Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial.

Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses.

Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell-specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.

Research on the Surface-State Parameterization of a Refill Friction Stir Spot Welding Joint Made of Aluminum Alloy and Its Connection to the Fracture Mode.

Surface features are crucial for assessing welding quality because they serve as an intuitive depiction of the quality of the joint and have a major influence on welding strength. According to the characteristics of the refill friction stir spot welding (RFSSW) process and an analysis of the surface-state and internal morphology of RFSSW joints, a method of predicting the mechanical properties of RFSSW joints based on surface-state characteristics was proposed. In this paper, a laser-ranging sensor was used to characterize the surface state of RFSSW joints, and parametric characterization methods of the surface-state features of RFSSW joints were proposed. On this basis, a support vector machine was used to predict and analyze the fracture mode of RFSSW joints. The accuracy of the analysis of the test samples reached 95.8%. This paper provides a more efficient and convenient new method for the quality evaluation of RFSSW joints.

VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.

Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.

Analysis of the Correlation and Prognostic Significance of Tertiary Lymphoid Structures in Breast Cancer: A Radiomics-Clinical Integration Approach.

BACKGROUND: Tertiary lymphoid structures (TLSs) are potential prognostic indicators. Radiomics may help reduce unnecessary invasive operations. PURPOSE: To analyze the association between TLSs and prognosis, and to establish a nomogram model to evaluate the expression of TLSs in breast cancer (BC) patients. STUDY TYPE: Retrospective. POPULATION: Two hundred forty-two patients with localized primary BC (confirmed by surgery) were divided into BC + TLS group (N = 122) and BC - TLS group (N = 120). FIELD STRENGTH/SEQUENCE: 3.0T; Caipirinha-Dixon-TWIST-volume interpolated breath-hold sequence for dynamic contrast-enhanced (DCE) MRI and inversion-recovery turbo spin echo sequence for T2-weighted imaging (T2WI). ASSESSMENT: Three models for differentiating BC + TLS and BC - TLS were developed: 1) a clinical model, 2) a radiomics signature model, and 3) a combined clinical and radiomics (nomogram) model. The overall survival (OS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were compared to evaluate the prognostic value of TLSs. STATISTICAL TESTS: LASSO algorithm and ANOVA were used to select highly correlated features. Clinical relevant variables were identified by multivariable logistic regression. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC), and through decision curve analysis (DCA). The Kaplan-Meier method was used to calculate the survival rate. RESULTS: The radiomics signature model (training: AUC 0.766; test: AUC 0.749) and the nomogram model (training: AUC 0.820; test: AUC 0.749) showed better validation performance than the clinical model. DCA showed that the nomogram model had a higher net benefit than the other models. The median follow-up time was 52 months. While there was no significant difference in 3-year OS (P = 0.22) between BC + TLS and BC - TLS patients, there were significant differences in 3-year DFS and 3-year DMFS between the two groups. DATA CONCLUSION: The nomogram model performs well in distinguishing the presence or absence of TLS. BC + TLS patients had higher long-term disease control rates and better prognoses than those without TLS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Efficacy and safety of ripretinib vs. sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: A phase 2, multicenter, randomized, open-label study in China.

