Oocyte quality is a key factor in determining embryo development; however, we have a poor understanding of what constitutes oocyte quality or the mechanisms governing it. Postovulatory aging of ...oocytes that have not been fertilized for a prolonged time after ovulation is known to significantly impair oocyte quality and subsequent embryo development after fertilization. Embryos derived from postovulatory‐aged oocytes are prone to undergo apoptosis due to the decreased Bcl‐2 expression. Postovulatory aging of oocytes changes the patterns of Ca2+ oscillations at fertilization as a result of impaired Ca2+ regulation in the endoplasmic reticulum. Moreover, postovulatory aging of oocytes impairs mitochondrial adenosine triphosphate production as a result of increasing oxidative stresses. Oxidative stresses also affect intracellular Ca2+ regulation and impair embryo development after fertilization. Collectively, the mechanism of postovulatory oocyte aging might be involved in reactive oxygen species‐induced mitochondrial injury followed by abnormal intracellular Ca2+ regulation in the endoplasmic reticulum.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We examined whether impairment of intracellular Ca²⁺ homeostasis is related to poor embryo development in in vitro-aged oocytes. We found that in vitro aging of mouse oocytes affected the patterns of ...Ca²⁺ oscillations at fertilization: these Ca²⁺ oscillations were lower in amplitude and higher in frequency compared with oocytes without in vitro aging. We also observed that the intracellular Ca²⁺ store was decreased in in vitro-aged oocytes. A decrease in the Ca²⁺ store induced by thapsigargin, a specific endoplasmic reticulum (ER) membrane Ca²⁺-ATPase inhibitor, resulted in a lower fertilization rate and in poorer embryo development. The frequency of Ca²⁺ oscillations was significantly increased at fertilization, whereas their amplitude was decreased in thapsigargin-treated oocytes. These results suggest that impairment of intracellular Ca²⁺ homeostasis (such as a decrease in the ER Ca²⁺ store) caused an alteration in Ca²⁺ oscillations and the poor embryo development in in vitro-aged oocytes. Because embryo fragmentation is closely related to apoptosis, we examined expression of BAX (a proapototic protein) and BCL2 (an antiapoptotic protein) in in vitro-aged oocytes. Although BCL2 was strongly expressed in oocytes without in vitro aging, expression of BCL2 was significantly reduced in oocytes of other culture conditions and treatments such as those in in vitro aging and those that were pretreated with H₂O₂ or thapsigargin. Acting together, alteration in Ca²⁺ oscillations and decrease in BCL2 expression in in vitro-aged oocytes may lead to poor embryo development.
Background
Anaplastic lymphoma kinase (ALK)‐positive lung cancer has a better long‐term prognosis with ALK‐inhibitor than other lung cancers. However, resistance to ALK‐inhibitors and the control of ...metastases in the central nervous system (CNS) remain to be a challenge in the management of ALK‐positive lung cancer.
Case
We present the case of a 23‐year‐old man who developed multiple brain metastases while receiving alectinib treatment for ALK‐positive lung cancer. After 3 months of lorlatinib initiation, brain metastases disappeared, and complete response (CR) was maintained.
Conclusion
While lorlatinib can be used as first line therapy, this drug may be considered as second line or later option for patients with multiple brain metastases if the patient has already been treated with other ALK‐inhibitors since lorlatinib is thought to have good CNS penetration. This treatment option should be verified by further research.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We examined the molecular mechanisms of the antiestrogenic effects of clomiphene citrate (CC) in the endometrium using two types of cell lines, Ishikawa and EM-E6/E7/hTERT cells. CC or ICI182780 ...inhibited 17β-estradiol (E2)-induced endometrial cell proliferation and transcriptional activation of the estrogen response element (ERE) gene. We directly visualized the ligand-estrogen receptor (ER)α interaction using green fluorescent protein (GFP)-tagged ERα in a single living cell. Whereas E2 changed the nuclear localization of GFP-ERα to a punctate distribution within 5 min, CC or ICI182780 changed the slower and less mobilization of GFP-ERα compared with E2. Pretreatment with CC or ICI182780 partly prevented the E2-induced nuclear redistribution of GFP-ERα. Fluorescence recovery after photobleaching revealed that GFP-ERα mobility treated with E2 was more rapid than that treated by CC or ICI182780. As coactivator recruitment to the ER is essential for ER-dependent transcription, we examined the interaction between ERα and steroid receptor coactivator-1 (SRC-1). The complex formation between ERα and SRC-1 was significantly increased by E2 but was prevented in the presence of CC or ICI182780 by coimmunoprecipitation. Moreover, the E2-induced colocalization of GFP-ERα and SRC-1 was prevented in the presence of CC or ICI182780 according to an immunofluorescence assay. We also observed that the reduction of SRC-1 using small interfering RNA for SRC-1 resulted in the inhibition of E2-induced cell proliferation and transcriptional activation of the ERE gene. Collectively, these results suggest that CC may inhibit E2-induced endometrial epithelial cell proliferation and ERE transactivation by inhibiting the recruitment of SRC-1 to ERα.
