A Diagnostic Nomogram Incorporating Prognostic Nutritional Index for Predicting Vaginal Invasion in Stage IB - IIA Cervical Cancer.

INTRODUCTION: With the advancements in cancer prevention and diagnosis, the proportion of newly diagnosed early-stage cervical cancers has increased. Adjuvant therapies based on high-risk postoperative histopathological factors significantly increase the morbidity of treatment complications and seriously affect patients' quality of life. OBJECTIVES: Our study aimed to establish a diagnostic nomogram for vaginal invasion (VI) among early-stage cervical cancer (CC) that can be used to reduce the occurrence of positive or close vaginal surgical margins. METHODS: We assembled the medical data of early-stage CC patients between January 2013 and December 2021 from the Fujian Cancer Hospital. Data on demographics, laboratory tests, MRI features, physical examination (PE), and pathological outcomes were collected. Univariate and multivariate logistic regression analyses were employed to estimate the diagnostic variables for VI in the training set. Finally, the statistically significant factors were used to construct an integrated nomogram. RESULTS: In this retrospective study, 540 CC patients were randomly divided into training and validation cohorts according to a 7:3 ratio. Multivariate logistic analyses showed that age [odds ratio (OR) = 2.41, 95% confidence interval (CI), 1.29-4.50, P = 0.006], prognostic nutritional index (OR = 0.18, 95% CI, 0.04-0.77, P = 0.021), histological type (OR = 0.28, 95% CI, 0.08-0.94, P = 0.039), and VI based on PE (OR = 3.12, 95% CI, 1.52-6.45, P = 0.002) were independent diagnostic factors of VI. The diagnostic nomogram had a robust ability to predict VI in the training [area under the receiver operating characteristic curve (AUC) = 0.76, 95% CI: 0.70-0.82] and validation (AUC = 0.70, 95% CI: 0.58-0.83) cohorts, and the calibration curves, decision curve analysis, and confusion matrix showed good prediction power. CONCLUSION: Our diagnostic nomograms could help gynaecologists quantify individual preoperative VI risk, thereby optimizing treatment options, and minimizing the incidence of multimodality treatment-related complications and the economic burden.

The management of uterine tumor resembling an ovarian sex cord tumor (UTROSCT): case series and literature review.

AIMS: To present a case series of 11 rare uterine tumors resembling ovarian sex cord tumors (UTROSCTs), and review the literature on this topic to offer up-to-date treatment management for UTROSCTs. METHOD: Eight cases from Fujian Cancer Hospital between January 2017 and May 2023 and three patients from Fujian Union Hospital between October 2012 and October 2020 were retrospectively reviewed. All cases were pathologically confirmed as UTROSCTs by two senior and experienced pathologists. Clinical behaviors, medical data, histopathological features, therapy approaches, and survival outcomes were discussed. RESULTS: The median age at initial diagnosis was 53 years (29-70 years). 3 (27.3%) patients were under 40. Seven cases presented with abnormal vaginal bleeding, one with menstrual disorder, one with abnormal vaginal secretion, and two patients were accidentally found by physical examination without any symptoms. Three patients were initially misdiagnosed with endometrial cancer by MRI. Curettage was performed in all cases. Nine of them were well diagnosed by routine curettage, except for two samples, which were identified after surgery. Immunohistochemical biomarkers, such as CD99, Desmin, WT-1, CK, Vimentin, SMA, α-Inhibin, Ki67, CD56, ER, PR, and CR, tend to be positive in UTRO SCs patients. Six patients underwent hysterectomy with bilateral salpingo-oophorectomy. Two cases received a radical hysterectomy with bilateral salpingo-oophorectomy, retroperitoneal lymph node dissection, and omentum dissection. Three UTROSCTs were under observation after mass resection. The median PFS was 24 months (range 1-125 months). CONCLUSION: UTROSCT is a rare mesenchymal tumor with low malignant potential. Treatment modalities should be carefully considered to balance the therapy outcomes and patient needs. Surgery conservative management might be suitable for young women with fertility desires.

A novel complementary pathway of cordycepin biosynthesis in Cordyceps militaris.

