Phosphorylation of IDH1 Facilitates Progestin Resistance in Endometrial Cancer.

The progestin regimen is one of the main therapeutic strategies for women with endometrial cancer who undergo conservative management. Although many patients respond well to initial therapy, progestin-refractory disease inevitably emerges, and the molecular basis underlying progestin resistance has not been comprehensively elucidated. Herein, they demonstrated progestin results in p38-dependent IDH1 Thr 77 phosphorylation (pT77-IDH1). pT77-IDH1 translocates into the nucleus and is recruited to chromatin through its interaction with OCT6. IDH1-produced α-ketoglutarate (αKG) then facilitates the activity of OCT6 to promote focal adhesion related target gene transcription to confer progestin resistance. Pharmacological inhibition of p38 or focal adhesion signaling sensitizes endometrial cancer cells to progestin in vivo. The study reveals p38-dependent pT77-IDH1 as a key mediator of progestin resistance and a promising target for improving the efficacy of progestin therapy.

Investigating the influence of excavating a tunnel undercrossing an existing tunnel at zero distance.

In urban areas with limited underground space, the new tunnel construction introduces additional loads and displacements to existing tunnels, raising serious safety concerns. These concerns become particularly pronounced in the case of closely undercrossing excavation at zero-distance. The conventional elastic foundation beam model, which assumes constant reaction coefficients for the subgrade, fails to account for foundation loss. In this study, the existing tunnel is modeled as an Euler-Bernoulli beam supported by the Pasternak elastic foundation, and the foundation loss caused by zero-distance undercrossing excavations is considered. Furthermore, an analytical solution is proposed to evaluate the mechanical response in segments, by establishing governing differential equations and boundary conditions for the excavation and neutral zones, and underpinning loads are also considered. The analytical solution is validated in two case studies. Finally, a parametric analysis is performed to explore the influence of various parameters on the mechanical response of the existing tunnel.

Oncogenic ETS fusions promote DNA damage and proinflammatory responses via pericentromeric RNAs in extracellular vesicles.

Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.

Impact of different oxygen therapy strategies on the risk of endotracheal reintubation in mechanically ventilated patients: A systematic review and meta-analysis.

BACKGROUND: Mechanical ventilation (MV) is a crucial intervention for the support of patients with acute and severe respiratory failure in modern intensive care medicine. However, the mechanical forces resulting from the interplay between the ventilator and the respiratory system may cause pulmonary injury. OBJECTIVE: To compare the effects of high-flow nasal cannula (HFNC) therapy and other oxygen therapy modalities on the risk of endotracheal reintubation in mechanically ventilated patients after extubation in the intensive care unit (ICU). METHODS: An electronic search was carried out across various databases including PubMed, Embase, Ovid, Medline, Cochrane Library, Embase, VIP, and Wanfang. The objective of this search was to locate prospective randomized controlled trials that examined the effects of multiple oxygen therapy approaches on the incidence of reintubation in patients in the ICU after undergoing mechanical ventilation. The meta package in R language was used to analyze parameters adopted by the included studies such as reintubation rate, mortality rate, and length of hospital stay. RESULTS: This study enrolled 22 articles, involving 4,160 participants, with 2,061 in the study group and 2,099 in the control group. Among these, 20 articles presented data on the reintubation rate of the patients included with an odds ratio (OR) of 0.90 (95% CI: 0.74, 1.09) for HFNC and an OR of 1.77 (95% CI: 0.93, 3.38) for HFNC in the chronic obstructive pulmonary disease (COPD) subgroup. Moreover, 10 articles assessed the incidence of respiratory failure after extubation, revealing an OR for HFNC was 0.68 (95% CI: 0.55, 0.84) using a fixed-effects model. Nine articles addressed ICU mortality, while 13 pieces of literature examined hospital mortality. HFNC showed no significant impact on either ICU mortality or hospital mortality. CONCLUSION: HFNC therapy markedly reduces the incidence of respiratory failure in mechanically ventilated patients following extubation in the ICU. Furthermore, it specifically reduces the risk of reintubation in patients diagnosed with COPD.

Assisted reproductive technology treatment failure and the detection of intrauterine HPV through spent embryo transfer media sample.