AIM: A bridging study of INTRIGUE study to assess the efficacy and safety of ripretinib versus sunitinib as second-line treatment in Chinese GIST patients. METHODS: This was a phase 2, multicenter, randomized, open-label study in China. GIST patients previously treated with imatinib were randomized (1:1) to receive ripretinib 150 mg once daily (QD) by continuous dosing in 42-day cycles or sunitinib 50 mg QD in 42-day cycles (four weeks on/two weeks off). Primary endpoint was progression-free survival (PFS) by independent radiological review (IRR). RESULTS: Between 6 December 2020 and 15 September 2021, 108 patients were randomized to receive ripretinib (n = 54) or sunitinib (n = 54) (all-patient [AP] intention-to-treat [ITT] population). Seventy patients had primary KIT exon 11 mutations (ripretinib, n = 35; sunitinib, n = 35; Ex11 ITT population). By data cut-off (20 July 2022), in AP ITT population, PFS by IRR was comparable between ripretinib and sunitinib arms (HR 0·99, 95 % CI 0·57, 1·69; nominal p = 0·92; median PFS [mPFS] 10·3 vs 8·3 months). In Ex11 ITT population, PFS by IRR was longer for ripretinib than sunitinib (HR 0·46, 95 % CI 0·23, 0·92; nominal p = 0·03; mPFS not reached in ripretinib arm and 4·9 months in sunitinib arm). Fewer patients experienced grade 3/4 treatment-related treatment-emergent adverse events with ripretinib (17%) versus sunitinib (56%). CONCLUSIONS: Ripretinib demonstrated similar efficacy and a favorable safety profile versus sunitinib as second-line treatment in Chinese GIST patients. Furthermore, ripretinib provided greater clinically meaningful benefit versus sunitinib in patients with KIT exon 11 mutation.

Nanotechnological approaches for the treatment of placental dysfunction: recent trends and future perspectives.

The transitory placenta develops during pregnancy and mediates the blood flow between the mother and the developing baby. Placental dysfunction, including but not limited to placenta accreta spectrum, fetal growth restriction, preeclampsia and gestational trophoblastic disease, arises from abnormal placental development and can result in significant adverse maternal and fetal health outcomes. Unfortunately, there is a lack of treatment alternatives for these disorders. Nanocarriers offer versatility, including extended circulation, organ-specific targeting and intracellular transport, finely tuning therapeutic placental interactions. This thorough review explores nanotechnological strategies for addressing placental disorders, encompassing dysfunction insights, potential drug-delivery targets and recent strides in placenta-targeted nanoparticle (NP) therapies, instilling hope for effective placental malfunction treatment.

The placenta, essential for mother­baby blood exchange, may experience catastrophic abnormalities during pregnancy. Treating these issues is challenging since you must focus on the placenta while protecting the infant. Nanotechnology might be helpful in this scenario. Nanocarriers are small carriers that can transport medications to the placenta and other particular locations in the body. They can aid in the treatment of various placental issues. In our present review, we discuss nanotechnology's solutions to these issues. We discuss what goes wrong, potential therapeutic applications for nanocarriers and recent developments in their use. This might be a novel approach to treating placenta issues and maintaining the health of mothers and infants.

Coding RNA expression profile and transcription factor analysis of H.pylori-associated chronic atrophic gastritis.

PURPOSE: Atrophic gastritis, one of the processes leading to gastric cancer (GC), is closely related to Helicobacter pylori (HP) infection. This study aimed to understand how HP causes chronic inflammation that leads to ulcers and stomach problems. METHODS: Twenty-eight CAG patients were included in the study (9 HP-infected and 19 HP-uninfected). Endoscopy, histopathology, and high-throughput mRNA sequencing were performed. Differentially expressed genes (DEGs) were validated via qRT-PCR. RESULTS: Principal component analysis (PCA) results showed that more than 88.9 â€‹% of the samples were classified into the HP (+) group. A total of 157 DEGs were identified, of which 38 were up-regulated and 119 were down-regulated. The DEGs were mainly enriched in the biological process (BP) terms associated with immune system process, adaptive immune response, G protein-coupled receptor signaling pathway, as well as point to numerous key pathways, including fat digestion and absorption, retinol metabolism, steroid hormone biosynthesis, ascorbate and aldarate metabolism, and chemical carcinogenesis. APOA1, APOA4, FOXP3, NR1H4, ABCG5, ACTA1, CCL19, CCR7, CYP3A4, and PDCD had the highest degrees in protein-protein interaction network as the hub genes; they were also included into the transcription factor (TF)-target network except for PDCD. APOA1 and CYP3A4 were extremely significantly up-regulated in HP (+) CAG patients compared with the HP (-) CAG patients, while FOXP3, CCR7 and CCL19 were significantly down-regulated. CONCLUSION: The expression of APOA1, CYP3A4, FOXP3, CCR7, and CCL19 are the potential indicators for CAG to GC development, being the biomarkers to predict progression of CAG and poor prognosis of GC.