We determined whether there exists a complementary pathway of cordycepin biosynthesis in wild-type Cordyceps militaris, high-cordycepin-producing strain C. militaris GYS60, and low-cordycepin-producing strain C. militaris GYS80. Differentially expressed genes were identified from the transcriptomes of the three strains. Compared with C. militaris, in GYS60 and GYS80, we identified 145 and 470 upregulated and 96 and 594 downregulated genes. Compared with GYS80, in GYS60, we identified 306 upregulated and 207 downregulated genes. Gene Ontology analysis revealed that upregulated genes were mostly involved in detoxification, antioxidant, and molecular transducer in GYS60. By Clusters of Orthologous Groups of Proteins and Kyoto Encyclopedia of Genes and Genomes analyses, eight genes were significantly upregulated: five genes related to purine metabolism, one to ATP production, one to secondary metabolite transport, and one to RNA degradation. In GYS60, cordycepin was significantly increased by upregulation of ATP production, which promoted 3',5'-cyclic AMP production. Cyclic AMP accelerated 3'-AMP accumulation, and cordycepin continued to be synthesized and exported. We verified the novel complementary pathway by adding the precursor adenosine and analyzing the expression of four key genes involved in the main pathway of cordycepin biosynthesis. Adenosine addition increased cordycepin production by 51.2% and 10.1%, respectively, in C. militaris and GYS60. Four genes in the main pathway in GYS60 were not upregulated.

Degradation of de-esterified pctin/homogalacturonan by the polygalacturonase GhNSP is necessary for pollen exine formation and male fertility in cotton.

The pollen wall exine provides a protective layer for the male gametophyte and is largely composed of sporopollenin, which comprises fatty acid derivatives and phenolics. However, the biochemical nature of the external exine is poorly understood. Here, we show that the male sterile line 1355A of cotton mutated in NO SPINE POLLEN (GhNSP) leads to defective exine formation. The GhNSP locus was identified through map-based cloning and confirmed by genetic analysis (co-segregation test and allele prediction using the CRISPR/Cas9 system). In situ hybridization showed that GhNSP is highly expressed in tapetum. GhNSP encodes a polygalacturonase protein homologous to AtQRT3, which suggests a function for polygalacturonase in pollen exine formation. These results indicate that GhNSP is functionally different from AtQRT3, the latter has the function of microspore separation. Biochemical analysis showed that the percentage of de-esterified pectin was significantly increased in the 1355A anthers at developmental stage 8. Furthermore, immunofluorescence studies using antibodies to the de-esterified and esterified homogalacturonan (JIM5 and JIM7) showed that the Ghnsp mutant exhibits abundant of de-esterified homogalacturonan in the tapetum and exine, coupled with defective exine formation. The characterization of GhNSP provides new understanding of the role of polygalacturonase and de-esterified homogalacturonan in pollen exine formation.

A comprehensive pan-cancer analysis of necroptosis molecules in four gynecologic cancers.

BACKGROUND: In recent years, it has been proved that necroptosis plays an important role in the occurrence, development, invasion, metastasis and drug resistance of malignant tumors. Hence, further evaluation and targeting of necroptosis may be of clinical benefit for gynecologic cancers (GCs). METHODS: To compare consistency and difference, we explored the expression pattern and prognostic value of necroptosis-related genes (NRGs) in pan-GC analysis through Linear regression and Empirical Bayesian, Univariate Cox analysis, and public databases from TCGA and Genotype-Tissue Expression (GTEx), including CESC, OV, UCEC, and UCS. We explored the copy number variation (CNV), methylation level and enrichment pathways of NRGs in the four GCs. Based on LASSO Cox regression analysis or principal component analysis, we established the prognostic NRG-signature or necroptosis-score for the four GCs. In addition, we predicted and compared functional pathways, tumor mutational burden (TMB), somatic mutation features, immunity status, immunotherapy, chemotherapeutic drug sensitivity of the NRG-signature based on NRGs. We also examined the expression level of several NRGs in OV samples that we collected using Quantitative Real-time PCR. RESULTS: We confirmed the presence of NRGs in expression, prognosis, CNV, and methylation for four GCs, thus comparing the consistency and difference among the four GCs. The prognosis and independent prognostic value of the risk signatures based on NRGs were determined. Through the results of subclass mapping, we found that GC patients with lower risk score may be more sensitive to PDL1 response and more sensitive to immune checkpoint blockade therapy. Drug susceptibility analysis showed that, 51, 45, 64, and 29 drugs with differences between risk groups were yielded in CESC, OV, UCEC, and UCS respectively. For OV, the expression differences of several NRGs in the tissues we collected were similar to that in TCGA. CONCLUSION: Our comprehensive analysis of NRGs and NRG-signature demonstrated their similarity and difference, as well as their potential roles in prognosis and could guide therapeutic strategies, thus improving the outcome of GC patients.

