Enhancing Fractionated Cancer Therapy: A Triple-Anthracene Photosensitizer Unleashes Long-Persistent Photodynamic and Luminous Efficacy.

Conventional photodynamic therapy (PDT) is often limited in treating solid tumors due to hypoxic conditions that impede the generation of reactive oxygen species (ROS), which are critical for therapeutic efficacy. To address this issue, a fractionated PDT protocol has been suggested, wherein light irradiation is administered in stages separated by dark intervals to permit oxygen recovery during these breaks. However, the current photosensitizers used in fractionated PDT are incapable of sustaining ROS production during the dark intervals, leading to suboptimal therapeutic outcomes (Table S1). To circumvent this drawback, we have synthesized a novel photosensitizer based on a triple-anthracene derivative that is designed for prolonged ROS generation, even after the cessation of light exposure. Our study reveals a unique photodynamic action of these derivatives, facilitating the direct and effective disruption of biomolecules and significantly improving the efficacy of fractionated PDT (Table S2). Moreover, the existing photosensitizers lack imaging capabilities for monitoring, which constraints the fine-tuning of irradiation parameters (Table S1). Our triple-anthracene derivative also serves as an afterglow imaging agent, emitting sustained luminescence postirradiation. This imaging function allows for the precise optimization of intervals between PDT sessions and aids in determining the timing for subsequent irradiation, thus enabling meticulous control over therapy parameters. Utilizing our novel triple-anthracene photosensitizer, we have formulated a fractionated PDT regimen that effectively eliminates orthotopic pancreatic tumors. This investigation highlights the promise of employing long-persistent photodynamic activity in advanced fractionated PDT approaches to overcome the current limitations of PDT in solid tumor treatment.

Endoscopically guided interventional photodynamic therapy for orthotopic pancreatic ductal adenocarcinoma based on NIR-II fluorescent nanoparticles.

Rationale: Pancreatic cancer, comprising mostly pancreatic ductal adenocarcinoma (PDAC), is a highly malignant disease, typically known as a hypoxic tumor microenvironment. The application of PDT in pancreatic cancer in clinic is still hampered by several shortcomings, including the (i) deep location of pancreatic cancer, (ii) tissue damage induced by optical fibers, (iii) hypoxic microenvironment, (iv) short excitation wavelengths of traditional photosensitizers, and (v) poor delivery efficiency of photosensitizers. Methods: We designed an organic nanoparticle as photosensitizer for near-infrared II (NIR-II) fluorescent (FL) imaging that exerts a type I PDT effect on deep orthotopic pancreatic tumors under excitation by a NIR (808 nm) laser. Results: This novel photosensitizer exhibits enhanced accumulation in orthotopic pancreatic cancer in mice and could be used to effectively detect pancreatic cancer and guide subsequent laser irradiation for accurate PDT of deep pancreatic cancer. In addition, we built an endoscopic platform monitored by NIR-II FL imaging to achieve minimally invasive endoscopically guided interventional photodynamic therapy (EG-iPDT) with efficient inhibition of orthotopic pancreatic cancer, which prolonged overall survival up to 78 days compared to PBS + EG-iPDT group (*p < 0.05) in a mouse model. Conclusions: Minimally invasive EG-iPDT has promise as an intraoperative treatment for early-stage or unresectable or metastatic pancreatic cancer.

Emerging biomedical imaging-based companion diagnostics for precision medicine.

The tumor heterogeneity, which leads to individual variations in tumor microenvironments, causes poor prognoses and limits therapeutic response. Emerging technology such as companion diagnostics (CDx) detects biomarkers and monitors therapeutic responses, allowing identification of patients who would benefit most from treatment. However, currently, most US Food and Drug Administration-approved CDx tests are designed to detect biomarkers in vitro and ex vivo, making it difficult to dynamically report variations of targets in vivo. Various medical imaging techniques offer dynamic measurement of tumor heterogeneity and treatment response, complementing CDx tests. Imaging-based companion diagnostics allow for patient stratification for targeted medicines and identification of patient populations benefiting from alternative therapeutic methods. This review summarizes recent developments in molecular imaging for predicting and assessing responses to cancer therapies, as well as the various biomarkers used in imaging-based CDx tests. We hope this review provides informative insights into imaging-based companion diagnostics and advances precision medicine.

