Development and psychometric properties of a perceived social support scale for nurses returning to work after childbirth.

BACKGROUND: There has been an increase in the number of nurses returning to work after childbirth (NRWCs) in Chinese hospital. Social support is important for NRWCs. OBJECTIVE: To develop and validate a perceived social support scale for NRWCs in China. METHOD: The original items were based on a literature review, the social support theory, and semi-structured interviews. The Delphi technique was used to adjust further and screen the scale entries to form an initial draft of the scale. From February to October 2023, we recruited 627 NRWCs from hospitals in 12 provinces of China. The psychometric attributes of the scale were examined by construct validity, content validity, test-retest reliability, and internal consistency reliability. The STROBE checklist was used to guide the submission. RESULTS: 4 dimensions and 22 items compose the initial scale. Exploratory factor analysis verified a four-factor scale structure. The confirmatory factor analysis results showed that the four-factor structure model fitted well. The resulting scale contains 4 dimensions with 18 items. The item-level content validity index ranged from 0.83 to 1.00. The Cronbach's alpha coefficient of four dimensions and total scale were respectively 0.957, 0.899, 0.870, 0.945, 0.967. The reliability of the scale over time was further verified, with a coefficient of 0.809 for the overall scale and a range from 0.682 to 0.718 for each domain. CONCLUSION: The perceived social support scale for NRWCs is a reliable and valid instrument. The application of the perceived social support scale for NRWCs would improve the assessment of social support among NRWCs.

The clinical value of intelligent wound measurement devices in patients with chronic wounds: A scoping review.

Chronic wounds are common in clinical practice, with long treatment cycle and high treatment cost. Changes in wound area can well predict the effectiveness of treatment and the possibility of healing. Therefore, continuous wound monitoring and evaluation are particularly important. Traditional manual wound measurement tends to overestimate wound area. Recently, various intelligent wound measurement devices have been introduced into clinical practice. This review aims to summarise the reliability, validity, types and measurement principles of different intelligent wound measurement devices, so as to analyse the clinical value and application prospect. Articles numbering 2610 were retrieved from the database, and 14 articles met the inclusion criteria. The results showed that the intelligent wound measurement devices included in the study reported good reliability and validity. Contact devices can lead to wound bed damage, wound deformation, patient pain, and is not convenient for electronic wound recording; partial contact devices can complete continuous monitoring and recording of wounds, but are not sensitive to wound depth measurement. Non-contact devices are more accurate in capturing wound images. In addition to wound measurement, they also have the function of wound assessment. In general, handheld and portable non-contact devices have great clinical value and promotion prospects.

2-Anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-derived CDK2 inhibitors as anticancer agents: Design, synthesis & evaluation.

Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (Ki = 0.023 and 0.001 µM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI50 = 0.025-0.780 µM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer.

Discovery of N,4-Di(1H-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation.

Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (Ki = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI50 = 0.127-0.560 µM). Mechanistic studies in ovarian cancer cells revealed that 15 reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.

A first-in-class CDK4 inhibitor demonstrates in vitro, ex-vivo and in vivo efficacy against ovarian cancer.

INTRODUCTION: Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are involved in the initiation and progression of various cancers. Deregulation of the CDK4/6-cyclin D-retinoblastoma (Rb) pathway is common in ovarian cancer and is associated with an aggressive phenotype and poor prognosis. Patients with advanced ovarian cancer whose tumor demonstrates Rb-positivity, a low expression of p16 and overexpression of cyclin D1 are most likely to benefit from CDK4/6 inhibition. MATERIALS AND METHOD: Anti-proliferative activity and mechanistic investigations for CDDD2-94, employing palbociclib as comparator, were evaluated by MTT assay, cell cycle and apoptosis analysis, western blotting as well as senescence and colony formation assay. In vivo safety and efficacy studies were done in A2780 tumor-bearing nude mice. Combinations of CDDD2-94 with mTOR, MEK, PI3K or PARP inhibitors were evaluated in A2780 and OVCAR5 ovarian cancer cells. RESULTS: Consistent with a CDK4-targeted mechanism, CDDD2-94 arrested the G1/G0 cell cycle, induced senescence and inhibited the proliferation of Rb-proficient ovarian cancer cells. CDDD2-94 exhibited synergistic anti-proliferative activities with mTOR, MEK, PI3K or PARP inhibitors. Importantly, unlike palbociclib which caused significant reductions in the number of lymphocytes and neutrophils, CDDD2-94 had little effect. CDDD2-94, as single agent and in combination with everolimus, delayed tumor growth and significantly increased survival of mice. CONCLUSION: Given its high specificity in targeting CDK4 and excellent anti-tumor efficacy with low toxicity, CDDD2-94 has potential to be developed as a standalone agent or in combination with targeted therapeutics for the treatment of ovarian cancer.