Self-Assembled pH-Responsive Metal-Organic Frameworks for Enhancing the Encapsulation and Anti-Oxidation and Melanogenesis Inhibition Activities of Glabridin.

Metal organic frameworks (MOFs) are formed by self-assembly of metal ions and organic ligands. A special type of MOF called ZIF-8, which is formed by self-assembly of zinc ions and 2-methylimidazole, shows excellent stability in aqueous solutions and disintegrates under acidic conditions. These properties make ZIF-8 a suitable carrier material for pH-stimulated drug delivery systems. Glabridin is an isoflavane compound that is widely present in the roots of licorice. Because of its outstanding skin whitening properties, glabridin is widely used as a whitener in the cosmetics industry. In this study, ZIF-8 was employed to encapsulate glabridin. Glabridin-loaded ZIF-8 was successfully prepared with a drug encapsulation efficiency of 98.67%. The prepared sample showed a fusiform or cruciate flower-like structure, and its size was about 3 µm. ZIF-8 enabled pH-controlled release of glabridin. Moreover, ZIF-8 encapsulation significantly enhanced the intracellular anti-oxidant activity and melanogenesis inhibitory activity of glabridin. This study provides a new approach that shows great potential to improve the biological application of glabridin.

[Gene variant analysis of a fetus with autosomal recessive polycystic kidney disease].

OBJECTIVE: To explore the genetic basis for a fetus with autosomal recessive polycystic kidney disease (ARPKD). METHODS: Fetal tissue and peripheral blood samples were respectively obtained from the abortus and the couple. Following extraction of genomic DNA, genetic testing was carried out. RESULTS: The fetus was found to carry compound heterozygous variants of the PKHD1 gene, namely c.5336A>T (p.N1779I) and c.9455delA (p.N3152Tfs*10), which were respectively inherited from the husband and wife. CONCLUSION: The c.5336A>T and c.9455delA variants of the PKHD1 gene probably account for the ARPKD in the fetus. Above results have enabled genetic counseling and prenatal diagnosis for the couple.

Positively Charged Polyprodrug Amphiphiles with Enhanced Drug Loading and Reactive Oxygen Species-Responsive Release Ability for Traceable Synergistic Therapy.

Due to the vast differences in chemical properties among small molecule drugs, nucleotide drugs, and superparamagnetic iron oxide nanocubes (SPIONs), such as charge and hydrophobicity, entrapment of these within a single carrier for traceable synergistic therapy has been proven difficult. Herein, we synthesize positively charged polyprodrug amphiphiles. The hydrophobic polyprodrug unit of the amphiphiles is positively charged, which can simultaneously load hydrophobic SPIONs and absorb negative let-7b antisense oligonucleotide to construct traceable co-delivery nanoparticles (NPs). This characteristic avoids the use of inert materials and enhances drug loading of the traceable NPs. The traceable NPs can achieve controlled release of drugs to reduce the differentiation of exogenous neural stem cells (NSCs) and enhance their secretion of brain-derived neurotrophic factor (BDNF) synergistically. Exogenous NSCs treated with the NPs significantly rescue the memory deficits in 2xTg-AD mice. In addition, the transplantation site and migration of exogenous NSCs can be traced using the SPIONs with high r2 value for magnetic resonance imaging. Therefore, traceable NPs self-assembled from the positively charged polyprodrug amphiphiles may have the potential to open up a new avenue for treatment of Alzheimer's disease (AD), as well as other neurodegenerative disorders.

The effectiveness of creatine treatment for Parkinson's disease: an updated meta-analysis of randomized controlled trials.