Antagonistic RALF peptides control an intergeneric hybridization barrier on Brassicaceae stigmas.

Pollen-pistil interactions establish interspecific/intergeneric pre-zygotic hybridization barriers in plants. The rejection of undesired pollen at the stigma is crucial to avoid outcrossing but can be overcome with the support of mentor pollen. The mechanisms underlying this hybridization barrier are largely unknown. Here, in Arabidopsis, we demonstrate that receptor-like kinases FERONIA/CURVY1/ANJEA/HERCULES RECEPTOR KINASE 1 and cell wall proteins LRX3/4/5 interact on papilla cell surfaces with autocrine stigmatic RALF1/22/23/33 peptide ligands (sRALFs) to establish a lock that blocks the penetration of undesired pollen tubes. Compatible pollen-derived RALF10/11/12/13/25/26/30 peptides (pRALFs) act as a key, outcompeting sRALFs and enabling pollen tube penetration. By treating Arabidopsis stigmas with synthetic pRALFs, we unlock the barrier, facilitating pollen tube penetration from distantly related Brassicaceae species and resulting in interspecific/intergeneric hybrid embryo formation. Therefore, we uncover a "lock-and-key" system governing the hybridization breadth of interspecific/intergeneric crosses in Brassicaceae. Manipulating this system holds promise for facilitating broad hybridization in crops.

Structure-based discovery of novel α-aminoketone derivatives as dual p53-MDM2/MDMX inhibitors for the treatment of cancer.

The function of the p53 protein is impaired by the overexpression of its negative regulator murine double minute 2 protein (MDM2) and homologous protein MDMX. Disruption of the p53-MDM2/MDMX interaction to restore the transcriptional function of p53 is considered a promising strategy for cancer therapy. To design dual MDM2/MDMX inhibitors, the binding modes of MDM2 or MDMX with their inhibitors are elucidated. Several hot-spot residues of MDM2 or MDMX are identified by molecular dynamics simulations, alanine scanning and MM-GBSA calculations. Then, focusing on the interaction with hot-spot residues, two series of derivatives bearing 1,3-diketone and α-aminoketone scaffolds are designed and synthesized. Among these compounds, C16 is identified as the most potent compound with low micromolar binding affinities with MDM2 and MDMX. C16 also displays moderate antiproliferative activities against MDM2-overexpressing and MDMX-overexpressing cells, with IC50 values of 0.68 µM in HCT116 cells and 0.54 µM in SH-SY5Y cells. Furthermore, C16 inhibits cell migration and invasion, reactivates the function of p53, arrests the cell cycle and induces cellular apoptosis in HCT116 and SH-SY5Y cells. Collectively, C16 can be developed as a dual MDM2 and MDMX inhibitor for cancer therapy.

Astragaloside IV alleviates cytarabine-induced intestinal mucositis by remodeling macrophage polarization through AKT signaling.