Cervical human papillomavirus (HPV) infection is believed to increase the risks of pregnancy failure and abortion, however, whether the uterine cavity HPV infection reduces pregnancy rate or increases miscarriage rate remains unclarified in infertile women undergoing assisted reproductive technology (ART) treatment. Therefore, we aimed to assess ART outcomes in the presence of intrauterine HPV. This was a hospital-based multicenter (five reproductive medicine centers) matched cohort study. This study involved 4153 infertile women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection treatment in five reproductive medicine centers between October 2018 and 2020. The spent embryo transfer media sample with endometrium tissue were collected and performed with flow-through hybridization and gene chips to detect HPV DNA. According to basic characteristics, HPV-positive and negative patients were matched in a ratio of 1:4 by age, body mass index transfer timing, transfer type, and number of embryos transferred. The primary outcome was pregnancy and clinical miscarriage rates in the transfer cycle underwent HPV detection. 92 HPV-positive and 368 HPV-negative patients were screened and analyzed statistically. Univariate analysis showed uterine cavity HPV infection resulted in lower rates of ongoing pregnancy (31.5% vs. 44.6%; p = 0.023), implantation (32.3% vs. 43.1%; p = 0.026), biochemical pregnancy (47.8% vs. 62.5%; p = 0.010), and clinical pregnancy (40.2% vs. 54.3%; p = 0.015) compared with HPV negative group. The infertile female with positive HPV also had a slightly higher frequency of biochemical miscarriage (15.9% vs. 13.0%; p = 0.610) and clinical miscarriage (24.3% vs. 15.5%; p = 0.188). These findings suggest that HPV infection in the uterine cavity is a high risk for ART failure. HPV screening is recommended before ART treatment, which may be benefit to improving pregnancy outcome.

TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway.

BACKGROUND: The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC). METHODS: The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments. RESULTS: TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour. CONCLUSIONS: Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.

Tumor microenvironment-mediated NIR-I-to-NIR-II transformation of Au self-assembly for theranostics.

The misdiagnosis of tumors due to insufficient penetration depth or signal interference and damage to normal tissues due to indiscriminate treatment are the biggest challenges in using photothermal agents for clinical translation. To overcome these limitations, a strategy of switching from the near-infrared (NIR)-I region to the NIR-II region was developed based on tumor microenvironment (TME)-mediated gold (Au) self-assembly. Using zeolitic imidazolate framework-8 (ZIF-8) metal-organic framework-coated gold nanorods (AuNRs@ZIF-8) as a model photothermal agent, we demonstrated that only a NIR-I photoacoustic imaging signal was observed in normal tissue because ZIF-8 could prevent the aggregation of AuNRs. However, when ZIF-8 dissociated in the TME, the AuNRs aggregated to activate NIR-II photoacoustic imaging and attenuate the NIR-I signal, thereby allowing an accurate diagnosis of tumors based on signal transformation. Notably, TME-activated NIR-II photothermal therapy could also inhibit tumor growth. Therefore, this TME-activated NIR-I-to-NIR-II switching strategy could improve the accuracy of deep-tumor diagnoses and avoid the injury caused by undifferentiated treatment. STATEMENT OF SIGNIFICANCE: Photothermal agents used for photoacoustic imaging and photothermal therapy have garnered great attention for tumor theranostics. However, always "turned on" near-infrared (NIR)-I laser (700-1000 nm)-responsive photothermal agents face issues of penetration depth and damage to normal tissues. In contrast, tumor microenvironment-activated NIR-II "smart" photothermal agents exhibit deeper penetration depth and tumor selectivity. Therefore, a NIR-I-to-NIR-II switching strategy was developed based on tumor microenvironment-mediated Au self-assembly. This work provides a new strategy for developing tumor microenvironment-activated NIR-II smart photothermal agents.

Advances in the Mining of Disease Resistance Genes from Aegilops tauschii and the Utilization in Wheat.

Aegilops tauschii is one of the malignant weeds that affect wheat production and is also the wild species ancestor of the D genome of hexaploid wheat (Triticum aestivum, AABBDD). It contains many disease resistance genes that have been lost in the long-term evolution of wheat and is an important genetic resource for the mining and utilization of wheat disease resistance genes. In recent years, the genome sequence of Aegilops tauschii has been preliminarily completed, which has laid a good foundation for the further exploration of wheat disease resistance genes in Aegilops tauschii. There are many studies on disease resistance genes in Aegilops tauschii; in order to provide better help for the disease resistance breeding of wheat, this paper analyzes and reviews the relationship between Aegilops tauschii and wheat, the research progress of Aegilops tauschii, the discovery of disease resistance genes from Aegilops tauschii, and the application of disease resistance genes from Aegilops tauschii to modern wheat breeding, providing a reference for the further exploration and utilization of Aegilops tauschii in wheat disease resistance breeding.

