Development and validation of a nomogram for predicting sever cancer-related fatigue in patients with cervical cancer.

OBJECTIVE: Cancer-related fatigue (CRF) has been considered the biggest influencing factor for cancer patients after surgery. This study aimed to develop and validate a nomogram for severe cancer-related fatigue (CRF) patients with cervical cancer (CC). METHODS: A cross-sectional study was conducted to develop and validate a nomogram (building set = 196; validation set = 88) in the Department of Obstetrics and Gynecology of a Class III hospital in Shenyang, Liaoning Province. We adopted the questionnaire method, including the Cancer Fatigue Scale (CFS), Medical Uncertainty in Illness Scale (MUIS), Medical Coping Modes Questionnaire (MCMQ), Multidimensional Scale of Perceived Social Support (MSPSS), and Sense of Coherence-13 (SOC-13). Binary logistic regression was used to test the risk factors of CRF. The R4.1.2 software was used to develop and validate the nomogram, including Bootstrap resampling method, the ability of Area Under Curve (AUC), Concordance Index (C-Index), Hosmer Lemeshow goodness of fit test, Receiver Operating Characteristic (ROC) curve, Calibration calibration curve, and Decision Curve Analysis curve (DCA). RESULTS: The regression equation was Logit(P) = 1.276-0.947 Monthly income + 0.989 Long-term passive smoking - 0.952 Physical exercise + 1.512 Diagnosis type + 1.040 Coping style - 0.726 Perceived Social Support - 2.350 Sense of Coherence. The C-Index of the nomogram was 0.921 (95% CI: 0.877∼0.958). The ROC curve showed the sensitivity of the nomogram was 0.821, the specificity was 0.900, and the accuracy was 0.857. AUC was 0.916 (95% CI: 0.876∼0.957). The calibration showed that the predicted probability of the nomogram fitted well with the actual probability. The DCA curve showed when the prediction probability was greater than about 10%, the benefit of the nomogram was positive. The results in the validation group were similar. CONCLUSION: This nomogram had good identifiability, accuracy and clinical practicality, and could be used as a prediction and evaluation tool for severe cases of clinical patients with CC.

Successful treatment of recalcitrant generalized pustular psoriasis of pregnancy with spesolimab.

Generalized pustular psoriasis (GPP) in pregnancy can lead to severe complications for both mother and fetus. The treatment of this disease is challenging, especially in recalcitrant and severe cases. Until present, there are no evidence-based guidelines for the treatment of GPP in pregnancy. Spesolimab, a human monoclonal antibody against the IL-36 receptor, has recently attracted attention as a new therapy for GPP flare. This biologic provides rapid and sustained control of symptoms of GPP flare, although its use in pregnant women has not been reported to date. Here, we report a pregnant woman with refractory GPP who did not respond well to systemic steroids. Administration of spesolimab resulted in complete control of the disease and the birth of a healthy baby. Our case demonstrates that IL-36RN inhibitors are a potentially effective and safe treatment option for GPP in pregnancy.

Configurational paths to turnover intention among primary public health workers in Liaoning Province, China: a fuzzy-set qualitative comparative analysis.

BACKGROUND: A stable public health workforce plays an indispensable role in the realization of the goal of health for all. However, there is an exodus of public health workers from the Centers for Disease Control and Prevention (CDC). Given the limited evidence on the mechanisms shaping turnover intention (TI) among public health workers, the study aims to investigate the triggering mechanisms of high and low turnover intention by combining job demands, job resources, and personal resources through a set theory perspective based on the Job-Demand-Resources (JD-R) model. METHODS: The cross-sectional study was conducted from September 7 to 18, 2020 at district (county) level CDC in Liaoning Province, China. A total of 584 public health professionals were included. Overcommitment, effort, social respect, occupational identity, job rewards, self-efficacy, and psychological resilience were included in the study as configuration factors. The data were gathered through an online questionnaire and were analyzed using multiple regression and fuzzy-set Qualitative Comparative Analysis (fsQCA). RESULTS: Social respect (B = -0.682, P < 0.001), occupational identity (B = -0.168, P < 0.001), and effort (B = 0.114, P < 0.001) were associated with turnover intention. Five configurations for high turnover intention and five for low turnover intention were obtained through the fsQCA, with occupational identity and effort playing an essential role in all pathways. Moreover, the configurations for low turnover intention are not the antithesis of the configurations for high turnover intention. CONCLUSION: Managers should synthesize the combined effects of factors when implementing interventions and formulating policies. Given the vital role of occupational identity and effort, mechanisms for the rational distribution of work to avoid excessive efforts and measures to promote occupational identity should be implemented to reduce the turnover intentions of primary public health workers and encourage their intention to stay.

PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism.

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

Interaction of anxiety and hypertension on quality of life among patients with gynecological cancer: a cross-sectional study.