BACKGROUND: The effectiveness of creatine in treating Parkinson's disease (PD) has not been conclusively determined. Therefore, we performed a meta-analysis to address this issue. METHODS: The Cochrane Central Register of Controlled Trials, PUBMED, EMBASE, and other databases were searched, and outcomes measured by the Total Unified Parkinson's Disease Rating Scale (UPDRS) and the Schwab & England Scale were analyzed. RESULTS: Five randomized controlled trials (RCTs) were selected, and 1339 participants were included in the analysis. There were no significant differences between the control and treatment groups in the total, mental, activities of daily living (ADL), or motor UPDRS scores, but an improvement in Schwab & England Scale scores was observed. CONCLUSIONS: Creatine has no observed benefit in PD patients, although more correlated studies are still needed.

Interaction between charged nanoparticles and vesicles: coarse-grained molecular dynamics simulations.

An enhanced understanding of the interactions between charged nanoparticles (CNPs) and a curved vesicle membrane may have important implications for the design of nanocarrier agents and drug delivery systems. In this work, coarse-grained molecular dynamics (CGMD) simulations of the CNPs with vesicles were performed to evaluate the effects of hydrophobicity, surface charge density and distribution on the curved vesicle membrane. The simulations reveal that there exist four distinct modes (insertion, repulsion, adhesion, and penetration) in the CNP-vesicle interaction. In contrast to previous studies on a planar membrane, the interactions of CNPs and a curved vesicle membrane show some novel properties. CNPs with low surface charge density (or neutral ones) can penetrate into the interior of the vesicle membrane more easily because of the increased membrane tension. The asymmetry between two leaflets of the membrane induces different interaction strengths of the negatively CNPs with the outer and inner leaflets. After penetration, the negatively CNPs prefer to stay close to the inner leaflet inside the vesicle where CNPs have stronger interactions with their surroundings. In the present work, we analyze the detailed mechanism of CNP's spontaneous penetration into vesicles, which is rarely mentioned in previous simulations. Moreover, we found that the negatively CNPs with the same surface charge density but different distribution result in different modes: the homogeneous mode is more likely to adsorb on the vesicle surface while the inhomogeneous mode tends to be more penetrable. In addition, the flip-flop phenomenon of the lipid membrane and the exchanging of water in or out of the vesicle were observed during penetration. Our results demonstrate that the electrostatic effect plays an essential role in the interaction between CNPs and vesicles. These findings suggest a way of controlling the CNP-vesicle interaction by coupling the hydrophobic properties, surface charge density and distribution of CNPs to enhance the probability of CNP's penetration into vesicles.

A novel nomogram based on inflammation biomarkers for predicting radiation cystitis in patients with local advanced cervical cancer.

BACKGROUNDS: Platelet-to-albumin ratio (PAR) is a new systemic inflammatory prognostic indicator associated with many inflammatory diseases. However, its role in radiation cystitis (RC) is obscure. This study aimed to explore whether PAR could be used as an effective parameter for predicting the RC risk in local advanced cervical cancer (CC) treated with radiotherapy. METHODS: A total of 319 local advanced CC patients who received radical radiotherapy at Fujian Cancer Hospital were enrolled between December 2018 and January 2021. Demographics and clinical parameters were retrospectively analyzed. Univariate and multivariate analyses were used to identify the risk factors for RC. Backward and stepwise regression was applied to construct two monograms-one with primary significant factors and the other with extra inflammatory biomarkers. A DeLong test was applied to compare the prediction abilities of two nomograms. Calibration curves and decision curve analysis (DCA) evaluated its prediction consistency, discrimination ability, and clinical net benefit. RESULTS: Univariate analysis showed that age, tumor size, stage, total radiation dose, pelvic radiation dose, Systemic Immune-Inflammation Index (SII), platelet-to-lymphocyte ratio (PLR), and PAR were significantly associated with RC occurrence (all p < 0.05). Multivariate analyses indicated that age, tumor size, stage, total radiation dose, and PAR were independent factors (all p < 0.05). Then, the area under curve (AUC) value of the nomogramSII+PAR was higher (AUC = 0.774) compared to that of the baseline nomogram (AUC = 0.726) (pDelong = 0.02). Also, the five-cross validation confirmed the stability of the nomogramSII+PAR. Moreover, the calibration curve and DCA exhibited the nomograms' good prediction consistency and clinical practicability. CONCLUSIONS: PAR and SII could be valued for CC patients who are treated with radiation therapy. The nomogram based on PAR and SII could stratify patients who need extra intervention and nursing care to prevent bladder radiation damage and improve patients' quality of life.