A novel ROS-Related chemiluminescent semiconducting polymer nanoplatform for acute pancreatitis early diagnosis and severity assessment.

Acute pancreatitis (AP) is a common and potentially life-threatening inflammatory disease of the pancreas. Reactive oxygen species (ROS) play a key role in the occurrence and development of AP. With increasing ROS levels, the degree of oxidative stress and the severity of AP increase. However, diagnosing AP still has many drawbacks, including difficulties with early diagnosis and undesirable sensitivity and accuracy. Herein, we synthesized a semiconducting polymer nanoplatform (SPN) that can emit ROS-correlated chemiluminescence (CL) signals. The CL intensity increased in solution after optimization of the SPN. The biosafety of the SPN was verified in vitro and in vivo. The mechanism and sensitivity of the SPN for AP early diagnosis and severity assessment were evaluated in three groups of mice using CL intensity, serum marker evaluations and hematoxylin and eosin staining assessments. The synthetic SPN can be sensitively combined with different concentrations of ROS to produce different degrees of high-intensity CL in vitro and in vivo. Notably, the SPN shows an excellent correlation between CL intensity and AP severity. This nanoplatform represents a superior method to assess the severity of AP accurately and sensitively according to ROS related chemiluminescence signals. This research overcomes the shortcomings of AP diagnosis in clinical practice and provides a novel method for the clinical diagnosis of pancreatitis in the future.

Identification of TUBB8 Variants in 5 Primary Infertile Women with Multiple Phenotypes in Oocytes and Early Embryos.

Tubulin beta 8 class VIII (TUBB8) is a ß-tubulin isotype that is specifically expressed in human oocytes and early embryos. It has been identified as a disease-causing gene in primary female infertility by affecting oocyte maturation arrest. This study investigated the genetic cause of female infertility in five patients from four families. Five women with primary infertility were recruited. Medical-exome sequencing and Sanger sequencing were performed on the patients, and their family members to identify candidate genes that explained infertility. Additionally, the morphology of oocytes and zygotes from the patients and controls were assessed. We observed recurrent oocytes MI arrest, oocytes abnormal fertilization, uncleaved embryos, and embryo transfer failure in the patients. Heterozygous missense variants in TUBB8, c.538G > A (p.V180M), c.527C > G (p.S176W), c.124C > G (p.L42V), and c.628A > C (p.I210L), were verified in four unrelated families. This study expanded the mutational spectrum of TUBB8 by identifying three novel heterozygous missense variants. Screening for TUBB8 mutation demonstrated the diagnostic utility of female infertility.

Overcoming Hypoxia-Induced Ferroptosis Resistance via a 19 F/1 H-MRI Traceable Core-Shell Nanostructure.

Lipid peroxides accumulation induced ferroptosis is an effective cell death pathway for cancer therapy. However, the hypoxic condition of tumor microenvironment significantly suppresses the efficacy of ferroptosis. Here, we design a novel nanoplatform to overcome hypoxia-induced ferroptosis resistance. Specifically, we synthesize a novel kind of perfluorocarbon (PFOB)@manganese oxide (MnOx) core-shell nanoparticles (PM-CS NPs). Owing to the good carrier of O2 as fuel, PM-CS NPs can induce higher level of ROS generation, lipid peroxidation and GSH depletion, as well as lower activity of GPX4, compared with MnOx NPs alone. Moreover, the supplement of O2 can relieve tumor hypoxia to break down the storage of intracellular lipid droplets and increase expression of ACSL4 (a symbol for ferroptosis sensitivity). Furthermore, upon stimulus of GSH or acidity, PM-CS NPs exhibit the "turn on" 19 F-MRI signal and activatable T1 /T2 -MRI contrast for correlating with the release of Mn. Finally, PM-CS NPs exert high cancer inhibition rate for ferroptosis based therapy via synergetic combination of O2 -mediated enhancement of key pathways of ferroptosis.