BACKGROUND: Intestinal mucositis (IM) is one of the common side effects of chemotherapy with Cytarabine (Ara-C) and contributes to the major dose-limiting factor of chemotherapy, while the effective drug for IM is little. Astragalus, one of the main active components extrated from the roots of Astragalus membranaceus (AS-IV), is a common Chinese herbal medicine used in gastrointestinal diseases. However, the effect and mechanism of AS-IV on IM is unclear. Accumulating evidence suggests that M1 macrophages play a pivotal role in IM progression. PURPOSE: The purpose of the study was to explore the protection of AS-IV and its potential molecular mechanism on intestinal mucositis injury induced by Ara-C. METHOD: The protective effect of AS-IV was investigated in LPS-induced macrophages and Ara-C-induced intestinal mucositis mouse model. H&E, immunofluorescence and western blotting were used to evaluate the damage in different doses of Ara-C. Silencing AKT targeted by siRNA was performed to explore the potential mechanisms regulating macrophage polarization effect of Ara-C, which was investigated by CCK-8, immunofluorescence and western blotting. Flow cytometry, immunofluorescence and Western blotting were used to detect macrophage surface marker proteins and inflammatory genes to explore the potential molecular mechanism of AS-IV regulating macrophage polarization. RESULTS: The Cytarabine intervention at dose of 100mg/kg significantly induced IM in mice, with the ileum the most obvious site of injury, accompanied by decreased intestinal barrier, intestinal macrophage polarization to M1 and inflammation response. The administration of AS-IV improved weight loss, food intake, ileal morphological damage, intestinal barrier destruction and inflammatory factor release in mice induced by Ara-c, and also suppressed macrophage polarization to M1, regulating in phenotypic changes in macrophages. In vitro, the expression of M1 macrophage surface marker protein was markedly decreased in LPS-induced macrophages after silencing AKT. Similarly, the western blotting of intestinal tissues and molecular docking indicated that the key mechanisms of AS-IV were remodel AKT signaling, and finally regulating M1 macrophages and decrease inflammation response. CONCLUSION: Our study highlights that AS-IV exerts protective effect in Ara-C-induced IM through inhibit polarization to M1 macrophages based on AKT, and AS-IV may serve as a novel AKT inhibitor to counteract the intestinal adverse effects of chemotherapeutic agents.

Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling.

Previous studies show that notoginsenoside R1 (NG-R1), a novel saponin isolated from Panax notoginseng, protects kidney, intestine, lung, brain and heart from ischemia-reperfusion injury. In this study we investigated the cardioprotective mechanisms of NG-R1 in myocardial ischemia/reperfusion (MI/R) injury in vivo and in vitro. MI/R injury was induced in mice by occluding the left anterior descending coronary artery for 30 min followed by 4 h reperfusion. The mice were treated with NG-R1 (25 mg/kg, i.p.) every 2 h for 3 times starting 30 min prior to ischemic surgery. We showed that NG-R1 administration significantly decreased the myocardial infarction area, alleviated myocardial cell damage and improved cardiac function in MI/R mice. In murine neonatal cardiomyocytes (CMs) subjected to hypoxia/reoxygenation (H/R) in vitro, pretreatment with NG-R1 (25 µM) significantly inhibited apoptosis. We revealed that NG-R1 suppressed the phosphorylation of transforming growth factor ß-activated protein kinase 1 (TAK1), JNK and p38 in vivo and in vitro. Pretreatment with JNK agonist anisomycin or p38 agonist P79350 partially abolished the protective effects of NG-R1 in vivo and in vitro. Knockdown of TAK1 greatly ameliorated H/R-induced apoptosis of CMs, and NG-R1 pretreatment did not provide further protection in TAK1-silenced CMs under H/R injury. Overexpression of TAK1 abolished the anti-apoptotic effect of NG-R1 and diminished the inhibition of NG-R1 on JNK/p38 signaling in MI/R mice as well as in H/R-treated CMs. Collectively, NG-R1 alleviates MI/R injury by suppressing the activity of TAK1, subsequently inhibiting JNK/p38 signaling and attenuating cardiomyocyte apoptosis.

[Animal Model Establishment and Its Mechanism of Cytarabine-Iduced Myelosuppression].