BACKGROUND: Patients with gynecological cancer are prone to anxiety, and many of them are accompanied by hypertension, which seriously affects the quality of life (QOL). The study was to explore the interaction of anxiety and hypertension on QOL, and the moderating effect of perceived social support (PSS) in the impact of anxiety and hypertension on QOL of patients with gynecological cancer. METHODS: A cross-sectional study was conducted in 2020, and 566 patients have been collected from the Affiliated Hospital of China Medical University. The Self-Rating Anxiety Scale (SAS), the Functional Assessment of Cancer Therapy Genera tool (FACT-G), and the Multidimensional Scale of Perceived Social Support Scale (MSPSS) were used. The interaction was analyzed by additive model, and the moderating effect was conducted by regression analysis and the simple slope analysis. RESULTS: We found that 68.8% of patients had poor QOL due to the interaction between anxiety and hypertension. The relative excess risk ratio (RERI) was 22.238 (95%CI:44.119-88.596); the attribution ratio (AP) was 0.688 (95%CI:0.234-1.142); The interaction index (S) was 3.466 (95%CI: 0.823-14.435). The interaction items of PSS and anxiety were negatively correlated with QOL (ß = -0.219, P < 0.01) and explained an additional 4.0% variance (F = 68.649, Adjusted R2 = 0.399, ΔR2 = 0.040, P < 0.01); PSS and blood pressure interaction item was not associated with QOL (ß = 0.013, F = 55.138, Adjusted R2 = 0.365, ΔR2 = 0.001, P = 0.730). CONCLUSIONS: When anxiety and hypertension coexist, the QOL was affected. PSS played a moderating role in the impact of anxiety on QOL. Healthcare providers should take intervention measures to improve patients' social support to reduce the impact of anxiety on QOL.

Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers.

The resistance to drugs, ability to enter quiescence and generate heterogeneous cancer cells, and enhancement of aggressiveness, make cancer stem cells (CSCs) integral part of tumor progression, metastasis and recurrence after treatment. The epigenetic modification machinery is crucial for the viability of CSCs and evolution of aggressive forms of a tumor. These mechanisms can also be targeted by specific drugs, providing a promising approach for blocking CSCs. In this review, we summarize the epigenetic regulatory mechanisms in CSCs which contribute to drug resistance, quiescence and tumor heterogeneity. We also discuss the drugs that can potentially target these processes and data from experimental and clinical studies.

Functional metabolome profiling may improve individual outcomes in colorectal cancer management implementing concepts of predictive, preventive, and personalized medical approach.

Objectives: Colorectal cancer (CRC) is one of the most common solid tumors worldwide, but its diagnosis and treatment are limited. The objectives of our study were to compare the metabolic differences between CRC patients and healthy controls (HC), and to identify potential biomarkers in the serum that can be used for early diagnosis and as effective therapeutic targets. The aim was to provide a new direction for CRC predictive, preventive, and personalized medicine (PPPM). Methods: In this study, CRC patients (n = 30) and HC (n = 30) were recruited. Serum metabolites were assayed using an ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technology. Subsequently, CRC cell lines (HCT116 and HCT8) were treated with metabolites to verify their function. Key targets were identified by molecular docking, thermal shift assay, and protein overexpression/inhibition experiments. The inhibitory effect of celastrol on tumor growth was also assessed, which included IC50 analysis, nude mice xenografting, molecular docking, protein overexpression/inhibition experiments, and network pharmacology technology. Results: In the CRC group, 15 serum metabolites were significantly different in comparison with the HC group. The level of glycodeoxycholic acid (GDCA) was positively correlated with CRC and showed high sensitivity and specificity for the clinical diagnostic reference (AUC = 0.825). In vitro findings showed that GDCA promoted the proliferation and migration of CRC cell lines (HCT116 and HCT8), and Poly(ADP-ribose) polymerase-1 (PARP-1) was identified as one of the key targets of GDCA. The IC50 of celastrol in HCT116 cells was 121.1 nM, and the anticancer effect of celastrol was supported by in vivo experiments. Based on the potential of GDCA in PPPM, PARP-1 was found to be significantly correlated with the anticancer functions of celastrol. Conclusion: These findings suggest that GDCA is an abnormally produced metabolite of CRC, which may provide an innovative molecular biomarker for the predictive identification and targeted prevention of CRC. In addition, PARP-1 was found to be an important target of GDCA that promotes CRC; therefore, celastrol may be a potential targeted therapy for CRC via its effects on PARP-1. Taken together, the pathophysiology and progress of tumor molecules mediated by changes in metabolite content provide a new perspective for predictive, preventive, and personalized medical of clinical cancer patients based on the target of metabolites in vivo.Clinical trials registration number: ChiCTR2000039410. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-021-00269-8.

Incorporation of a histone mutant with H3K56 site substitution perturbs the replication machinery in mouse embryonic stem cells.

