Visualization of specific cells in the three-dimensional organ architecture is one of the key steps to develop our knowledge about pathophysiological mechanisms in various organs. In this study, we ...successfully obtained stereoscopic whole images of the intrauterine murine embryo and placenta through the uterus using a modified tissue clearing CUBIC method. By this procedure, we can recognize the three-dimensional relationships among various tissues within the pregnant uterus and analyze free-angle images of cross-sections with single-cell resolution using a computer system. Based on these data, we can select optimal cross-section angles and then produce the corresponding tissue slices that are adequate for further immunohistochemical examination. Furthermore, using transgenic mice, distinct images of an EGFP-positive embryo and the placenta can be obtained, confirming the precise three-dimensional location of invading trophoblasts in the feto-maternal interface in the uterus. These results indicate that this procedure will significantly contribute to analyzing pathophysiological mechanisms in reproductive organs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We report a case of twin anemia‐polycythemia sequence with blood chimerism in monochorionic dizygotic twins born to a 30‐year‐old woman who conceived via ovulation induction. The neonates developed ...twin anemia‐polycythemia sequence; the female twin had anemia and the male had polycythemia. We detected blood chimerism using fluorescence in situ hybridization (FISH). Twin anemia‐polycythemia sequence carries not only perinatal risks, but also genetic and immunological implications due to blood chimerism. Although previous reports have described twin‐to‐twin transfusion syndrome in monochorionic dizygotic twins, we report the first case of twin anemia‐polycythemia sequence in monochorionic dizygotic twins.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Human extravillous trophoblast (EVT) invades the maternal endometrium and reconstructs uterine spiral arteries cooperatively with maternal immune cells. Although EVT has allogeneic paternal antigens, ...the maternal immune system does not reject it. Here, we found that laeverin (LVRN), an EVT-specific cell surface peptidase, interacts with monocytes to produce indoleamine 2,3-dioxygenase-1 (IDO1). LVRN-transfected Swan71 cells, a cytotrophoblast-derived cell line, and increased IDO1 expression in PBMC under cell-to-cell interacting conditions. Soluble recombinant LVRN (r-LVRN) interacted with CD14-positive monocytes and induced their IDO1 expression without the intervention of other immune cell populations. LVRN-induced IDO1 production was promoted in PMA-activated monocyte-like THP-1 cells. Furthermore, r-LVRN decreased the tryptophan level and increased the kynurenine/tryptophan ratio in the culture media of the PMA-treated THP-1 cells. These findings suggest that LVRN is one of the key molecules that mediate the interaction between EVT and monocytes/macrophages and creates an immunosuppressive environment at the maternal-fetal interface in the uterus.
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•The cell surface LVRN and a soluble r-LVRN interacted with PBMC to produce IDO1•r-LVRN induced IDO1 expression in monocytes without other immune cell populations•r-LVRN increased the kynurenine/tryptophan ratio in MPA-activated THP-1 cells•LVRN may create an immunosuppressive environment at the maternal-fetal interface
Molecular biology; Developmental biology; Embryology
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Since the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We ...previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1‐derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study we examined the effects of androgen on CIN progression.
Methods
Since AR expression was negative in W12 cells and HaCaT cells, a human male skin‐derived keratinocyte cell line, we transfected AR to these cell lines and investigated the effects of dihydrotestosterone (DHT) on their proliferation and squamous differentiation. We also examined the immunohistochemical expression of AR in CIN lesions.
Results
DHT reduced the intranuclear expression of FOXP4, attenuating cell proliferation and promoting squamous differentiation in AR‐transfected W12 cells. Si‐RNA treatments showed that DHT induced the expression of squamous differentiation‐related genes in AR‐transfected W12 cells via an ELF3‐dependent pathway. DHT also reduced FOXP4 expression in AR‐transfected HaCaT cells. An immunohistochemical study showed that AR was expressed in the basal to parabasal layers of the normal cervical epithelium. In CIN1 and 2 lesions, AR was detected in atypical squamous cells, whereas AR expression had almost disappeared in the CIN3 lesion and was not detected in SCC, suggesting that androgens do not act to promote squamous differentiation in the late stages of CIN.
Conclusion
Androgen is a novel factor that regulates squamous differentiation in the early stage of CIN, providing a new strategy for nonsurgical and hormone‐induced differentiation therapy against CIN1 and CIN2.
Androgen inhibits cell proliferation and promotes the differentiation of atypical cells in CIN lesions via an ELF3‐dependent pathway partially by attenuating FOXP4 function. This indicates that androgen is a possible therapeutic agent for non‐surgical CIN treatment that inhibits CIN progression by inducing squamous differentiation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Circulating tumor cells (CTC) are newly discovered biomarkers of cancers. Although many systems detect CTC, a gold standard has not yet been established. We analyzed CTC in uterine cervical cancer ...patients using an advanced version of conditionally replicative adenovirus targeting telomerase‐positive cells, which was enabled to infect coxsackievirus‐adenovirus receptor‐negative cells and to reduce false‐positive signals in myeloid cells. Blood samples from cervical cancer patients were hemolyzed and infected with the virus and then labeled with fluorescent anti‐CD45 and anti‐pan cytokeratin antibodies. GFP (+)/CD45 (−) cells were isolated and subjected to whole‐genome amplification followed by polymerase chain reaction analysis of human papillomavirus (HPV) DNA. CTC were detected in 6 of 23 patients with cervical cancers (26.0%). Expression of CTC did not correlate with the stage of cancer or other clinicopathological factors. In 5 of the 6 CTC‐positive cases, the same subtype of HPV DNA as that of the corresponding primary lesion was detected, indicating that the CTC originated from HPV‐infected cancer cells. These CTC were all negative for cytokeratins. The CTC detected by our system were genetically confirmed. CTC derived from uterine cervical cancers had lost epithelial characteristics, indicating that epithelial marker‐dependent systems do not have the capacity to detect these cells in cervical cancer patients.