Loss-of-function mutations of SOX17 lead to YAP/TEAD activation-dependent malignant transformation in endometrial cancer.

Aberrant hyperactivation of the Hippo pathway effector YAP/TEAD complex causes tissue overgrowth and tumorigenesis in various cancers, including endometrial cancer (EC). The transcription factor SOX17 (SRY [sex-determining region Y]-box 17) is frequently mutated in EC; however, SOX17 mutations are rare in other cancer types. The molecular mechanisms underlying SOX17 mutation-induced EC tumorigenesis remain poorly understood. Here, we demonstrate that SOX17 serves as a tumor suppressor to restrict the proliferation, migration, invasion, and anchorage-independent growth of EC cells, partly by suppressing the transcriptional outputs of the Hippo-YAP/TEAD pathway. SOX17 binds to TEAD transcription factors through its HMG domain and attenuates the DNA-binding ability of TEAD. SOX17 loss by inactivating mutations leads to the malignant transformation of EC cells, which can be reversed by small-molecule inhibitors of YAP/TEAD or cabozantinib, an FDA-approved drug targeting the YAP/TEAD transcriptional target AXL. Our findings reveal novel molecular mechanisms underlying Hippo-YAP/TEAD pathway-driven EC tumorigenesis, and suggest potential therapeutic strategies targeting the Hippo-YAP/TEAD pathway in SOX17-mutated EC.

FOXO3a-dependent up-regulation of HSP90 alleviates cisplatin-induced apoptosis by activating FUNDC1-mediated mitophagy in hypoxic osteosarcoma cells.

Hypoxia-induced decrease in cisplatin (CDDP) sensitivity in human osteosarcoma (OS) is a significant obstacle to effective chemotherapy. Recently, mitophagy has been shown to be associated with CDDP sensitivity. However, whether it regulates hypoxia-induced decreases in CDDP sensitivity in OS and the underlying mechanisms remain unknown. In this study, we found that hypoxia activated mitophagy and suppressed mitophagy with specific inhibitors, mitochondrial division inhibitor-1 (Mdivi-1) or lysosome inhibitor chloroquine (CQ), which inhibited CDDP-induced apoptosis in hypoxic U-2OS and MG-63 cells. In addition, hypoxia upregulated the phosphorylation level of FUN14 domain-containing protein 1 (FUNDC1), whereas the activation of mitophagy and decreased CDDP sensitivity were inhibited by transfection with FUNDC1 small interfering RNA (siRNA). Hypoxia treatment also led to the up-regulation of heat shock protein 90 (HSP90), whereas HSP90 siRNA inhibited FUNDC1-mediated activation of mitophagy and decreased CDDP sensitivity. Furthermore, activation of Unc-51 like autophagy activating kinase 1 (Ulk1) was found in U-2OS and MG-63 cells after induction of hypoxia. Overexpression of Ulk1 prevented the inhibitory effect of HSP90 siRNA on the activation of FUNDC1 and mitophagy and decreased CDDP sensitivity in hypoxic U-2OS and MG-63 cells. Finally, hypoxia induced the activation of forkhead box transcription factor 3a (FOXO3a), whereas FOXO3a siRNA inhibited hypoxia-induced HSP90 up-regulation, Ulk1 activation, and FUNDC1-mediated activation of mitophagy, and decreased CDDP sensitivity in U-2OS and MG-63 cells. Using a chromatin immunoprecipitation (ChIP) assay, we confirmed that FOXO3a binds to the HSP90 promoter region. In conclusion, our findings suggest that hypoxia alleviates CDDP-induced apoptosis by activating mitophagy through the FOXO3a/HSP90/Ulk1/FUNDC1 signaling pathway in OS cells.

Progestin Resistance and Corresponding Management of Abnormal Endometrial Hyperplasia and Endometrial Carcinoma.

With a younger tendency in morbidity age, endometrial cancer (EC) incidence has grown year after year. Worse, even more commonly occurring is endometrial hyperplasia (EH), which is a precancerous endometrial proliferation. For young women with early EC and EH who want to preserve fertility, progestin therapy has been utilized as a routine fertility-preserving treatment approach. Nevertheless, progestin medication failure in some patients is mostly due to progestin resistance and side effects. In order to further analyze the potential mechanisms of progestin resistance in EH and EC, to provide theoretical support for effective therapeutic strategies, and to lay the groundwork for searching novel treatment approaches, this article reviews the current therapeutic effects of progestin in EH and EC, as well as the mechanisms and molecular biomarkers of progestin resistance, and systematically expounds on the potential therapeutic methods to overcome progestin resistance.