Metal-fluorouracil networks with disruption of mitochondrion enhanced ferroptosis for synergistic immune activation.

Rationale: Ferroptosis drugs inducing cancer immunogenic cell death (ICD) have shown the potential of immunotherapy in vivo. However, the current ferroptosis drugs usually induce the insufficient immune response because of the low ROS generation efficiency. Methods: Herein, we design zinc-fluorouracil metallodrug networks (Zn-Fu MNs), by coordinating Zn and Fu via facile one-pot preparation, to inactivate mitochondrial electron transport for enhanced ROS production and immune activation. Results: Zn-Fu MNs can be responsive toward acidity and adenosine triphosphate (ATP) with the release of Fu and Zn2+, during which Zn2+ can induce mitochondrion disruption to produce ROS, resulting in ferroptosis of cancer cells and 5-Fu interferes with DNA synthesis in nuclei with 19F-MRI signal to be switched on for correlating drug release. With the synergistic effect of DNA damage and ferroptosis, the cancer cells are forced to promote ICD. Thereby, Zn-Fu MNs exhibit the excellent immune response without any other antigens loading. As a result, the infiltration of T cells within tumor and activation of immune cells in spleen have been greatly enhanced. Conclusions: Combined DNA damage and ferroptosis, Zn-Fu MNs induce the violent emission of tumor associated antigens within cancer cells which will sensitize naive dendritic cells and promote the activation and recruitment of cytotoxic T lymphocytes to exterminate cancer cells. Therefore, the obtained Zn-Fu MNs as ferroptosis inducers can effectively remodel immunosuppressive tumor microenvironment and activate antitumor immune reaction.

Degradable Magnetic Nanoplatform with Hydroxide Ions Triggered Photoacoustic, MR Imaging, and Photothermal Conversion for Precise Cancer Theranostic.

Theranostic agents based on inorganic nanomaterials are still suffered from the nonbiodegradable substances with long-term retention in body and unavoidable biological toxicity, as well as nonspecificity biodistribution with potential damage toward normal tissues. Here, we develop magnetic ions (FeIII, FeII, GdIII, MnII, and MnIII) coordinated nanoplatform (MICN) with framework structure and modify them with PEG (MICN-PEG). Notably, MICN-PEG demonstrates hydroxide ions (OH-) triggered the structure collapse along with responsive near-infrared photoacoustic (PA) signal, magnetic resonance imaging (MRI), and photothermal therapy (PTT) performances. Thereby, MICN-PEG is able to remain stable in tumors and exert excellent PA/MRI and PTT effects for multimodal imaging-guided cancer treatment. In contrast, MICN-PEG is gradually collapsed in normal tissues, resulting in the significant improvement of imaging accuracy and treatment specificity. MICN-PEG is gradually cleared after administration, minimizing concerns about the long-term toxicity.

Chemical Design of Activatable Photoacoustic Probes for Precise Biomedical Applications.

Photoacoustic (PA) imaging technology, a three-dimensional hybrid imaging modality that integrates the advantage of optical and acoustic imaging, has great application prospects in molecular imaging due to its high imaging depth and resolution. To endow PA imaging with the ability for real-time molecular visualization and precise biomedical diagnosis, numerous activatable molecular PA probes which can specifically alter their PA intensities upon reacting with the targets or biological events of interest have been developed. This review highlights the recent developments of activatable PA probes for precise biomedical applications including molecular detection of the biotargets and imaging of the biological events. First, the generation mechanism of PA signals will be given, followed by a brief introduction to contrast agents used for PA probe design. Then we will particularly summarize the general design principles for the alteration of PA signals and activatable strategies for developing precise PA probes. Furthermore, we will give a detailed discussion of activatable PA probes in molecular detection and biomedical imaging applications in living systems. At last, the current challenges and outlooks of future PA probes will be discussed. We hope that this review will stimulate new ideas to explore the potentials of activatable PA probes for precise biomedical applications in the future.