OBJECTIVE: To establish an optimized model of bone marrow suppression induced by cytarabine (Ara-C) in C57BL/6 mice and preliminarily explore the mechanism of myelosuppression based on the cycle and apoptosis of BMNC. METHODS: C57BL/6 mice were intraperitoneally injected with Ara-C 50, 100 and 200 mg/kg for 7 days, respectively. The survival rate and body weight of C57BL/6 mice were monitored. The number of peripheral blood cells and bone marrow nucleated cells (BMNC) was detected, and the morphology of bone marrow, thymus and spleen were measured on the 7th, 14th and 21st day of the experiment. The cycle and apoptosis of BMNC were also detected by flow cytometry. RESULTS: Ara-C 200 mg/kg caused 46.7% mortality in mice, and other doses had no significant effect on mortality. All doses of Ara-C induced bone marrow suppression in mice, as shown by a decrease in the number of peripheral blood cells (WBC, Neu, RBC, PLT) and BMNC (P<0.05), decrease in bone marrow hyperplasia, accompanied by immunosuppression and compensatory hematopoiesis of the spleen, and the above manifestations and duration were dose-dependent. Among them, the myelosuppression caused by Ara-C 50 mg/kg recovered quickly, and caused by Ara-C 200 mg/kg was too severe. The result of flow cytometry showed that Ara-C could cause S and G2/m arrest and increased apoptosis in BMNC. CONCLUSION: Ara-C can induce myelosuppression in mice with a dose-dependent severity and duration, and the model of myelosuppression with Ara-C 100 mg/kg is more optimized. The mechanism is related to the inhibition of BMNC proliferation and the promotion of apoptosis.

Follicle-Stimulating Hormone Alleviates Ovarian Aging by Modulating Mitophagy- and Glycophagy-Based Energy Metabolism in Hens.

As a predominant hormone in the reproductive axis, follicle-stimulating hormone (FSH) is known as the primary surviving factor for follicular growth. In this study, the alleviating effect of FSH on aging chicken granulosa cells (GCs) was investigated. Results showed that FSH activated mitophagy and relieved mitochondrial edema in D-gal-induced senescent GCs, which was evidenced by an increased number of mitophagosomes as well as increased mitochondria-light chain 3 (LC3) colocalization. Mitophagy activation was accompanied by the activation of the AMP-activated protein kinase (AMPK) signaling pathway. Furthermore, upregulated glycophagy was demonstrated by an increased interaction of starch-binding domain protein 1 (STBD1) with GABA type A receptor-associated protein-like 1 (GABARAPL1) in D-gal-induced senescent GCs. FSH treatment further promoted glycophagy, accompanied by PI3K/AKT activation. PI3K inhibitor LY294002 and AKT inhibitor GSK690693 attenuated the effect of FSH on glycophagy and glycolysis. The inhibition of FSH-mediated autophagy attenuated the protective effect of FSH on naturally aging GC proliferation and glycolysis. The simultaneous blockage of PI3K/AKT and AMPK signaling also abolished the positive effect of FSH on naturally senescent ovarian energy regulation. These data reveal that FSH prevents chicken ovarian aging by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/AKT and AMPK pathways.

Correlation between the neutrophil-to-lymphocyte ratio and clinicopathological parameters in epithelial ovarian cancer patients and its effect on prognosis-a retrospective cohort study.

Background: Ovarian cancer is a common malignant tumor of the female reproductive system, and its mortality rate is high. In recent years, studies have found that the neutrophil-to-lymphocyte ratio (NLR) has a correlation with the prognosis of patients with malignant tumors; however, its association with the prognosis of ovarian cancer patients has not been studied. Therefore, we designed this study to investigate the correlation between the NLR and clinicopathological parameters in patients with epithelial ovarian cancer and its effect on prognosis. Methods: A total of 168 ovarian cancer patients (received operation in our hospital and age ≥18 years) admitted to the Pu Ren Hospital in Wuhan City and Shandong Qingdao Hospital of Integrated Traditional and Western Medicine from January 2015 to January 2017 were retrospectively included. The patients were equally divided into high NLR (n=84) and low NLR (n=84) groups according to their preoperative NLR levels (under preoperative fasting conditions, 5 mL venous blood was taken and immediately sent for examination), and the clinical characteristics and prognoses of the two groups were compared. All patients were followed up for 5 years to study the 5 years progression-free survival and 5-year mortality rate. Results: Preoperative NLR levels were associated with Federation International of Gynecology and Obstetrics (FIGO) staging, ascites, and lymph node metastasis in patients with ovarian cancer (P<0.05). The area under the curve (AUC) of NLR in predicting recurrence or metastasis in ovarian cancer patients within 5 years after surgery was 0.675 [95% confidence interval (CI): 0.594-0.757, P=0.000]. Furthermore, the AUC of NLR in predicting death in ovarian cancer patients within 5 years after surgery was 0.785 (95% CI: 0.717-0.853, P=0.000). Patients in the high NLR group had a significant reduction in 5-year progression-free survival and an increased mortality rate (P=0.000). Conclusions: High NLR in patients with ovarian cancer is related to clinicopathological parameters and poor prognosis in ovarian cancer patients.