Circulating tumor cells from cervical cancer patients were detected by conditionally replicative adenovirus targeting telomerase‐positive cells. They were HPV‐positive which was identical with their primary lesions and lacked expression of cytokeratins.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The greater omentum is an apron-like peritoneal mesothelial sheet that was described by ultrasound as a floating fluid-filled viscus in ascites during the fetal period. To examine the association ...between the etiology of fetal ascites and ultrasound findings of the greater omentum, a retrospective study was conducted. Ultrasound findings of fetal omentum were defined as follows: (1) a cyst-like shape with a thin membrane observed as wavy in the ascites, (2) beside the stomach and below the liver, and (3) no blood flow noted on color Doppler. Eleven pregnancies had fetal ascites. A fetal greater omentum was confirmed in eight cases in which ascites were caused by non-peritonitis: fetal hydrops (
= 4), congenital cytomegalovirus infection (
= 2), idiopathic chylous ascites (
= 1), and unknown cause (
= 1). Of these eight cases, no abdominal surgical management was required in three live babies. However, a fetal greater omentum was not confirmed in all three cases of meconium peritonitis. It was suggested that the finding of the greater omentum can be an important clue for estimating the pathophysiological etiology of fetal ascites and helping with postnatal management. It should be reasonable to add the finding of the greater omentum to the detailed ultrasound examination checklist.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Visualization of specific cells and structures in intact organs would greatly facilitate our knowledge about pathological changes; therefore, a tissue clearing method applicable to the intact eye may ...be valuable. Here we report a novel imaging method for the retina using the hyperhydration-based tissue clearing technique CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational Analysis).
Eyes of Institute of Cancer Research (ICR) mice, C57BL/6 mice, and normally pigmented sable ferrets (
) were used. Intact eyes were subjected to CUBIC, melanin bleaching with H
O
, and immunostaining. Images of the retina in intact eyes were taken using epifluorescence microscopes and confocal microscopes.
The combination of melanin bleaching and CUBIC efficiently made the eyes of C57BL/6 mice transparent. By combining melanin bleaching, CUBIC, and immunostaining, we succeeded in visualization of retinal structures from the outside of the intact eyes of mice. Furthermore, we found that our methods were applicable not only to mouse eyes but also to ferret eyes, which are much larger than those of mice.
Our method was useful for visualizing specific cells and structures in the retina of intact eyes with single-cell resolution without making tissue sections.
This simple and efficient method can be applicable to various rodent models, including those associated with glaucoma or myopia, and will facilitate evaluating the effects of novel therapy for relevant eye diseases by visualizing changes from the retina to the sclera at both molecular and macroscopic levels simultaneously in a whole-eye preparation.
This study demonstrates a case of a huge genital hematoma after delivery, associated with fibrinogen Dorfen. Fibrinogen Dorfen is the mutation of a fibrinogen‐coded exon gene, which has a single ...heterozygous GCC → GTC transition at codon 289 of the γ gene, predicting an Ala → Val substitution. Because Ala289 plays a crucial role in maintaining the structure of the polymerization site of hole ‘a’ via a hydrogen bond, it is speculated that the γ 289Ala → Val substitution can change not only the fibrinogen structure, but also the function of polymerization. In our case, although the patient's gene mutation was the same as that of her mother, there was a discrepancy in the clinical outcomes. Although the precise mechanism regarding this discrepancy remains unknown, it may cause different perinatal outcomes in terms of vaginal delivery, such as the severe bleeding in this patient and the absence of clinical symptoms in her mother. This is the first report suggesting the heterogeneity of fibrinogen functions of fibrinogen Dorfen, which may be critical to the clinical outcome.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The current report describes a case of extragenital gestational choriocarcinoma in the kidney. A 36-year-old woman with a history of two deliveries of male babies visited the present hospital due to ...secondary amenorrhea following a positive urinary pregnancy test. Despite a high serum level of human chorionic gonadotropin, at 51,800 mIU/ml, diagnostic imaging methods and pathological examination did not detect any conceptus in the genital tract. Positron emission tomography-computed tomography detected 18F-FDG-positive tumors in the left kidney and right lung. A fine needle biopsy of the renal lesion pathologically revealed the presence of choriocarcinoma and a subsequent polymerase chain reaction analysis verified the presence of a Y-chromosome-specific the sex-determining region Y (SRY) gene, diagnosed as extragenital gestational choriocarcinoma. Clinically, 10 cycles of EMA/CO chemotherapy were administered and an optimal response was obtained. In conclusion, this is the first report of the diagnosis of extragenital gestational choriocarcinoma by the detection of the SRY gene with PCR using biopsy samples.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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