Generation of hydroxyl radical-activatable ratiometric near-infrared bimodal probes for early monitoring of tumor response to therapy.

Tumor response to radiotherapy or ferroptosis is closely related to hydroxyl radical (•OH) production. Noninvasive imaging of •OH fluctuation in tumors can allow early monitoring of response to therapy, but is challenging. Here, we report the optimization of a diene electrochromic material (1-Br-Et) as a •OH-responsive chromophore, and use it to develop a near-infrared ratiometric fluorescent and photoacoustic (FL/PA) bimodal probe for in vivo imaging of •OH. The probe displays a large FL ratio between 780 and 1113 nm (FL780/FL1113), but a small PA ratio between 755 and 905 nm (PA755/PA905). Oxidation of 1-Br-Et by •OH decreases the FL780/FL1113 while concurrently increasing the PA755/PA905, allowing the reliable monitoring of •OH production in tumors undergoing erastin-induced ferroptosis or radiotherapy.

Smart Nanozyme Platform with Activity-Correlated Ratiometric Molecular Imaging for Predicting Therapeutic Effects.

Nanozymes with intrinsic enzyme-like characteristics have attracted enormous research interest in biological application. However, there is a lack of facile approach for evaluating the catalytic activity of nanozymes in living system. Herein, we develop a novel manganese-semiconducting polymer-based nanozyme (MSPN) with oxidase-like activity for reporting the catalytic activity of itself in acid-induced cancer therapy via ratiometric near-infrared fluorescence (NIRF)-photoacoustic (PA) molecular imaging. Notably, MSPN possess oxidase-like activity in tumor microenvironment, owing to the mixed-valent MnOx nanoparticles, which can effectively kill cancer cells. Because the semiconducting polymer (PFODBT) is conjugated with oxidase-responsive molecule (ORM), the catalytic activity of nanozyme can be correlated with the ratiometric signals of NIRF (FL695 /FL825 ) and PA (PA680 /PA780 ), which may provide new ideas for predicting anticancer efficacy of nanozymes in living system.

Oxygen-embedded quinoidal acene based semiconducting chromophore nanoprobe for amplified photoacoustic imaging.

In this chapter, we summarize the advantages of photoacoustic imaging and the current methods of enhancing photoacoustic. We then provide detailed procedures for the synthesis and characterization of a photoacoustic imaging molecule, Nano(O-Nonacene)-PEG, developed in our research group. At the same time, we proved that the incorporation of Zn0.4Fe2.6O4 can enhance the photoacoustic imaging effect of Nano(O-Nonacene)-PEG. This provides a new material for photoacoustic imaging to guide tumor treatment.

Tumor-Specific Multipath Nucleic Acid Damages Strategy by Symbiosed Nanozyme@Enzyme with Synergistic Self-Cyclic Catalysis.

The high proliferation efficiency, redox imbalance, and elevated nucleic acid repair capabilities of tumor cells severely restrict the theranostic efficacy. Selectively interference chaotic tumors with devastating nucleic acid damages (NUDs) properties are expected to overcome theranostic barriers. Here, an exquisite catalytic-based strategy with comprehensive NUDs mechanisms is demonstrated. In this regard, enzyme (glucose oxidase, GOD) symbioses nanozyme Cu3+x (PO4 )2 through biomineralization (abbreviated as Cu@GOD), GOD can disorder the metabolism by consuming glucose, thereby inhibiting the nutrition supply for nucleic acid repair. GOD-catalyzed H2 O2 guarantees the self-cyclic glutathione depletion and reactive oxygen species generation caused by Cu3+x (PO4 )2 , resulted the reduced antioxidation defense and enhanced oxidation assault, ensures an indiscriminate NUDs ability. Moreover, the high photothermal effect of Cu3+x (PO4 )2 induces effective tumor inhibition. Consequently, this substantial multipath NUDs strategy, with potentials of suppressing the cytoprotective mechanisms, amplifying the cellular oxidative stress, and disrupting the redox balance to ensure substantial irreversible NUDs, completely breaks the obstacle of chaotic tumors, providing new conceptual thinking for tumor proliferation inhibition.