Clomiphene citrate may inhibit estradiol-induced endometrial epithelial cell proliferation and estrogen receptor α (ERα) transactivation by inhibiting the recruitment of steroid receptor coactivator-1 to ERα.
A 67-year-old woman was transported to our emergency outpatient department for continuous vomiting and abdominal pain while taking medicine prescribed by her previous doctor. She had undergone ...pituitary tumor resection 6 years prior and was receiving hormone replacement therapy. She presented with sudden-onset hypotension during the examination. Although sufficient fluid resuscitation and vasopressors were administered, she continued to exhibit hypotension and her serum lactate level was high. The physical examination suggested intestinal necrosis, which needed to be confirmed. As she had contrast agent allergy, we performed a laparoscopic examination instead of contrast CT to investigate the condition of the intestines. We changed to laparotomy because of a poor visual field due to distention of the intestines but found no necrotic change. She recovered after the administration of antibiotics and hormone replacement therapy after surgery. On the 4th day, Salmonella species O8 was cultured from blood and fecal samples; therefore, we suspected adrenal insufficiency caused by Salmonella enteritidis.
It is well established that age-related decline of a woman's fertility is related to the poor developmental potential of her gametes. The age-associated decline in female fertility is largely ...attributable to the oocyte aging caused by ovarian aging. Age-associated oocyte aging results in a decrease in oocyte quality. In contrast to ovarian aging, there is a concept of postovulatory oocyte aging. Postovulatory aging of oocytes, not being fertilized for a prolonged time after ovulation, is known to significantly affect the development of oocytes. Both categories of oocyte aging have similar phenotypes of reproductive failure. However, the mechanisms of the decline in oocyte quality are not necessarily equivalent. An age-dependent increase in aneuploidy is a key determinant of oocyte quality. The reduced expression of molecules regulating cell cycle control during meiosis might be involved in the age-dependent increase in aneuploidy. The mechanism of age-associated oocyte aging might be involved in mitochondrial dysfunction, whose etiologies are still unknown. Alternatively, the mechanism of postovulatory oocyte aging might be involved in reactive oxygen species-induced mitochondrial injury pathways followed by abnormal intracellular Ca
2+
regulation of the endoplasmic reticulum. We suggest that future research into the mechanism of oocyte aging will be necessary to develop a method to rescue the poor developmental potential of aged oocytes.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
We recently reported that bezafibrate, a lipid-lowering drug of the fibrate class, administered in addition to clomiphene citrate (CC) successfully induced ovulation in CC-resistant polycystic ovary ...syndrome (PCOS) patients. We hypothesized that bezafibrate may directly affect ovarian follicle development. Insulin resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS. In this study, we first examined the effects of tumor necrosis factor-alpha (TNF), which plays a role in insulin resistance, on follicle development by using the follicle culture system. TNF significantly inhibited follicle-stimulating hormone (FSH)-induced follicle development, 17beta-estradiol (E2) secretion, and ovulation rate in a dose-dependent manner. We then examined whether bezafibrate treatment could rescue the inhibition of FSH-induced follicle development and steroidogenesis by TNF. Bezafibrate treatment rescued inhibition of follicle development, secretion of E2, and ovulation rate by TNF. We examined the expression of peroxisome proliferator-activated receptor (PPAR) subtypes in mouse preantral follicles. As the protein expression of only PPARG was observed in mouse preantral follicles, we examined whether bezafibrate could affect follicle development and steroidogenesis through PPARG pathways. Treatment with GW1929, a selective PPARG agonist, restored inhibition of FSH-induced follicle development and steroidogenesis by TNF, whereas treatment with GW9662, a selective PPARG antagonist, canceled the restorative effects of bezafibrate. Collectively, the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by TNF through the PPARG pathway.