Survival analysis of gynecological cancers in Southeast China, 2011-2020: A population-based study.

PURPOSE: To analyze the survival outcomes of female patients with cervical, uterine, and ovarian cancers in Southeast China (Fujian Province) from 2011 to 2020 and to provide a reference basis for prognostic evaluation and prevention of gynecological malignancies. METHODS: The data of 5823 patients with cervical, uterine, and ovarian cancers registered in the Fujian Provincial Cancer Prevention and Control System from 2011 to 2020 were enrolled for survival analysis and further stratified by age at diagnosis and township. Survival time was calculated up to March 30, 2022, and relative survival (RS) and age-standardized RS were calculated according to the International Cancer Survival Standards (ICSS). RESULTS: During 2011-2015, the 5-year RS for cervical, uterine, and ovarian cancers were 64.3 %, 64.2 %, and 44.7 %, respectively, while the age-standardized 5-year RS were 56.8 %, 47.9 %, and 27.9 %, respectively. During 2016-2020, the 5-year RS for cervical, uterine, and ovarian cancers were 72.3 %, 78.9 %, and 50.8 %, respectively, while the age-standardized 5-year RS were 64.5 %, 54.6 %, and 34.2 %, respectively. The 5-year RS for cervical and ovarian cancer all declined with age, while the 5-year RS for uterine cancer was highest at 45-54 years and lowest at 75 years. In addition, survival rates were broadly higher in urban than rural areas. CONCLUSION: Survival rates for cervical, uterine, and ovarian cancers have generally increased in the population covered by the Fujian Cancer Registry. However, survival rates remain lower than in developed countries. Emphasis should be placed on gynecological cancer screening and the introduction of effective treatments to improve survival rates for gynecological cancers.

Trends in incidence and mortality for gynaecological cancers in Southeastern China during 2011-2020: a retrospective analysis of registry data.

OBJECTIVES: This study aimed to investigate the changes in the incidence and mortality trends of ovarian cancer (OC), cervical cancer (CC) and uterine cancer (UC) in the Fujian Province, southeastern China. DESIGN: Provincial, population-based, retrospective observational study. SETTING: Fujian province, southeastern China between 2011-2020. PARTICIPANTS: From 2011 to 2020, 6178 new cases and 2037 deaths caused by 3 gynaecological cancers were eligible for analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measures were the incidence and mortality rates, including the age-standardised incidence rate (ASIR) and age-standardised mortality rate (ASMR), of three gynaecological cancers. The secondary outcome measure was the prevalence (average annual per cent changes (AAPC)). RESULTS: The incidence of all three gynaecological cancers increased from 2011 to 2020. CC had the slowest upward trend, with an AAPC of 2.54% over the period. However, it had the highest ASIR among the 3 cancers in 2020 (10.41/100 000). UC showed a rapid increase, with an AAPC of 15.15% from 2016 to 2020. While the mortality rate of UC remained stable, both CC and OC also exhibited rising trends, with the CC having the highest ASMR (3.05/100 000) in 2020. The ASMR for CC increased rapidly, with the highest AAPC of 5.51%. Conversely, changes in the ASMR for UC were not statistically significant (p=0.601). Moreover, high incidence rates were more common among perimenopausal women and older participants in the respective cancer groups where the increased mortality was observed. CONCLUSIONS: Gynaecological cancer burden remains a public health issue in Fujian Province, with an increasing incidence. Improving the healthcare system and promoting a healthy lifestyle should be highlighted to reduce the cancer burden.

Identification of Disulfidptosis-Related LncRNA Subtypes, Establishment of a Prognostic Signature, and Characterization of Immune Infiltration in Ovarian Cancer.

