YBX1 promotes homologous recombination and resistance to platinum-induced stress in ovarian cancer by recognizing m5C modification.

Platinum-based chemotherapy causes genetic damage and induces apoptosis in ovarian cancer cells. Enhancing the ability to resist platinum drug-induced DNA damage and apoptotic stress is critical for tumor cells to acquire drug resistance. Here, we found that Y-box binding protein 1 (YBX1) was highly expressed in cisplatin-resistant patient-derived organoids (PDOs) and was a crucial gene for alleviating platinum-induced stress and maintaining drug resistance characteristics in ovarian cancer cells. Mechanistically, YBX1 recognized m5C modifications in CHD3 mRNA and maintained mRNA stability by recruiting PABPC1 protein. This regulatory process enhanced chromatin accessibility and improved the efficiency of homologous recombination (HR) repair, facilitating tumor cells to withstand platinum-induced apoptotic stress. In addition, SU056, an inhibitor of YBX1, exhibited the potential to reverse platinum resistance in subcutaneous and PDO orthotopic xenograft models. In conclusion, YBX1 is critical for ovarian cancer cells to alleviate the platinum-induced stress and may be a potential target for reversing drug-resistant therapies.

FSP1 inhibition enhances olaparib sensitivity in BRCA-proficient ovarian cancer patients via a nonferroptosis mechanism.

Poly ADP-ribose polymerase inhibitors (PARPis) exhibit promising efficacy in patients with BRCA mutations or homologous repair deficiency (HRD) in ovarian cancer (OC). However, less than 40% of patients have HRD, it is vital to expand the indications for PARPis in BRCA-proficient patients. Ferroptosis suppressor protein 1 (FSP1) is a key protein in a newly identified ferroptosis-protective mechanism that occurs in parallel with the GPX4-mediated pathway and is associated with chemoresistance in several cancers. Herein, FSP1 is reported to be negatively correlated with the prognosis in OC patients. Combination therapy comprising olaparib and iFSP1 (a FSP1 inhibitor) strongly inhibited tumour proliferation in BRCA-proficient OC cell lines, patient-derived organoids (PDOs) and xenograft mouse models. Surprisingly, the synergistic killing effect could not be reversed by ferroptosis inhibitors, indicating that mechanisms other than ferroptosis were responsible for the synergistic lethality. In addition, cotreatment was shown to induce increased γH2A.X foci and to impair nonhomologous end joining (NHEJ) activity to a greater extent than did any single drug. Mass spectrometry and immunoprecipitation analyses revealed that FSP1 interacted with Ku70, a classical component recruited to and occupying the end of double-strand breaks (DSBs) in the NHEJ process. FSP1 inhibition decreased Ku70 PARylation, impaired subsequent DNA-PKcs recruitment to the Ku complex at DSB sites and was rescued by restoring PARylation. These findings unprecedentedly reveal a novel role of FSP1 in DNA damage repair and provide new insights into how to sensitize OC patients to PARPi treatment.

CircRAD23B promotes proliferation and carboplatin resistance in ovarian cancer cell lines and organoids.

BACKGROUND: Circular RNAs (circRNAs) are involved in the regulation of progression and drug resistance in ovarian cancer (OC). In the present study, we aimed to explore the role of circRAD23B, a newly identified circRNA, in the regulation of carboplatin-resistant OC. METHODS: CircRAD23B expression levels were measured using qRT-PCR. The biological roles of circRAD23B were analysed using CCK-8, colony formation, EDU, flow cytometry, and cell viability assays. RNA pull-down and luciferase assays were used to investigate the interactions of circRAD23B with mRNAs and miRNAs. RESULTS: CircRAD23B was significantly increased in carboplatin-resistant OC tissues. CircRAD23B promoted proliferation and reduced sensitivity to carboplatin in cell lines and patient-derived organoids (PDOs), consistent with in vivo findings. Mechanistically, circRAD23B acted as a molecular sponge, abrogating its inhibitory effect on Y-box binding protein 1 (YBX1) by adsorbing miR-1287-5p. Rescue experiments confirmed that the pro-proliferation and carboplatin resistance mediated by circRAD23B was partially reversed by the upregulation of miR-1287-5p. CONCLUSIONS: Our results demonstrated, for the first time, the role of the circRAD23B/miR-1287-5p/YBX1 axis in OC progression and carboplatin resistance in cell lines, PDOs, and animal models, providing a basis for the development of targeted therapies for patients with OC.