Ratiometric Semiconducting Polymer Nanoparticle for Reliable Photoacoustic Imaging of Pneumonia-Induced Vulnerable Atherosclerotic Plaque in Vivo.

Acute pneumonia can greatly increase the vulnerable risk of atherosclerotic plaque and contribute to the mortality of cardiovascular disease. To accurately assess the rupture risk caused by acute pneumonia, we developed a novel kind of ratiometric semiconducting polymer nanoparticle (RSPN) for photoacoustic imaging of vulnerable plaque in apolipoprotein E-deficient mice complicated with pneumonia. Specifically, RSPN can react with O2•- and exhibit the enhanced photoacoustic signals at about 690 nm, while 800 nm is regarded as an internal photoacoustic reference. As a result, RSPN can provide reliable determination of O2•- within aortic atherosclerosis by analyzing the ratios of photoacoustic signals, which can successfully reflect the oxidative stress level in vulnerable plaque. Therefore, RSPN enable to specifically distinguish plaque-bearing mice and plaque-bearing mice complicated with pneumonia from healthy mice, which provides a promising tool to predict the vulnerability of plaque for reducing the mortality of atherosclerotic-induced cardiovascular disease.

Validation of preimplantation genetic tests for aneuploidy (PGT-A) with DNA from spent culture media (SCM): concordance assessment and implication.

BACKGROUND: Spent culture medium (SCM) as a source of DNA for preimplantation genetic tests aneuploidy (PGT-A) has been widely discussed. METHODS: Seventy-five blastocysts that were donated for research provided a unique possibility in which multiple specimens, including trophectoderm (TE) biopsy, SCM, and paired corresponding whole blastocyst (WB) specimens from the same blastocyst source, could be utilized for the purpose of this preclinical validation. RESULTS: To conduct a validation ploidy concordance assessment, we evaluated the full chromosomal concordance rates between SCM and WB (SCM-to-WB), and between TE and WB (TE-to-WB) as well as sensitivity, specificity and overall diagnostic accuracy. 78.67% (59/75) of NGS results in the SCM group were interpretable, a significantly lower percentage than their corresponding TE and WB groups. This discrepancy manifests itself in intrinsically low quantity and poor integrity DNA from SCM. Subsequently, remarkable differences in full concordance rates (including mosaicism, and segmental aneuploidies) are seen as follows: 32.2% (SCM-to-WB, 19/59) and 69.33% (TE-to-WB, 52/75), (p < 0.001). In such cases, full concordance rates were 27.27% (15/55) in SCM-to-WB, and, 76% (57/75) in TE-to-WB (p < 0.001). Collectively, the NGS data from SCM also translated into lower sensitivities, Positive Predictive Value (PPV), Negative Predictive Value (NPV), overall diagnostic accuracies, and higher Negative Likelihood Ratio (NLR). CONCLUSIONS: Our study reveals that DNA is detectable in the majority of SCM samples. Individual chromosomal aberration, such as segmental aneuploidy and mosaicism, can be quantitatively and qualitatively measured. However, TE still provides a more accurate and reliable high-throughput methodology for PGT-A. Meanwhile, cell-free DNA in SCM reporting lacks uniform diagnostic interpretations. Considering that this test is meant to determine which embryos are relegated to be discarded, PGT-A with cell-free DNA in SCM should not be permitted to be applied in routine clinical settings for diagnosis purpose.