Detection of Cancer Marker Flap Endonuclease 1 Using One-Pot Transcription-Powered Clustered Regularly Interspaced Short Palindromic Repeat/Cas12a Signal Expansion.

As a critical functional protein in DNA replication and genome stability, flap endonuclease 1 (FEN1) has been considered a promising biomarker and druggable target for multiple cancers. We report here a transcription-powered clustered regularly interspaced short palindromic repeat (CRISPR)/Cas12a signal expansion platform for rapid and sensitive detection of FEN1. In this method, the probe cleavage by FEN1 generated a free 5' flap single-stranded DNA which could hybridize with the single-stranded T7 promoter-bearing template and trigger the extension. Then, the CRISPR guide RNA (crRNA) transcribed from the extended template activated the collateral DNase activity of Cas12a, releasing the fluorophore from the quenched DNA signal probe to report the FEN1 detection result. The high specificity for FEN1 was validated by comparing with other repair-relevant proteins. The limit of detection (LOD) could be as low as 0.03 mU, which is sensitive enough to detect the FEN1 activity in biological samples. In addition, the inhibition assay of FEN1 was also successfully achieved with this platform, proving its potential in inhibitor screening. In summary, this study provides a novel biosensor for FEN1 activity analysis and provides new insights into the development of CRISPR-based biosensors for non-nucleic acid targets.

Umami polypeptide detection system targeting the human T1R1 receptor and its taste-presenting mechanism.

Umami is one of five basic tastes, the elucidation of its mechanism by the study of the interaction between umami polypeptides and hT1R1 umami receptors is of great significance. However, research on umami peptides targeting human T1R1 receptors is lacking, and the molecular mechanism remains elusive. Here, we successfully established a system to detect umami peptides targeting human T1R1 receptors by fluorescence spectroscopy, Surface Plasmon Resonance (SPR) and computational simulation. The sensory evaluation, calculated Kd value, and experimental affinity results between the four selected umami peptides (GRVSNCAA, KGDEESLA, KGGGGP, and TGDPEK) and glutamate were tested using this system, and all matched well. The maximum Ka value of GRVSNCAA was 479.55 M-1, and the minimum affinity of TGDPEK was 2.67 M-1. Computational simulations showed that the different peptide binding sites in the hT1R1 binding pocket occupied due to conformational changes are important factors for different taste thresholds, and that peptide hydrophobicity plays an important role in regulating affinity. Thus, our study enables rapid screening of high-intensity umami peptides and the development of T1R1 receptor-based umami detection sensors.

Efficacy and Safety of Ripretinib in Chinese Patients with Advanced Gastrointestinal Stromal Tumors as a Fourth- or Later-Line Therapy: A Multicenter, Single-Arm, Open-Label Phase II Study.