Impact of surgical approach on progress of disease by type of histology in stage IA endometrial cancer: a matched-pair analysis.

BACKGROUND: To compare the impact of surgical approach on progression free survival (PFS) stratified by histologic type in women diagnosed with stage IA endometrial cancer. METHODS: Myometrial invasion is classified into no myometrial invasion, <50% and ≥50%, with only no myometrial invasion and <50% are included in stage IA patients. A retrospective study is designed by collecting data from women diagnosed as stage IA endometrial cancer from January 2010 to December 2019 in a tertiary hospital. A propensity score is conducted for 1:1 matching in the low-risk histologic patients. Progression free survival and disease-specific survival data are evaluated by the Kaplan-Meier method and compared by the log-rank test in both the whole population and the matched-pair groups. A sub-group analysis is performed to figure out risk factors associated with the effect of surgical approach on PFS and disease-specific survival (DSS). RESULTS: 534 (84.49%) low-risk histologic endometrial cancer women, with 389 (72.85%) operated by minimally invasive surgery and 145 (27.15%) by open approach, and 98 (15.51%) high-risk histology, with 71 (72.45%) by laparoscopy and 27 (27.55%) by open surgery, are included. Compared to open surgery, laparoscopy results in lower progression free survival in low-risk patients before and after matching (p = 0.039 and p = 0.033, respectively), but shows no difference in high-risk patients (p = 0.519). Myometrial invasion is associated with lower progression free survival in laparoscopy in low-risk histology (p = 0.027). CONCLUSION: Surgical approaches influence progression free survival in stage IA low-risk histologic diseases, especially in those with myometrial invasion, but not in high-risk histologic endometrial cancer.

Preoperative hysteroscopy shortened progression-free survival in advanced FIGO stage in endometrial cancer: Ten year analysis.

OBJECTIVE: To investigate the impact of preoperative hysteroscopy on progression-free survival (PFS) and disease-specific survival (DFS), and to explore the factors which contribute to poor clinical outcomes between hysteroscopy and dilation and curettage (D&C) in endometrial cancer (EC). METHODS: A retrospective study was designed by collecting data from women diagnosed with EC through hysteroscopy or D&C from January 2010 to December 2019 in a tertiary hospital in China. A propensity score was used for 1:1 matching of advanced stage patients. Univariate and multivariate analysis were conducted to determine whether hysteroscopy was a prognostic factor in EC and to identify factors associated with its impact on PFS and DFS in different subgroups. RESULTS: Overall, 543 and 272 women who underwent D&C and hysteroscopy, respectively were included. Compared to D&C, preoperative hysteroscopy was related to reduced PFS and DFS, with a hazard ratio (HR) of 1.904 and 3.905, respectively. Hysteroscopy contributed to an increased risk of positive wash cytology (48.27% vs 24.13%), recurrence (48.28% vs 20.69%) and shorter PFS after matching in FIGO Stage I-IV EC, while there was no significance in positive ascites cytology (14.04% vs 13.45%), PFS and DFS in FIGO Stage I EC. CONCLUSIONS: Hysteroscopy was an independent predictive factor for poor prognosis in EC. Hysteroscopy appeared to be a safe diagnostic method as D&C in FIGO Stage I EC but was a risk factor for increased recurrence and reduced PFS in advanced stage disease. Its impact on DFS is uncertain.

Spin Manipulation in a Metal-Organic Layer through Mechanical Exfoliation for Highly Selective CO2 Photoreduction.

Spin manipulation of transition-metal catalysts has great potential in mimicking enzyme electronic structures to improve activity and/or selectivity. However, it remains a great challenge to manipulate room-temperature spin state of catalytic centers. Herein, we report a mechanical exfoliation strategy to in situ induce partial spin crossover from high-spin (s=5/2) to low-spin (s=1/2) of the ferric center. Due to spin transition of catalytic center, mixed-spin catalyst exhibits a high CO yield of 19.7 mmol g-1 with selectivity of 91.6 %, much superior to that of high-spin bulk counterpart (50 % selectivity). Density functional theory calculations reveal that low-spin 3d-orbital electronic configuration performs a key function in promoting CO2 adsorption and reducing activation barrier. Hence, the spin manipulation highlights a new insight into designing highly efficient biomimetic catalysts via optimizing spin state.