BACKGROUND: Ovarian Cancer (OC) is a lethal malignant tumor with a poor prognosis. Disulfidptosis is a newly identified form of cell death caused by disulfide stress. Targeting disulfidptosis is a new metabolic therapeutic strategy in cancer treatment. We aimed to establish a disulfidptosis- related lncRNA signature for prognosis prediction and explore its treatment values in OC patients. METHOD: Data from the TCGA and GTEx databases and a disulfidptosis gene set were used to establish a disulfidptosis-related lncRNA signature for prognosis prediction in OC patients. Then, we internally and externally (PCR) validated our model. We also built a nomogram to improve our model's predictive power. Afterward, GSEA was employed to explore our model's potential functions. The ESTIMATE, CIBERSORT, TIMER, and ssGSEA were applied to estimate the immune landscape. Finally, the drug sensitivity of certain drugs for OC patients was analyzed. RESULTS: We built a prognosis model based on seven drlncRNAs, including AL157871.2, HCP5, AC027348.1, AL109615.3, AL928654.1, LINC02585, and AC011445.1. Our model performed well by internal validation. PCR data also confirmed the same trend in the lncRNA levels. Furthermore, the nomogram-integrated age, grade, stage, and risk score could accurately predict the survival outcomes of OC patients. Subsequently, GSEA unveiled that our model genes enriched the Hedgehog signaling pathway, a key regulator in OC tumorigenesis. Our predictive signature was associated with immune checkpoints, such as PD-1(P < 0.01), PD-L1(P < 0.001), and CTLA4 (P < 0.01), which might help screen out OC patients who are sensitive to immunotherapy. Small molecule drugs, such as AZD-2281, GDC-0449, imatinib, and nilotinib, might benefit OC patients with different risk scores. CONCLUSION: Our disulfidptosis-related lncRNA signature comprised of AL157871.2, HCP5, AC027348.1, AL109615.3, AL928654.1, LINC02585, and AC011445.1 could serve as a prognostic biomarker and guidance to therapy response for OC patients.

Causes of death analysis and the prognostic model construction in neuroendocrine carcinoma of the cervix: A SEER-based study.

PURPOSE: Neuroendocrine carcinoma of the cervix (NECC) is rare but results in poor prognosis. The causes of death (CODs) in NECC patients are rarely reported. Our study aimed to explore the distributions of death causes of NECC patients compared with squamous cell carcinoma (SCC) and adenocarcinoma (ADC) and to develop a validated survival prediction model. METHODS: Patients diagnosed with NECC, SCC, or ADC were identified from the Surveillance, Epidemiology, and End Results Program database from 1975 to 2019. We analyzed the standardized mortality ratio (SMR) to determine each cause of death for each survival time category. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate Cox regression analyses were used to establish a nomogram model. RESULTS: A total of 358 NECC patients were included in this study, and 270 (75.4%) died during the follow-up period. Patients with NECC had 5.55 times (95% CI, 4.53-6.79, p < 0.0001) higher risk of death compared with patients with SCC and 10.38 times (95% CI, 8.28-13.01, p < 0.0001) higher compared with ADC. Cervical cancer is the main cause of death in NECC. As the diagnosis time increased, the risk of death from all causes and cervix cancer gradually decreased. While after at least 10 years of follow-up time, the highest and most dramatical SMR values were observed for metastasis (SMR, 138.81; 95% CI, 37.82-355.40; p < 0.05) and other cancers as the reason for death has an over 7-fold higher SMR (SMR: 7.07; 95% CI: 2.60-15.40, p < 0.05) more than 5 years after the cancer diagnosis. Race, FIGO stage, and surgery were independent risk factors for the overall survival (OS) of NECC patients. For the predictive nomogram, the C-index was 0.711 (95% CI: 0.697-0.725) and was corrected to 0.709 (95% CI: 0.680, 0.737) by bootstrap 1000 resampling validation. CONCLUSION: Compared with SCC and ADC, NECC patients have an elevated risk of mortality due to cervical cancer and metastasis. We successfully constructed a prognostic nomogram for patients with NECC. Based on refractoriness and high mortality of NECC, targeted treatment strategies and follow-up plans should be further developed according to the risk of death and distribution characteristics of CODs.

Notch 2 signaling contributes to intestinal eosinophil adaptations in steady state and tissue burden following oral allergen challenge.