Sense mutations in several conserved modifiable sites of histone H3 have been found to be strongly correlated with multiple tissue-specific clinical cancers. These clinical site mutants acquire a distinctively new epigenetic role and mediate cancer evolution. In this study, we mimicked histone H3 at the 56th lysine (H3K56) mutant incorporation in mouse embryonic stem cells (mESCs) by lentivirus-mediated ectopic expression and analyzed the effects on replication and epigenetic regulation. The data show that two types of H3K56 mutants, namely H3 lysine 56-to-methionine (H3K56M) and H3 lysine 56-to-alanine (H3K56A), promote replication by recruiting more minichromosome maintenance complex component 3 and checkpoint kinase 1 onto chromatin compared with wild-type histone H3 and other site substitution mutants. Under this condition, the frequency of genomic copy number gain in H3K56M and H3K56A cells globally increases, especially in the Mycl1 region, a known molecular marker frequently occurring in multiple malignant cancers. Additionally, we found the disruption of H3K56 acetylation distribution in the copy-gain regions, which indicates a probable epigenetic mechanism of H3K56M and H3K56A. We then identified that H3K56M and H3K56A can trigger a potential adaptation to transcription; genes involved in the mitogen-activated protein kinase pathway are partially upregulated, whereas genes associated with intrinsic apoptotic function show obvious downregulation. The final outcome of ectopic H3K56M and H3K56A incorporation in mESCs is an enhanced ability to form carcinomas. This work indicates that H3K56 site conservation and proper modification play important roles in harmonizing the function of the replication machinery in mESCs.

The essential roles of Mps1 in spermatogenesis and fertility in mice.

Monopolar spindle 1 (MPS1), which plays a critical role in somatic mitosis, has also been revealed to be essential for meiosis I in oocytes. Spermatogenesis is an important process involving successive mitosis and meiosis, but the function of MPS1 in spermatogenesis remains unclear. Here, we generated Mps1 conditional knockout mice and found that Ddx4-cre-driven loss of Mps1 in male mice resulted in depletion of undifferentiated spermatogonial cells and subsequently of differentiated spermatogonia and spermatocytes. In addition, Stra8-cre-driven ablation of Mps1 in male mice led to germ cell loss and fertility reduction. Spermatocytes lacking Mps1 have blocked at the zygotene-to-pachytene transition in the prophase of meiosis I, which may be due to decreased H2B ubiquitination level mediated by MDM2. And the expression of many meiotic genes was decreased, while that of apoptotic genes was increased. Moreover, we also detected increased apoptosis in spermatocytes with Mps1 knockout, which may have been the reason why germ cells were lost. Taken together, our findings indicate that MPS1 is required for mitosis of gonocytes and spermatogonia, differentiation of undifferentiated spermatogonia, and progression of meiosis I in spermatocytes.

Synthesis and Structural Elucidation of Bisdibenzocorannulene in Multiple Redox States.

We report an anti-folded bowl-shaped bisdibenzocorannulene (BDBC) featuring a new chair-cyclohexane-like hexagon as a bridge of two dibenzocorannulene moieties. The neutral compound showed multiple redox-active properties and could be converted to the corresponding redox states through chemical reduction or oxidation. Chemical reduction of BDBC by stoichiometric addition of metallic potassium in the presence of [18]crown-6 ether, provided a radical anion BDBC.- and a dianion BDBC2- , respectively; while chemical oxidation by silver hexafluoroantimonate(V), converted the neutral compound to an open-shell singlet diradical dication (BDBC.. )2+ . The structural consequences of both electron-reduction and oxidation were closely related to the release of ring-strain of the bowl-shaped π-scaffold and imposed steric hindrance of the hexagonal bridge. In addition, the unusual open-shell nature of the dication could mainly be attributed to the changing of localized antiaromaticity in the closed-shell structure to delocalized character in the biradical, and thus the emergence of weakly bonded π-electrons.

Immunosuppressive Effects of Mesenchymal Stem Cells-derived Exosomes.

Mesenchymal stem cells (MSCs) have become important seed cells in therapy because of their immunosuppressive function and anti-inflammatory effects. MSCs exert immunosuppressive effects through direct contact or paracrine action. The paracrine functions of MSCs are at least partially mediated by exosomes, which are membrane vesicles, carrying abundant proteins, nucleic acids and other active molecules. MSC-exos have heterogeneity. The exosomes from different donors, tissues generations of MSCs carry different bioactive molecules. These cargos are transferred to recipient cells by endocytosis or binding to proteins on the receptor surface to mediate intercellular communication between different cell types and affect the functions of the recipient cells. Exosomes play an important role in the regulation of the immune system. Exosomes derived from MSCs (MSC-exos) carry immunomodulatory effectors or transmit active signal molecules to regulate the biological activities of immune cells and thus mediating immune suppression, especially on macrophages and T cells. Mitochondria and autophagy-related pathways are also associated with MSC-exos immunosuppressive effects. Graphical Abstract.