Multicomponent Anti-Kasha's Rule Emission from Nanotubular Metal-Organic Frameworks for Selective Detection of Small Molecules.

The peak photoluminescence (PL) of conventional fluorophores is independent of the excitation wavelength (called Kasha's rule), while the search of metal-organic framework materials with the so-called anti-Kasha's rule emission remains very limited. Herein, we report the observation of anti-Kasha's rule emission in a multicomponent PL three-dimensional nanotubular metal-organic framework (abbr. MOF-NT), [Zn(µ-L)(µ-bix)]n·0.33nH2O [H2L = biphenyl-3,5-dicarboxylic acid; bix = 1,4-bis(imidazole-1-ylmethyl)benzene]. The MOF-NT crystalline sample represents a notable example of strong excitation-dependent fluorescence from the ultraviolet to the visible spectral region. Moreover, by virtue of electronic flexibility and high PL efficiency, MOF-NT shows a discriminative PL response between isomeric nitroaromatic compounds. The work demonstrated the intrinsic anti-Kasha's rule emission in the crystalline-state MOF materials, providing new visions for the development of advanced solid-state emissive materials.

Maternal Outcomes Among Pregnant Women With Congenital Heart Disease-Associated Pulmonary Hypertension.

BACKGROUND: Studies focused on pregnant women with congenital heart disease (CHD)-associated pulmonary hypertension (PH) are scarce and limited by small sample sizes and single-center design. This study sought to describe the pregnancy outcomes in women with CHD with and without PH. METHODS: Outcomes for pregnant women with CHD were evaluated retrospectively from 1993 to 2016 and prospectively from 2017 to 2019 from 7 tertiary hospitals. PH was diagnosed on the basis of echocardiogram or catheterization. The incidence of maternal death, cardiac complications, and obstetric and offspring complications was compared for women with CHD and no PH, mild, and moderate-to-severe PH. RESULTS: A total of 2220 pregnant women with CHD had completed pregnancies. PH associated with CHD was identified in 729 women, including 398 with mild PH (right ventricle to right atrium gradient 30-50 mm Hg) and 331 with moderate-to-severe PH (right ventricle to right atrium gradient >50 mm Hg). Maternal mortality occurred in 1 (0.1%), 0, and 19 (5.7%) women with CHD and no, mild, or moderate-to-severe PH, respectively. Of the 729 patients with PH, 619 (85%) had CHD-associated pulmonary arterial hypertension, and 110 (15%) had other forms of PH. Overall, patients with mild PH had better maternal outcomes than those with moderate-to-severe PH, including the incidence of maternal mortality or heart failure (7.8% versus 39.6%; P<0.001), other cardiac complications (9.0% versus 32.3%; P<0.001), and obstetric complications (5.3% versus 15.7%; P<0.001). Brain natriuretic peptide >100 ng/L (odds ratio, 1.9 [95% CI, 1.0-3.4], P=0.04) and New York Heart Association class III to IV (odds ratio, 2.9 [95% CI, 1.6-5.3], P<0.001) were independently associated with adverse maternal cardiac events in pregnancy with PH, whereas follow-up with a multidisciplinary team (odds ratio, 0.4 [95% CI, 0.2-0.6], P<0.001) and strict antenatal supervision (odds ratio, 0.5 [95% CI, 0.3-0.7], P=0.001) were protective. CONCLUSIONS: Women with CHD-associated mild PH appear to have better outcomes compared with women with CHD-associated moderate-to-severe PH, and with event rates similar for most outcomes with women with CHD and no PH. Multimodality risk assessment, including PH severity, brain natriuretic peptide level, and New York Heart Association class, may be useful in risk stratification in pregnancy with PH. Follow-up with a multidisciplinary team and strict antenatal supervision during pregnancy may also help to mitigate the risk of adverse maternal cardiac events.

High-temperature negative thermal quenching phosphors from molecular-based materials.

