Inhibitor cystine knot (ICK) peptides are knotted peptides with three intramolecular disulfide bonds that affect several types of ion channels. Some are proteolytically stable and are promising ...scaffolds for drug development. GTx1-15 is an ICK peptide that inhibits the voltage-dependent calcium channel Ca
3.1 and the voltage-dependent sodium channels Na
1.3 and Na
1.7. As a model molecule to develop an ICK peptide drug, we investigated several important pharmaceutical characteristics of GTx1-15. The stability of GTx1-15 in rat and human blood plasma was examined, and no GTx1-15 degradation was observed in either rat or human blood plasma for 24 h in vitro. GTx1-15 in blood circulation was detected for several hours after intravenous and intramuscular administration, indicating high stability in plasma. The thermal stability of GTx1-15 as examined by high thermal incubation and protein thermal shift assays indicated that GTx1-15 possesses high heat stability. The cytotoxicity and immunogenicity of GTx1-15 were examined using the human monocytic leukemia cell line THP-1. GTx1-15 showed no cytotoxicity or immunogenicity even at high concentrations. These results indicate that GTx1-15 itself is suitable for peptide drug development and as a peptide library scaffold.
Preeclampsia is a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. This condition targets several organs, including the kidneys, liver ...and brain, and is the leading cause of maternal and perinatal morbidity and mortality. Furthermore, recent evidence has revealed preeclampsia as a significant risk factor for future cardiovascular diseases in these women. Over the past decade, increasing evidence has indicated that maternal angiogenic imbalances caused by placental antiangiogenic factors play a central role in the systemic vascular dysfunction underling preeclampsia. The severity of the maternal antiangiogenic state correlates closely with maternal and perinatal outcomes. Assessing angiogenic imbalance and several vascular function tests have also emerged as a way of detecting systemic vascular dysfunction during pregnancy. This review summarizes the current understanding of the pathophysiology of preeclampsia, its clinical applications and clinical evidence for future cardiovascular risks.
Preeclampsia, a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, is the leading cause of maternal and perinatal morbidity and mortality. ...Maternal endothelial dysfunction caused by placental factors has long been accepted with respect to the pathophysiology of preeclampsia. Over the past decade, increased production of placental antiangiogenic factors has been identified as a placental factor leading to maternal endothelial dysfunction and systemic vascular dysfunction. This review summarizes the recent advances in understanding the molecular mechanisms of endothelial dysfunction caused by placental antiangiogenic factors, and the novel clinical strategies based on these discoveries.
In Japan, the serious adverse events after human papillomavirus (HPV) vaccination were widely reported in the media. The Ministry of Health, Labour and Welfare of Japan (MHLW) announced the ...suspension of the governmental recommendation of HPV vaccine in 2013, and the inoculation rate has since sharply declined. The estimated inoculation rate for each birth fiscal year (FY) announced by the MHLW and the actual numbers for each birth FY surveyed by local governments were very different. In particular, the cumulative vaccination rate of girls born in FY2000 was regarded to be as high as 42.9% by the Council of the MHLW. However, this estimation included a confusion. When the suspension of the governmental recommendation was announced in FY2013, the girls born in FY2000 turned 13 years old, the targeted starting age of the HPV vaccination. The vaccination rate of this generation is considered to be quite low. The numbers were recalculated in this study. This study revealed that the real vaccination rate is only 14.3%. Female individuals born in or after FY2000 have been confirmed to be exposed to the same cervical cancer risk as before the HPV vaccine was introduced in Japan.
Corrected human papillomavirus vaccination rate for each birth fiscal year in Japan.