PURPOSE: This is a phase II multicenter, single-arm, open-label study assessing the efficacy, safety, and pharmacokinetics (PK) of ripretinib in Chinese patients with advanced gastrointestinal stromal tumor (GIST) as a fourth- or later-line therapy. It was designed to show consistency with the phase III INVICTUS study. PATIENTS AND METHODS: Patients with disease progression on (or intolerance to) prior imatinib, sunitinib, and at least one other drug were recruited to receive ripretinib 150 mg once daily continuously in 28-day cycles. The primary endpoint was progression-free survival (PFS) based on independent radiologic review (IRR). Secondary efficacy endpoints included objective response rate (ORR) based on IRR and overall survival. Safety endpoints included the incidence and severity of adverse events (AE). RESULTS: Between April 2020 and August 2020, 39 patients were enrolled. All were included in the safety analysis while 38 were included in the efficacy analysis. By primary data cut-off (February 26, 2021), the median PFS [90% confidence interval (CI)] was 7.2 (2.9-7.3) months; the lower bound of the 90% CI exceeded 1 month, fulfilling the standard of bridging success. The ORR (95% CI) based on IRR was 18.4% (7.7%-34.3%). Treatment-related treatment-emergent AEs (TRAE) were reported in 37 (94.9%) patients. The majority of TRAEs were of grade 1/2. A total of 6 patients (15.4%) experienced grade 3/4 TRAEs. CONCLUSIONS: The results demonstrated that ripretinib can clinically improve the outcomes of Chinese patients with advanced GIST as a fourth- or later-line therapy. The efficacy, safety, and PK profiles of ripretinib are consistent with those in the global patient population.

cep-1 mediated the mitohormesis effect of Shengmai formula in regulating Caenorhabditis elegans lifespan.

Ageing is one of the major causes of many diseases such as cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer. It has been found that mitochondrion acts as a crucial regulator of healthy lifespan. In this work, traditional Chinese medicine Shengmai formula (SMH) was used to treat mitochondrial mutants of Caenorhabditis elegans. The results showed that SMH shortened the lifespan of short-lived mev-1 mutant, but lengthened the lifespan of long-lived isp-1 mutant. Acute SMH treatment has benefit effect by increasing resistance capacity and motion activity in both ETC mutants and wild type N2. Compared with N2, the genome-wide transcriptome profile of ETC mutants showed on a similar pattern after SMH treatment. GO and KEGG enrichment analysis addressed that SMH-induced genes mainly enriched in metabolic process and oxidation-reduction process. The ROS levels in ETC mutants and N2 firstly rose then fell after SMH treatment, in company with the elevation of SOD-1, SOD-3 and GST-4, the increment of HSP-16.2 combined with heat shock. SMH increased oxygen consumption and ATP content, improved the restoration of mitochondrial homeostasis. SMH-induced opposed lifespan outcomes were markedly counteracted by cep-1 RNAi, together with the mitochondrial dynamics. Western blot assay also demonstrated a SMH-induced CEP-1 expression. Collectively, SMH acts as a prooxidant to regulate mitochondrial homeostasis and causes mitohormesis to exert therapeutic effect based on the redox background of the recipients, and cep-1 was required for the mitochondrial hormetic responses. The results shed a light on the rational clinical anti-ageing applications of SMH in the future.

Autophagy participates in germline cyst breakdown and follicular formation by modulating glycolysis switch via Akt signaling in newly-hatched chicken ovaries.

In females, the establishment of the primordial follicle pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. In this study, the role of autophagy was investigated to serve as a protective mechanism for oocyte survival during chicken folliculogenesis. Inhibition of autophagy by 3-methyladenine (3-MA) led to a remarkable delay in germ cell cyst breakdown that resulted in fewer primordial follicles and retarded sequent follicular development either in vivo or in the ovarian organ culture. Furthermore, the glycolysis level was downregulated in ovaries treated with 3-MA, while Recilisib (a specific activator of Akt) reversed this inhibiting effect of 3-MA on primordial folliculogenesis. Collectively, these data indicate that autophagy functions to maintain germ cell cyst breakdown and primordial follicle assembly by regulating ovarian glycolysis involving Akt signaling in the ovaries of newly-hatched chickens.