Eosinophils not only function as inflammatory effectors in allergic diseases, but also contribute to tissue homeostasis in steady state. Emerging data are revealing tissue eosinophils to be adaptive cells, imprinted by their local tissue microenvironment and exhibiting distinct functional phenotypes that may contribute to their homeostatic vs. inflammatory capacities. However, signaling pathways that regulate eosinophil tissue adaptations remain elusive. Notch signaling is an evolutionarily conserved pathway that mediates differential cell fate programming of both pre- and postmitotic immune cells. This study investigated a role for notch receptor 2 signaling in regulating eosinophil functions and tissue phenotype in both humans and mice. Notch 2 receptors were constitutively expressed and active in human blood eosinophils. Pharmacologic neutralization of notch 2 in ex vivo stimulated human eosinophils altered their activated transcriptome and prevented their cytokine-mediated survival. Genetic ablation of eosinophil-expressed notch 2 in mice diminished steady-state intestine-specific eosinophil adaptations and impaired their tissue retention in a food allergic response. In contrast, notch 2 had no effect on eosinophil phenotype or tissue inflammation within the context of allergic airways inflammation, suggesting that notch 2-dependent regulation of eosinophil phenotype and function is specific to the gut. These data reveal notch 2 signaling as a cell-intrinsic mechanism that contributes to eosinophil survival, function, and intestine-specific adaptations. The notch 2 pathway may represent a viable strategy to reprogram eosinophil functional phenotypes in gastrointestinal eosinophil-associated diseases.

Evidence for Regulation of Cordycepin Biosynthesis by Transcription Factors Krüppel-Like Factor 4 and Retinoid X Receptor Alpha in Caterpillar Medicinal Mushroom Cordyceps militaris (Ascomycetes).

Cordyceps militaris, Chinese traditional medicinal fungus, has many bioactive properties. Cordycepin (3'-deoxyadenosine) is a major bioactive component of C. militaris. Various methods can significantly elevate cordycepin production, which suggests a diverse set of metabolic regulatory mechanisms. Thus, we aimed to identify transcription factors that regulate cordycepin biosynthesis pathways. Transcriptome analysis of wild-type C. militaris, C. militaris GYS60, a cordycepin high-producing strain, and C. militaris GYS80, a low-producing strain, were used to measure expression and function of genes related to cordycepin biosynthesis. The transcriptome expression data were confirmed by quantitative real-time polymerase chain reaction. We identified 155 relevant transcription factors in 19 families that included Fork head/winged helix factors, other C4 zinc finger-type factors, C2H2 zinc finger factors, tryptophan cluster factors, nuclear receptors with C4 zinc fingers, homeodomain factors, and Rel homology region factors. Energy generation and amino acid conversion pathways were activated in GYS60 so that abundance of cordycepin precursors was increased. Genes and transcription factors for rate-limiting enzymes in these pathways were identified. Overexpression of two key transcription factors, Kruppel-like factor 4 (Klf4) and Retinoid X receptor alpha (Rxra), promoted high cordycepin production in GYS60. In GYS60, Klf4 and Rxra were responsible for upregulation of genes in cordycepin biosynthesis, namely an oxidoreductase, 3',5'-cyclic AMP phosphodiesterase, a transferase, and adenylate cyclase. Upregulation of these genes increased 3'-AMP content, thereby elevating cordycepin synthesis.

A novel nomogram and risk stratification for early metastasis in cervical cancer after radical radiotherapy.

OBJECT: This study aimed to establish an effective risk nomogram to predict the early distant metastasis (EDM) probability of cervical cancer (CC) patients treated with radical radiotherapy to aid individualized clinical decision-making. METHODS: A total of 489 patients with biopsy-confirmed CC between December 2018 and January 2021 were enrolled. Logistic regression with the stepwise backward method was used to identify independent risk factors. The nomogram efficacy was evaluated by using the area under the receiver operating characteristic curve (AUC), C-index by 1000 bootstrap replications, etc. Finally, patients were divided into high- and low-risk groups of EDM based on the cut-off value of nomogram points. RESULTS: 36 (7.36%) CC patients had EDM, and 20 (55.6%) EDM had more than one metastatic site involved. Age below 51 (OR = 2.298, p < 0.001), tumor size larger than 4.5 cm (OR = 3.817, p < 0.001) and radiotherapy (OR = 3.319, p < 0.001) were independent risk factors of EDM. For the nomogram model, C-index was 0.701 (95% CI = 0.604-0.798), and 0.675 (95% CI = 0.578-0.760) after 1000 bootstrap resampling validations. The Hosmer-Lemeshow test demonstrated no overfitting (p = 0.924). According to the Kaplan-Meier curve of risk score, patients with high risk were more prone to get EDM (p < 0.001). CONCLUSION: This is the first research to focus on EDM in CC patients. We have developed a robust scoring system to predict the risk of EDM in CC patients to screen out appropriate cases for consolidation therapy and more intensive follow-up.