Reexamining the Environmental Kuznets Curve in Chinese Cities: Does Intergovernmental Competition Matter?

Since China's central authority began enforcing the environmental target responsibility system and introduced environmental indicators to the official ranking tournament in 2007, an ecological transformation has emerged in the intergovernmental competition (IGC) among localities. Because the extant literature on the environmental Kuznets curve (EKC) remains unclear regarding how that ecological IGC transformation changes the EKC economy-pollution correlation, this research investigates the degree to which the transformed IGC changes the form of the EKC, and how that altered EKC varies for different pollutants (i.e., SO2 and CO2) and in different regions (i.e., the eastern, central, and western regions). The results demonstrate a consistently inverted U-shaped relationship between income and SO2 emissions in all three regions, whereas when CO2 emissions are taken as the pollution indicator, the EKC hypothesis holds only in the eastern and central cities, and a positive linear income-CO2 nexus is found in the western region. Spatial analysis reveals that whereas the IGC flattens the inverted U-shaped curves between income and SO2 emissions, it has led to a higher economic cost, corresponding to the turning point of the EKC for CO2 emissions. The findings indicate that the ecological transformation of the IGC has facilitated a positive up-down yardstick competition in the strategic interactions of sustainable development across local Chinese governments, which can lead to a kind of balance between centralization and decentralization by inspiring local officials' adaptability and activity in reducing pollutant emissions and strengthening the officials' responsiveness to performance rankings. This study elucidates the environmental impacts of IGC in China and provides an institutional explanation for the strategic interactions among local governments when they are tackling the environment-economy nexus under multitask conditions.

Androgen Signaling in Uterine Diseases: New Insights and New Targets.

Common uterine diseases include endometriosis, uterine fibroids, endometrial polyps, endometrial hyperplasia, endometrial cancer, and endometrial dysfunction causing infertility. Patients with uterine diseases often suffer from abdominal pain, menorrhagia, infertility and other symptoms, which seriously impair their health and disturb their lives. Androgens play important roles in the normal physiological functions of the uterus and pathological progress of uterine diseases. Androgens in women are synthesized in the ovaries and adrenal glands. The action of androgens in the uterus is mainly mediated by its ligand androgen receptor (AR) that regulates transcription of the target genes. However, much less is known about the signaling pathways through which androgen functions in uterine diseases, and contradictory findings have been reported. This review summarizes and discusses the progress of research on androgens and the involvement of AR in uterine diseases. Future studies should focus on developing new therapeutic strategies that precisely target specific AR and their related signaling pathways in uterine diseases.

GnRH-agonist pretreatment in hormone replacement therapy improves pregnancy outcomes in women with male-factor infertility.

Objective: This study aimed to examine the efficacy of HRT with gonadotropin-releasing hormone agonist (GnRH-a) pre-treatment in women with male-factor infertility who underwent a frozen embryo transfer (FET) programme. Design: Between January 2016 and October 2020, 2733 women with male-factor infertility who underwent the HRT protocol as the endometrial preparation method were enrolled at two Reproductive Medicine Centres. Patients were divided into two groups based on whether they had GnRH-a pre-treatment before HRTs: the GnRHa-HRT group and the HRT group. The inverse probability of treatment weighting (IPTW) method was conducted to balance patient baseline characteristics between treatment cohorts to reduce selection bias. The live birth rate was considered regarded as the primary pregnancy outcome. Results: Multivariate logistic regression adjusted for confounding factors, the GnRHa-HRT group showed a notably higher rate of live birth (OR 2.154, 95% CI 1.636~2.835, P<0.001) when compared to the HRT group. Additionally, the rate of miscarriage was significantly lower in the GnRHa-HRT group. The GnRHa-HRT group had significantly higher rates of biochemical pregnancy, clinical pregnancy, multiple pregnancy, and term birth. Conclusion: The endometrial preparation protocol of HRT with GnRH-a pre-treatment could obviously increase the live birth rate for women with male-factor infertility undergoing the FET programme.