High-temperature negative thermal quenching (NTQ) phosphors are crucial to high-performance light-emitting devices. Herein, we report the high-temperature NTQ effect in deep-red to near-infrared (NIR) emitting copper iodide cluster-based coordination polymers as unconventional phosphors, whose NTQ operating temperature can reach as high as 500 K, the highest temperature reached by NTQ molecular-based materials.

Bractoppin, a BRCA1 carboxy-terminal domain (BRCT) inhibitor, suppresses tumor progression in ovarian borderline tumor organoids.

Borderline ovarian tumors are a special class of ovarian tumors between benign and malignant, which are not sensitive to traditional chemotherapy regimens, and the development of target drugs is limited due to the lack of cell lines. Tumor organoids can well preserve the genetic characteristics of the primary tumor, but there are only a few reports of application in borderline tumors. In this study, we successfully generated 13 ovarian borderline tumor organoids and tested the antitumor activity of Bractoppin, a BRCA1 carboxy-terminal domain (BRCT) inhibitor. Bractoppin promotes organoid apoptosis. Mechanistically, Bractoppin can inhibit organoid cell cycle progression, inhibit the repair of DSB damage and promote tumor cell apoptosis. In addition, Bractoppin can also promote the apoptosis of ovarian cancer cell lines and inhibit the HR and NHEJ repair ability of tumor cells. We demonstrate the value of ovarian borderline tumor organoids in the exploration of molecular therapy drugs, and Bractoppin may be a valuable small molecule drug in the treatment of BOT.

A Copper Iodide Cluster-Based Coordination Polymer as an Unconventional Zero-Thermal-Quenching Phosphor.

Phosphor-converted white light-emitting diodes (pc-wLEDs) are promising candidates for next-generation solid-state lighting and display technologies. However, most of the conventional phosphors in pc-wLED devices suffer from serious thermal quenching (TQ) at high temperatures. Herein, we investigate an unconventional high-efficiency metal-halide cluster-based phosphor with dynamic Cu-Cu interactions that can resist the TQ effect of photoluminescence. The temperature-dependent structure and solid-state and in situ NMR spectroscopy reveal that the weakening of the Cu-Cu interaction in such a phosphor system enables the electronic structural transition from a bonding to a nonbonding state and hence sustains the PL efficiency at high temperatures (up to 100 °C). The pc-wLEDs incorporating the zero-TQ phosphor show a rapid brightness rise even at a high bias current (1000 mA) with a color rendering index as high as 90, comparable to the commercial phosphor-based prototype LEDs (e.g., YAG:Ce3+). This work establishes a novel prototype of a cluster-based phosphor featuring dynamic intermetallic interactions, which paves the way for the exploration of pc-wLEDs against thermal quenching.

Hysterectomy by Transvaginal Natural Orifice Transluminal Endoscopic Surgery versus Transumbilical Laparoscopic Single-Site Surgery: A Single-Center Experience from East China.

Objective: To compare hysterectomy by transvaginal natural orifice transluminal endoscopic surgery (VNOTES) versus transumbilical laparoscopic single-site surgery (LESS) as a minimal invasive technique. Materials and Method. The women undergoing hysterectomy for benign diseases by VNOTES and LESS from January 2020 to June 2021 in a tertiary hospital in Shanghai were retrospectively analyzed. Results: 361 women were included in our study, with 228 in the VNOTES groups, 129 in the LESS groups, and 4 conversions from VNOTES to LESS technique. The length of a VNOTES hysterectomy was shorter than that of LESS (80.76 min versus 112.09 min; MD -31.34 min; 95% CI -40.24 to -22.43 min; P < 0.001). VNOTES hysterectomy has a quicker gas passage by the anus (18.80 versus 36.49 hours, MD -17.68 hours, 95% CI -20.23 to -15.14 hours, P < 0.001) and associated with a shorter length of hospital stay (2.31 versus 3.77 days, MD -1.46 days, 95% CI -1.75 to -1.17 days, P < 0.001), while with no increase in blood loss during the operation (median 50 versus 50 ml, P = 0.25). Besides, the VAS pain score in the 24th hour after the operation was lower (median 0 versus 0.5, P < 0.001) in the VNOTES group. Four unique phases of the learning curve were identified using cumulative analysis: the mean operation time of phase I was 82.81 ± 31.45 min (the initial learning curve of 43 cases), phase II was 72.48 ± 23.66 min (the acquisition of command of 91 cases), phase III was 103.77 ± 45.69 min (the further learning of 26 cases), and phase IV was 73.18 ± 26.89 min (postlearning in 68 cases). Conclusions: VNOTES is noninferior to LESS as a new minimal invasive procedure for hysterectomy, which also allows patients a faster recovery from surgery and to suffer less pain, and its efficiency and feasibility in large uterine need further exploring.