Nomograms constructed for predicting diagnosis and prognosis in cervical cancer patients with second primary malignancies: a SEER database analysis.

PURPOSE: Cervical cancer (CC) patients are more likely to develop second primary malignancies (SPMs) than general population. With the advancement in cancer therapy, CC patients are achieving long-term survival, leading SPMs to our attention. Our study aims to establish diagnostic and prognostic nomograms for CC patients with second primary malignancies (CCSPMs) to help make personalized follow-up plans and treatments. METHODS: Data of CCSPMs between 2000 and 2019 was extracted from SEER. The proportions and the median interval time of CCSPM onset were calculated. 11 related clinical characteristics, including age, race, marital status, grade, FIGO stage, radiotherapy, chemotherapy, and surgery, were further explore. Logistic and Cox regressions were employed to predict risk factors for CCSPMs diagnosis. Finally, two nomograms were developed to predict the probability occurrence and prognosis of CCSPMs, respectively. RESULTS: For diagnostic nomogram construction, 59,178 CC patients were randomly divided into training (n = 41,426) and validation cohorts (n = 17,752). For prognostic nomogram construction, 3527 CCSPMs patients were randomly divided into training (n = 2469) and validation cohorts (n = 1058). The diagnostic nomogram consisting of above 11 independent risk factors (all P < 0.05), had high accuracy (AUCtraining = 0.851 and AUCvalidating = 0.845). The prognostic nomogram integrated with eight independent prognostic factors such as treatments, FIGO stage and TNM stage performed well in predicting 5-year OS (AUCtraining = 0.835 and AUCvalidating = 0.837). CONCLUSION: Our diagnostic and prognostic nomograms could facilitate clinicians to quantify individual SPMs risk and survival probabilities and optimize the surveillance recommendations and personalized clinical decision-making.

[The nuclear translocation of circRNA CPSF6 promotes apoptosis of trophoblast cells induced by homocysteine].

Objective To investigate the role of circular RNA cleavage and polyadenylation specificity factor 6 (circRNA CPSF6) in the apoptosis of trophoblast cells induced by homocysteine (Hcy) and its mechanism. Methods HTR-8/SVneo human chorionic trophoblast cells were cultured in vitro and divided into control group (0 mmol/L Hcy treatment) and 1 mmol/L Hcy treatment group. Immunofluorescence cytochemical staining was used to detect the expression of caspase-3 in trophoblasts, and Western blot analysis was used to detect the caspase-3 protein level. The mRNA expression level of circRNA CPSF6 was detected by real-time quantitative PCR. Small interfering RNA (siRNA) was used to knock down the expression of circRNA CPSF6 in trophoblast cells. The expressions of caspase-3, caspase-9, Bcl2, and BAX were detected by Western blot analysis. Real-time quantitative PCR was used to detect the expression level of circRNA CPSF6 in the cytoplasm/nucleus of trophoblast cells before and after Hcy treatment. Results Compared with those in the control group, the expressions of caspase-3 and circRNA CPSF6 mRNA in the Hcy treatment group significantly increased. After knocking down circRNA CPSF6, the expression of caspase-3 decreased, and the mitochondrial apoptosis pathway was inhibited. In normal cultured trophoblast cells, circRNA CPSF6 was expressed in large amounts in the cytoplasm, and after Hcy treatment, circRNA CPSF6 was mainly expressed in the nucleus. Conclusion The mitochondrial apoptotic pathway is activated by circRNA CPSF6 nuclear translocation to promote trophoblast apoptosis induced by Hcy.