The aim of this study was to investigate the role of myeloid-derived suppressor cells (MDSC) in the induction of cancer stem-like cells (CSC) and programmed death ligand 1 (PD-L1) expression in ...ovarian cancer. CSC were defined as tumor cells expressing high levels of aldehyde dehydrogenase 1 (ALDH 1). We inoculated G-CSF-expressing or Mock-expressing ovarian cancer cells into mice, and the frequencies of MDSC and CSC in tumors of these models were compared by flow cytometry. To directly demonstrate the role of MDSC in the induction of CSC and the increase in PD-L1 expression, we performed in vitro co-culture. MDSC and CSC (ALDH-high cells) were more frequently observed in G-CSF-expressing cell-derived tumors than in Mock-expressing cell-derived tumors. Co-culture experiments revealed that MDSC increased the number of CSC via the production of PGE2. Moreover, PGE2 produced by MDSC increased tumor PD-L1 expression via the mammalian target of rapamycin (mTOR) pathway in ovarian cancer cells. In an in vitro experiment in which ovarian cancer cells were co-cultured with MDSC, higher expression of PD-L1 was observed in CSC than in non-CSC (ALDH-low cells). Furthermore, by immunofluorescence staining, we found that PD-L1 was co-expressed with ALDH1 in in vivo mouse models. In conclusion, PGE2 produced by MDSC increases the stem cell-like properties and tumor PD-L1 expression in epithelial ovarian cancer. Depleting MDSC may be therapeutically effective against ovarian cancer by reducing the number of CSC and tumor PD-L1 expression.
The Role of MicroRNAs in Ovarian Cancer Kinose, Yasuto; Sawada, Kenjiro; Nakamura, Koji ...
BioMed research international,
01/2014, Letnik:
2014
Journal Article
Recenzirano
Odprti dostop
Ovarian cancer is the most lethal of malignant gynecological tumors. Its lethality may be due to difficulties in detecting it at an early stage and lack of effective treatments for patients with an ...advanced or recurrent status. Therefore, there is a strong need for prognostic and predictive markers to diagnose it early and to help optimize and personalize treatment. MicroRNAs are noncoding RNAs that regulate target genes posttranscriptionally. They are involved in carcinogenesis, cell cycle, apoptosis, proliferation, invasion, metastasis, and chemoresistance. The dysregulation of microRNAs is involved in the initiation and progression of human cancers including ovarian cancer, and strong evidence that microRNAs can act as oncogenes or tumor suppressor genes has emerged. Several microRNA signatures that are unique to ovarian cancer have been proposed, and serum-circulating microRNAs have the potential to be useful diagnostic and prognostic biomarkers. Various microRNAs such as those in the miR-200 family, the miR-199/214 cluster, or the let-7 paralogs have potential as therapeutic targets for disseminated or chemoresistant ovarian tumors. Although many obstacles need to be overcome, microRNA therapy could be a powerful tool for ovarian cancer prevention and treatment. In this review, we discuss the emerging roles of microRNAs in various aspects of ovarian cancer.
Background:Some physicians report that patients with hallux valgus have hypermobility at the tarsometatarsal (TMT) joint of the first ray and 3-dimensional (3-D) deformity. With use of ...non-weight-bearing and weight-bearing computed tomography (CT), we evaluated the 3-D mobility of each joint of the first ray in feet with hallux valgus compared with normal feet.Methods:Ten feet of 10 patients with hallux valgus and 10 feet of 10 healthy volunteers with no foot disorders were examined. All participants were women. Weight-bearing (a load equivalent to body weight) and non-weight-bearing CT scans were made with use of a device that we developed. Orthogonal coordinate axes were set and a 3-D model was reconstructed. Each joint of the first ray was aligned with the respective proximal bone, and 3-D displacement of the distal bone relative to the proximal bone under loading was quantified.Results:At the talonavicular joint, significantly greater dorsiflexion of the navicular relative to the talus was observed in the hallux valgus group compared with the control group. At the medial cuneonavicular joint, the hallux valgus group showed significantly greater eversion and abduction of the medial cuneiform relative to the navicular. At the first TMT joint, the hallux valgus group showed significantly greater dorsiflexion, inversion, and adduction of the first metatarsal relative to the medial cuneiform. At the first metatarsophalangeal joint, the hallux valgus group showed significantly greater eversion and abduction of the first proximal phalanx relative to the first metatarsal (all p < 0.05).Conclusions:The results of this study suggest that loading of the foot causes significant 3-D displacement not only at the TMT joint but also at the other joints of the first ray. There is increased mobility in the first ray in patients who have hallux valgus.