A Red-Emitting Cu(I)-Halide Cluster Phosphor with Near-Unity Photoluminescence Efficiency for High-Power wLED Applications.

Solid-state lighting technology, where light-emitting diodes (LEDs) are used for energy conversion from electricity to light, is considered a next-generation lighting technology. One of the significant challenges in the field is the synthesis of high-efficiency phosphors for designing phosphor-converted white LEDs under high flux operating currents. Here, we reported the synthesis, structure, and photophysical properties of a tetranuclear Cu(I)-halide cluster phosphor, [bppmCu2I2]2 (bppm = bisdiphenylphosphinemethane), for the fabrication of high-performance white LEDs. The PL investigations demonstrated that the red emission exhibits a near-unity photoluminescence quantum yield at room temperature and unusual spectral broadening with increasing temperature in the crystalline state. Considering the excellent photophysical properties, the crystalline sample of [bppmCu2I2]2 was successfully applied for the fabrication of phosphor-converted white LEDs. The prototype white LED device exhibited a continuous rise in brightness in the range of a high bias current (100-1000 mA) with CRI as high as 84 and CCT of 5828 K, implying great potential for high-quality white LEDs.

Pregnancies in women with moderate and severe pulmonary hypertension remain challenging: A single-center experience in East China.

OBJECTIVE: To determine the outcomes in women with pulmonary hypertension (PH) and determine the factors related to adverse outcomes. METHODS: Data from 684 women with PH admitted to the Affiliated Renji Hospital from January 2001 to December 2020 were collected. Outcomes were compared based on the causes and severity of PH. RESULTS: The overall mortality was 2.8%, decreasing from 6.6% in 2001-2005 to 1.7% in 2016-2020 (P = 0.10). Idiopathic PH had the highest mortality (35.3%) and the lowest live birth rate (82.4%). Mortality was similar between moderate and severe PH (5.3% versus 9.7%), but the live birth rate was much lower in severe PH (78.6% versus 89.9%). Hypoxemia and vaginal birth were risk factors of maternal death (odds ratio [OR] 35.28, 95% confidence interval [CI] 1.42-878.75; OR 850.86, 95% CI 5.67-127 606.74, respectively). General anesthesia was a risk factor in the univariate analysis (OR 12.07, 95% CI 3.72-39.15) but was not significant in the multivariate analysis (P = 0.16). CONCLUSION: The mortality rate in this retrospective study was lower than that previously reported. Pregnancy is safe in mild PH but still has a high risk of complications in moderate and severe PH. Hypoxemia is a risk factor for maternal death, but cesarean section may be a protective factor.

Negative/Zero Thermal Quenching of Luminescence via Electronic Structural Transition in Copper-Iodide Cluster-Based Coordination Networks.

Photoluminescence (PL) intensity in organic or metal-organic emitters usually suffers from thermal quenching (TQ), which severely hinders their industrial applications. The development of negative thermal quenching (NTQ) and/or zero thermal quenching (ZTQ) materials depends on a better understanding of the mechanisms underpinning TQ in luminescent solids. In this work, we investigated the temperature dependence of thermally activated delayed fluorescence (TADF) in copper(I)-organic coordination polymers (CP) ligated with an imidazole or triazole derivative over a broad temperature range. The efficient PL emission of CP1 is heavily quenched as the crystalline samples are cooled to 77 K; the PL intensity shows the NTQ effect in the region of 77-238 K followed by a ZTQ effect in the temperature range of 238-318 K. No NTQ or ZTQ effect is observed for reference coordination polymer CP2, where the 1,2,4-triazole group was used instead of the imidazole one. Our work highlights the important role of the ligand's electronic structure in optimizing photophysical properties of coordination polymer emitters and may stimulate new efforts to design luminescent materials exhibiting NTQ and ZTQ effect at higher temperature.