Abstract
Background
The 1st line regimens including Immunocheckpoint Inhibitor (ICI) have lately been approved for unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC). ...However, evidence of these regimens in clinical practice remains limited.
Methods
A total of 67 unresectable advanced or recurrent ESCC patients who received FP (5-FU + CDDP) + Pembrolizumab/Nivolumab (FP + ICI group; n = 43) or Ipilimumab+Nivolumab (ICI + ICI group; n = 24) as the 1st line treatment from December 2017 to March 2023 at our hospital were evaluated.
Results
Patient characteristics(FP + ICI: ICI + ICI) were as follows; age = 69:74 year-old, male/female = 36/7:22/2, recurrent/unresectable = 17(40%)/26(60%):13(54%)/11(46%), number of administered courses = 4 1–35: 2 1–17, follow up period = 9: 6 months. Best response rate was CR/PR/SD/PD = 6/22/9/6:4/9/6/5 cases, while response/disease control rates were 65:54% and 86:79%, respectively. Regarding survival analysis, median OS = 23 months:did not reach, and 1-year OS = 83.7:87.5%, median PFS = 8:5 months, 1-year PFS = 48.8:49.3%, and DOR (duration of response) = 42–38:55–9 months. The most common treatment-related adverse events (CTCAE Grade 3 or higher) were neutropenia in 18 cases, followed by anorexia in 7 cases (FP + ICI group), and adrenal hypofunction in 2 cases and pruritus in 2 cases (ICI + ICI group).
Conclusion
Both 1st line regimens for unresectable advanced or recurrent esophageal squamous cell carcinoma seemed to be feasible and promising in clinical use.
Abstract: Although 60-80% of the women with polycystic ovary syndrome (PCOS) ovulate with clomiphene citrate (CC), the rest are CC-resistant. Recently, the use of insulin-sensitizing agents such as ...metformin and pioglitazone have been proposed for inducing ovulation in CC-resistant women with PCOS, and we have reported that administration of bezafibrate, a lipid-lowering fibrate, in addition to CC, successfully induced ovulation in CC-resistant women with PCOS and dyslipidemia. Both pioglitazone and bezafibrate are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists. This paper reviews the evidence for the direct effects of the drugs, which are PPAR-γ agonists, on follicle development and steroidogenesis, collected using an in vitro mouse preantral follicle culture system. We used the in vitro follicle culture system with the addition of tumor necrosis factor-alpha (TNF-α), which plays a role in insulin resistance, as a model for studying follicle development in women with PCOS. TNF-α inhibited FSH-induced follicle development and steroidogenesis in the follicle culture system. Both pioglitazone and bezafibrate prevented TNF-α-mediated inhibition of FSH-induced follicle development and steroidogenesis through the PPAR-γ-stimulating pathway. Our results suggest that insulin-sensitizing drugs, especially PPAR-γ agonists, may directly influence follicle development and steroidogenesis in women with PCOS.
Although 60–80% of the women with polycystic ovary syndrome (PCOS) ovulate with clomiphene citrate (CC), the rest are CC-resistant. Recently, the use of insulin-sensitizing agents such as metformin ...and pioglitazone have been proposed for inducing ovulation in CC-resistant women with PCOS, and we have reported that administration of bezafibrate, a lipid-lowering fibrate, in addition to CC, successfully induced ovulation in CC-resistant women with PCOS and dyslipidemia. Both pioglitazone and bezafibrate are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists. This paper reviews the evidence for the direct effects of the drugs, which are PPAR-γ agonists, on follicle development and steroidogenesis, collected using an in vitro mouse preantral follicle culture system. We used the in vitro follicle culture system with the addition of tumor necrosis factor-alpha (TNF-α), which plays a role in insulin resistance, as a model for studying follicle development in women with PCOS. TNF-α inhibited FSH-induced follicle development and steroidogenesis in the follicle culture system. Both pioglitazone and bezafibrate prevented TNF-α-mediated inhibition of FSH-induced follicle development and steroidogenesis through the PPAR-γ-stimulating pathway. Our results suggest that insulin-sensitizing drugs, especially PPAR-γ agonists, may directly influence follicle development and steroidogenesis in women with PCOS.
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