Ovarian stimulation in IVF couples with severe male factor infertility: GnRH antagonist versus long GnRH agonist.

Objective: To examine the efficacy of gonadotropin releasing hormone (GnRH) antagonist (GnRH-ant) protocol and the long GnRH agonist (GnRH-a) protocol during in vitro fertilization (IVF) therapy in patients with severe male infertile factors. Methods: A total of 983 women with severe male factor infertility undergoing IVF therapy from 2017 to 2020 at one center were retrospectively analyzed. Patients were divided into the GnRH-ant group (n=527) and the GnRH-a group (n=456) according to their ovarian stimulation protocols. Patient baseline characteristics, ovarian stimulation characteristics, and clinical pregnancy outcomes were compared between the groups. The live birth rate was considered the main pregnancy outcome. Results: GnRH-a group had a higher live birth rate compared with the GnRH-ant group (41.0% versus 31.3%, p=0.002). Moreover, the implantation (32.8% vs. 28.1%, p=0.033), biochemical pregnancy (52.4% versus 44.8%, p=0.017), clinical pregnancy (49.3% versus 39.7%, p=0.002) and ongoing pregnancy rates (43.2% vs. 34.9%, p=0.008) were higher in GnRH-a group. For patients with one embryo transferred, the GnRH-a group demonstrated higher live birth (37.0% vs. 19.4%, p=0.010) and ongoing pregnancy rate (38.9% vs. 24.5%, p=0.046) than the GnRH-ant group. Among patients with two embryos transferred, the live birth rate was also higher in the GnRH-a group than in the GnRH-ant group, with no statistical difference. No significant differences were observed in the biochemical abortion rate, clinical miscarriage rate, early miscarriage rate, late miscarriage rate, heterotopic pregnancy rate, twin pregnancy rate, and birth sex ratio between the two groups. Conclusion: For individuals with severe male infertility undergoing IVF, the GnRH-a protocol is considered a more efficient and feasible strategy with a higher live birth rate compared to the GnRH-ant protocol, especially in single embryo transfer.

Comparison of different endometrial preparation protocols on frozen embryo transfer pregnancy outcome in patients with normal ovulation.

RESEARCH QUESTION: What is the effect of letrozole use in patients undergoing frozen embryo transfer (FET) with normal ovulation? Although the number of FETs is increasing, an optimal protocol for FET (particularly vitrified-warmed embryo transfer) is yet to be determined. The aim of this study was to evaluate letrozole use on patients with normal menstrual cycles compared with hormone replacement therapy (HRT) cycles and natural cycles. DESIGN: The study involved 2849 patients. Patients were divided into three groups: HRT cycle (n = 2115), letrozole cycle (n = 532) and natural cycle (n = 202). Inverse probability of treatment weighting aimed to equate each group according to measured baseline covariates to achieve a comparison with reduced selection bias and live birth rate as main pregnancy outcome was analysed. RESULTS: In the crude analysis, the letrozole group had a higher live birth rate compared with the HRT cycle (OR 1.18, 95% CI 1.06 to 1.33) and natural cycle (OR 1.24, 95% CI 1.11 to 1.41); after adjusting for confounding factors, live birth rate was consistently higher in the letrozole group. Moreover, the biochemical pregnancy, clinical pregnancy, ongoing pregnancy and full-term delivery rates were higher in the letrozole group. CONCLUSION: For infertile women with normal menstrual cycle undergoing FET, mildly stimulated cycles with letrozole present a relatively large advantage compared with HRT cycle and natural cycle, with higher live birth pregnancy, indicating that letrozole administration could improve pregnancy outcomes in this population.

Serum concentrations of NLRP3 in relation to functional outcome and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) participates in neuroinflammation. We endeavored to determine the role of serum NLRP3 as a biomarker of neuroinflammation, severity, delayed cerebral ischemia (DCI) and functional outcome following aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In this prospective and observational study, a total of 118 aSAH patients and 118 healthy volunteers were enrolled. Serum NLRP3 concentrations, blood glucose concentrations, serum C-reactive protein concentrations, and blood leucocyte counts were quantified. A poor outcome was defined as extended Glasgow outcome scale scores of 1-4 at post-injury 90 days. RESULTS: As compared to controls, significantly increased serum NLRP3 concentrations after aSAH were intimately correlated with the Glasgow coma scale scores, World Federation of Neurological Surgeons scale scores, Hunt-Hess scores, modified Fisher scores, extended Glasgow outcome scale scores, blood glucose concentrations, serum C-reactive protein concentrations and blood leucocyte counts. Serum NLRP3 emerged as an independent predictor for DCI and poor 90-day outcome. Using receiver operating characteristic curve, serum NLRP3 concentrations were significantly predictive of DCI and poor 90-day outcome. Its prognostic predictive ability was comparable to those of the Glasgow coma scale scores, World Federation of Neurological Surgeons scale scores, Hunt-Hess scores and modified Fisher scores. CONCLUSIONS: Serum NLRP3 may represent an inflammatory biomarker in relation to the severity, DCI and poor functional outcome after aSAH.

Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism.

Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer.

The role of LCN2 and LCN2-MMP9 in spondylitis radiographic development: gender and HLA-B27 status differences.

BACKGROUND: Male HLA-B27-positive radiographic-axial spondyloarthritis (r-axSpA) patients are prone to have severe spinal radiographic progression, but the underlying mechanisms are unclear. We recently showed that persistently elevated Lipocalin 2 (LCN2; L) reflects sacroiliac joint (SIJ) inflammation. LCN2 binds to MMP9. Concomitant elevation of L and LCN2-MMP9 (LM) was detected in many inflammatory diseases. We asked whether L and LM play similar roles in r-axSpA pathogenesis. METHODS: We analyzed 190 axSpA patients (123 radiographic and 67 non-radiographic axSpA) who had no detectable circulating Oncostatin M, to avoid complications due to cross-talk between pathways. L and LM levels from a single blood sample of each patient were measured and were correlated with MRI and modified stoke AS (mSASS) scoring. Association of elevated L (L+) or concurrent L+ and elevated LM (LM+) patterns with B27 status and gender were assessed. RESULTS: In L+LM+ axSpA patients, both L and LM levels correlated with MRI SPARCC SIJ scores, but only LM levels correlated with MRI Berlin Spine Scores, suggesting LM is a biomarker for both SIJ and spinal inflammation. Among patients with minimal spinal ankylosis (mSASSS < 10), 65% of male r-axSpA patients are L+LM+, while 30% and 64% of female patients are L+LM+ and L+, respectively, supporting the role of LM with disease progression. In B27+ L+LM+ male patients, both L and LM (but not CRP) levels correlate with mSASSS. B27 positivity and maleness have additive effects on spondylitis progression, suggesting concurrent high L and LM elevations are associated with B27+ male patients having more significant radiographic damage. L+ B27-negative male patients or L+ female patients are more likely to have milder disease. CONCLUSION: L and LM are informative biomarkers for SIJ and spinal inflammation, as well as for ankylosing development in r-axSpA patients. Distinctive L+LM+ or L+ patterns not only could distinguish clinically aggressive vs milder course of disease, respectively, but also provide an explanation for B27-positive male patients being the most susceptible to severe ankylosis.

Self-Templating-Oriented Manipulation of Ultrafine Pt3 Cu Alloyed Nanoparticles into Asymmetric Porous Bowl-Shaped Configuration for High-Efficiency Methanol Electrooxidation.

The precise and comprehensive manipulation of the component, size, and geometric nano-architecture of platinum-based electrocatalysts into porous and hollow structure can effectively impart the catalysts with substantially improved electrochemical performance, yet remain formidably challenging. Herein, a straightforward fabrication of porous platinum-copper alloyed nanobowls (abbreviated as Pt3 Cu NBs hereafter) assembled by ultrafine nanoparticles (≈2.9 nm) via a one-pot hydrothermal approach with the assistance of a structure-directing agent of N,N'-methylenebisacrylamide (MBAA) is reported. The involvement of MBAA plays a decisive role in the formation of Pt-MBAA complex solid nanospheres, which serve as the self-sacrificial reactive template for the deposition/growth of Pt3 Cu nanoparticles and the eventual formation of the asymmetric open-shelled nanobowls. Benefitting from the 3D sufficient accessibility of exterior/interior surfaces, high atom-utilization efficiency, and PtCu bimetallic alloy synergy, the self-supported Pt3 Cu NBs demonstrate remarkably enhanced activity, better anti-poisoning capability, and reinforced robustness for the methanol oxidation reaction (MOR) as compared with the commercial Pt black benchmark, exhibiting great application promises in practical fuel cell systems. It is envisaged that the innovative self-templated synthetic strategy outlined here may provide a perspective to design a range of porous bowl-shaped high-performance nanocatalysts.