An Acidity-Unlocked Magnetic Nanoplatform Enables Self-Boosting ROS Generation through Upregulation of Lactate for Imaging-Guided Highly Specific Chemodynamic Therapy.

Chemodynamic therapy is an emerging tumor therapeutic strategy. However, the anticancer effects are greatly limited by the strong acidity requirements for effective Fenton-like reaction, and the inevitably "off-target" toxicity. Herein, we develop an acidity-unlocked nanoplatform (FePt@FeOx @TAM-PEG) that can accurately perform the high-efficient and tumor-specific catalysis for anticancer treatment, through dual pathway of cyclic amplification strategy. Notably, the pH-responsive peculiarity of tamoxifen (TAM) drug allows for the catalytic activity of FePt@FeOx to be "turn-on" in acidic tumor microenvironments, while keeping silence in neutral condition. Importantly, the released TAM within cancer cells is able to inhibit mitochondrial complex I, leading to the upregulated lactate content and thereby the accumulated intracellular H+ , which can overcome the intrinsically insufficient acidity of tumor. Through the positive feedback loop, large amount of active FePt@FeOx nanocatalyzers are released and able to access to the endogenous H2 O2 , exerting the improved Fenton-like reaction within the more acidic condition. Finally, such smart nanoplatform enables self-boosting generation of reactive oxygen species (ROS) and induces strong intracellular oxidative stress, leading to the substantial anticancer outcomes in vivo, which may provide a new insight for tumor-specific cascade catalytic therapy and reducing the "off-target" toxicity to surrounding normal tissues.

Oxygen-Embedded Quinoidal Acene Based Semiconducting Chromophore Nanoprobe for Amplified Photoacoustic Imaging and Photothermal Therapy.

Photoacoustic (PA) imaging as a noninvasive biomedical imaging technology exhibits high spatial resolution and deep tissue penetration for in vivo imaging. In order to fully explore the potential of PA imaging in biomedical applications, new contrast agents with improved PA stability and efficiency are in high demand. Herein, we present a new PA agent based on an oxygen-embedded quinoidal nonacene chromophore that is self-assembled into nanoparticles (Nano(O-Nonacene)-PEG), assisted by polyethylene glycol (PEG). Notably, the photothermal conversion efficiency of Nano(O-Nonacene)-PEG is 1.5 fold that of semiconducting polymer nanoparticles (Nano(PCPDTBT)-PEG) and 2.8 fold that of Au nanorods, owing to the low quantum yield of Nano(O-Nonacene)-PEG. Thereby, Nano(O-Nonacene)-PEG possess a greatly elevated PA signal intensity, compared to Nano(PCPDTBT)-PEG and Au nanorods, which have been widely explored for PA imaging. Due to the high resistance to photo bleaching, Nano(O-Nonacene)-PEG exhibits higher PA signal stability, which may be employed for long-term PA imaging. Moreover, when magnetic Zn0.4Fe2.6O4 nanoparticles are incorporated into Nano(O-Nonacene)-PEG, not only are magnetic resonance signals generated but also the photoacoustic efficacy is greatly enhanced. Therefore, Nano(O-Nonacene)-PEG offers distinct properties: (i) the elevated photoacoustic effect allows for high-resolution photoacoustic imaging, (ii) small size (10 nm in diameter) results in efficient tumor-targeting, and (iii) the facile application of efficient photothermal therapy in vivo. The current work offers the possibility of oxygen-embedded quinoidal acene as a promising PA probe for precision phototheranostics.

Increased maternal hCG concentrations in early in vitro pregnancy with elevated basal FSH.

