility, regardless of geography.

Young female cancer survivors' use of fertility care after completing cancer treatment.

PURPOSE: The purpose of the present study is to investigate factors associated with female young adult cancer survivors' (YCSs) use of fertility care (FC), including consultation or fertility treatment, after completing their cancer treatment. METHODS: In this cross-sectional study, females between that ages of 18 and 35 years who had been diagnosed with childhood, adolescent, or young adult cancers completed a 20-min web-based survey that included demographics, reproductive history, use of FC, fertility-related informational needs, and reproductive concerns. RESULTS: A total of 204 participants completed the survey. Participants' mean age was 28.3 ± 4.5 years. Thirty (15 %) participants reported using FC after cancer treatment. The majority of participants recalled not receiving enough information about fertility preservation options at the time of cancer diagnosis (73 %). In multivariable analysis, those with higher concerns about having children because of perceived risk to their personal health (P = 0.003) were less likely to report use of FC after cancer treatment. Those who had used FC before cancer treatment (P = 0.003) and who felt less fertile than age-matched women (P = 0.02) were more likely to use FC after their cancer treatment. CONCLUSIONS: While most YCSs in this cohort believed that they did not receive enough information about fertility and most wanted to have children, the vast majority did not seek FC. The findings of this study offer further evidence of the need for improved education and emotional support regarding reproductive options after cancer treatment is completed. Targeted discussions with YCSs about appropriate post-treatment FC options may improve providers' capacity to help YCSs meet their parenthood goals.

Long-Term Safety of Letrozole and Gonadotropin Stimulation for Fertility Preservation in Women With Breast Cancer.

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 0.28­2.13), 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. CONCLUSIONS: COSTLES is unlikely to cause a substantially increased recurrence risk in breast cancer during the 5 years after diagnosis.

Polycystic ovarian syndrome (PCOS), related symptoms/sequelae, and breast cancer risk in a population-based case-control study.

PURPOSE: Despite the overlap between the clinical symptoms/sequelae of polycystic ovarian syndrome (PCOS) and many known reproductive risk factors for breast cancer, the relationship between PCOS and breast cancer remains unclear, possibly because of the complex heterogeneity and challenges in diagnosing PCOS over time. We hypothesized that PCOS, specific PCOS-related symptoms/sequelae, or clusters of PCOS-related symptoms/sequelae may be differentially associated with pre- versus postmenopausal breast cancer risk. MATERIALS AND METHODS: Cases were 1,508 women newly diagnosed with a first primary in situ or invasive breast, and the 1,556 population-based controls were frequency-matched by age. RESULTS: History of physician-diagnosed PCOS was reported by 2.2 % (n = 67), among whom oral contraceptive (OC) use, irregular menstruation, and infertility due to ovulatory dysfunction were common. Using unconditional logistic regression, adjusted odds ratios (95 % CI) for PCOS were increased for premenopausal [2.74 (1.13, 6.63)], but not postmenopausal breast cancer [0.87 (0.44, 1.71)]. We used cluster analysis to investigate whether risk among all women varied by PCOS-related symptoms/sequelae, such as reproductive irregularities, OC use, and components of insulin resistance. In the cluster analysis, odds ratios were elevated among premenopausal women who had a history of OC use and no ovulatory dysfunction [1.39 (1.03, 1.88)], compared to those with fewer number of PCOS-related symptoms/sequelae. CONCLUSION: PCOS and associated PCOS-related symptoms/sequelae including OC use may play a role in the development of premenopausal breast cancer. Our findings require confirmation in studies with a larger number of premenopausal women with systematically applied diagnostic criteria for PCOS.