Increasing evidence suggests a relationship between in vitro fertilization-embryo transfer (IVF-ET) and placenta accreta spectrum (PAS). Some studies have reported a lower rate of antenatal diagnosis ...of PAS after IVF-ET compared to PAS with spontaneous conception. This study aimed to review the diagnostic accuracy of PAS after IVF-ET and to explore the relationship between IVF-ET pregnancy and PAS. According to the PRISMA guidelines, a comprehensive systematic review of the literature was conducted through August 31, 2020 to determine the effects of IVF-ET on PAS. In addition, a meta-analysis was conducted to explore the relationship between IVF-ET pregnancy and PAS. Twelve original studies (2011-2020) met the inclusion criteria. Among these, 190,139 IVF-ET pregnancies and 248,534 spontaneous conceptions met the inclusion criteria. In the comparator analysis between PAS after IVF-ET and PAS with spontaneous conception (n = 2), the antenatal diagnosis of PAS after IVF-ET was significantly lower than that of PAS with spontaneous conception (22.2% versus 94.7%, P < 0.01; < 12.9% versus 46.9%, P < 0.01). The risk of PAS was significantly higher in women who conceived with IVF-ET than in those with spontaneous conception (odds ratio OR: 5.03, 95% confidence interval CI: 3.34-7.56, P < 0.01). In the sensitivity analysis accounting for the type of IVF-ET, frozen ET was associated with an increased risk of PAS (OR: 4.60, 95%CI: 3.42-6.18, P < 0.01) compared to fresh ET. Notably, frozen ET with hormone replacement cycle was significantly associated with the prevalence of PAS compared to frozen ET with normal ovulatory cycle (OR: 5.76, 95%CI 3.12-10.64, P < 0.01). IVF-ET is associated with PAS, and PAS after IVF-ET was associated with a lower rate of antenatal diagnosis. Therefore, clinicians can pay more attention to the presence of PAS during antenatal evaluation in women with IVF-ET, especially in frozen ET with hormone replacement cycle.
Ovarian cancer is the leading cause of death among gynecologic malignancies. Since ovarian cancer develops asymptomatically, it is often diagnosed at an advanced and incurable stage. Despite many ...years of research, there is still a lack of reliable diagnostic markers and methods for early detection and screening. Recently, it was discovered that cell-free microRNAs (miRNAs) circulate in the body fluids of healthy and diseased patients, suggesting that they may serve as a novel diagnostic marker. This review summarizes the current knowledge regarding the potential clinical relevance of circulating cell-free miRNA for ovarian cancer diagnosis, prognosis, and therapeutics. Despite the high levels of ribonucleases in many types of body fluids, most of the circulating miRNAs are packaged in microvesicles, exosomes, or apoptotic bodies, are binding to RNA-binding protein such as argonaute 2 or lipoprotein complexes, and are thus highly stable. Cell-free miRNA signatures are known to be parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles. Since it is well established that the dysregulation of miRNAs is involved in the tumorigenesis of ovarian cancer, cell-free miRNAs circulating in body fluids such as serum, plasma, whole blood, and urine may reflect not only the existence of ovarian cancer but also tumor histology, stage, and prognoses of the patients. Several groups have successfully demonstrated that serum or plasma miRNAs are able to discriminate patients with ovarian cancer patients from healthy controls, suggesting that the addition of these miRNAs to current testing regimens may improve diagnosis accuracies for ovarian cancer. Furthermore, recent studies have revealed that changes in levels of cell-free circulating miRNAs are associated with the condition of cancer patients. Discrepancies between the results across studies due to the lack of an established endogenous miRNA control to normalize for circulating miRNA levels, as well as differing extraction and quantification methods, are the pitfalls to be resolved before clinical application. There is still a long way, however, before this can be achieved, and further evidence would make it possible to apply circulating cell-free miRNAs not only as biomarkers but also as potential therapeutic targets for ovarian cancer in the future.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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