OBJECTIVE: To investigate factors that influence maternal hCG concentration in early pregnancy and the relationship between hCG concentration in early pregnancy and basal FSH (bFSH) level. DESIGN: Retrospective cohort study. SETTING: Reproductive medical center. PATIENT(S): In total, 482 women aged 22 to 38 years with elevated basal FSH (> 10 IU/L) and who experienced a single live birth after in vitro fertilization-embryo transfer were selected. These 482 women were age-matched with an equal number of women with normal basal FSH (≤10 IU/L) who also experienced a single live birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): HCG concentration. RESULT(S): The hCG concentrations on Day 14 and Day 21 were 560.46 (363.63-842.52) IU/L and 9862.00 (6512.25-14029.50) IU/L, respectively, in the elevated bFSH group, and these values were significantly increased compared with the normal bFSH group. After adjusting for confounding factors, the concentrations of maternal hCG on Day 14 and Day 21 were significantly associated with basal FSH. In addition, crude linear regression analysis demonstrated that hCG concentrations increased as the basal serum levels of FSH increased. CONCLUSION(S): Elevated basal FSH has implications for the interpretation of hCG concentrations in early pregnancy after in vitro fertilization-embryo transfer (IVF-ET) that led to a single live birth.

Significantly lengthened telomere in granulosa cells from women with polycystic ovarian syndrome (PCOS).

PURPOSE: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women at reproductive age. However, its etiology remains poorly understood. Recent studies indicated that telomere length was related to PCOS. However, the association between telomere length and PCOS has only been shown in leucocytes and remained controversial across different studies. To clarify the association between telomere length and PCOS, the current study interrogated telomere length not only in leucocytes, but also in follicular granulosa cells, which is essential for folliculogenesis and steroidogenesis. METHODS: Seventy-five patients with PCOS and 81 controls with mechanical infertility undergoing their first in vitro fertilization cycle were enrolled. Their peripheral blood and granulosa cells were collected on the oocyte retrieval day. Telomere length of both leucocytes in the blood and granulosa cells was assayed by quantitative polymerase chain reaction. RESULTS: No significant difference was found in the leucocyte telomere length between controls and PCOS patients (0.99 ± 0.44 vs. 1.00 ± 0.38, p = 0.93). Interestingly, when comparing telomere length in granulosa cells between controls and PCOS subjects, significantly lengthened telomere length was found in PCOS subjects (1.00 ± 0.37 vs. 1.57±0.67, p < 0.0001). After adjustments for age and body mass index, the p value remained significant (p < 0.0001). CONCLUSIONS: This finding reinforced the association between telomere abnormalities and PCOS. Given the importance of telomere length in cellular proliferation, our findings provided novel insights into the pathophysiology of PCOS that abnormalities in telomere length possibly disturb folliculogenesis and subsequently result in PCOS.

Promoter methylation of yes-associated protein (YAP1) gene in polycystic ovary syndrome.

BACKGROUND: DNA methylation modification has been proved to influence the phenotype of polycystic ovary syndrome (PCOS). Genome-wide association studies (GWAS) demonstrate that yes-associated protein (YAP1) genetic sites are associated with PCOS. The study aims to detect the methylation status of YAP1 promoter in ovary granulosa cells (GCs) of PCOS patients and explore novel therapeutic targets for PCOS. METHODS: Randomized controlled trial was applied and a total of 72 women were included in the study, including 36 cases of PCOS patients and 36 cases of health controls. Ovary GCs were extracted from in vitro fertilization embryo transfer. Methylation status of YAP1 promoter was detected by bisulfite sequencing PCR (BSP). Protein and mRNA expression of YAP1 were measured by western blotting and real-time quantitate PCR. RESULTS: Overall methylation level of YAP1 promoter region from PCOS group was significantly lower than that from control group. CpG sites analysis revealed that 12 sites (-443, -431, -403, -371, -331, -120, -49, -5, +1, +9, +15, +22) were significantly hypomethylated in women with PCOS (P < 0.05). A significant upregulation of YAP1 mRNA and protein expression levels was observed. Testosterone concentration could alleviate the methylation status and demonstrate obvious dose-dependent relation. CONCLUSION: Our research achievements manifest that hypomethylation of YAP1 promoter promotes the YAP1 expression, which plays a key role in the pathogenesis and accelerate PCOS.