Synthesis and evaluation of 2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione derivatives as Mnk inhibitors.

Post-translational modulation of eIF4E through phosphorylation by Mnks is highly integral to the pathogenesis of different cancers. Therefore, inhibition of Mnks offers a strategy for cancer treatment. Herein, a series of 2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione derivatives is presented as Mnk inhibitors. Some of them showed sub-micromolar to low nanomolar inhibitory activities against Mnk1/2 with a high level of selectivity for both kinases over CDKs. Biochemical assays revealed that compounds 4c and 4t are non-ATP-competitive inhibitors of Mnks. Lead compound 4t demonstrated a high selectivity for Mnk1/2 over a selection of 51 kinases, and displayed anti-proliferative activities against a panel of cancer cell lines. However, this compound in combination with our in-house CDK4/6 inhibitor 83 did not show a synergistic effect in A2780 ovarian cancer cells, suggesting that caution be exercised in the selection of an agent to be combined with an Mnk inhibitor.

In Search of Novel CDK8 Inhibitors by Virtual Screening.

Aberrant activity of cyclin-dependent kinase (CDK) 8 is implicated in various cancers. While CDK8-targeting anticancer drugs are highly sought-after, no CDK8 inhibitor has yet reached clinical trials. Herein a large library of drug-like molecules was computationally screened using two complementary cascades to identify potential CDK8 inhibitors. Thirty-three hits were identified to inhibit CDK8 and seven of them were active against colorectal cancer cell lines. Finally, the primary target was confirmed using three promising hits.

Synthesis and biological evaluation of heteroaryl styryl sulfone derivatives as anticancer agents.

Herein we disclose a series of novel heteroaryl styryl sulfone derivatives as potential anticancer agents. Structure-activity relationships of these newly synthesised compounds were explored with respect to the significance of the position and number of nitrogen atom of the heteroaryl ring for anti-proliferative activity in human cancer cell lines. A lead compound 14f was tested against a panel of cancerous and untransformed cell lines, and found to be highly potent against cancer cells with minimal toxicity in the untransformed cells. Further mechanistic studies uncovered that 14f caused cell-cycle arrest at the G2/M phase and induced apoptosis by targeting CDC25C and Mcl-1 proteins in A2780 ovarian cells.

Pharmacologic Inhibition of MNKs in Acute Myeloid Leukemia.

The Ras/Raf/MAPK and PI3K/Akt/mTOR pathways are key signaling cascades involved in the regulation of cell proliferation and survival, and have been implicated in the pathogenesis of several types of cancers, including acute myeloid leukemia (AML). The oncogenic activity of eIF4E driven by the Mnk kinases is a convergent determinant of the two cascades, suggesting that targeting the Mnk/eIF4E axis may provide therapeutic opportunity for the treatment of cancer. Herein, a potent and selective Mnk2 inhibitor (MNKI-85) and a dual-specific Mnk1 and Mnk2 inhibitor (MNKI-19), both derived from a thienopyrimidinyl chemotype, were selected to explore their antileukemic properties. MNKI-19 and MNKI-85 are effective in inhibiting the growth of AML cells that possess an M5 subtype with FLT3-internal tandem duplication mutation. Further mechanistic studies show that the downstream effects with respect to the selective Mnk1/2 kinase inhibition in AML cells causes G1 cell cycle arrest followed by induction of apoptosis. MNKI-19 and MNKI-85 demonstrate similar Mnk2 kinase activity and cellular antiproliferative activity but exhibit different time-dependent effects on cell cycle progression and apoptosis. Collectively, this study shows that pharmacologic inhibition of both Mnk1 and Mnk2 can result in a more pronounced cellular response than targeting Mnk2 alone. However, MNKI-85, a first-in-class inhibitor of Mnk2, can be used as a powerful pharmacologic tool in studying the Mnk2/eIF4E-mediated tumorigenic mechanism. In conclusion, this study provides a better understanding of the mechanism underlying the inhibition of AML cell growth by Mnk inhibitors and suggests their potential utility as a therapeutic agent for AML.

Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2.

Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been implicated in many tumor types, and mitogen activated protein kinase-interacting kinases (Mnks) are the only known kinases that phosphorylate eIF4E at Ser209. The phosphorylation of eIF4E is essential for oncogenic transformation but is of no significance to normal growth and development. Pharmacological inhibition of Mnks therefore provides a nontoxic and effective strategy for cancer therapy. However, a lack of specific Mnk inhibitors has confounded pharmacological target validation and clinical development. Herein, we report the identification of a novel series of Mnk inhibitors and their binding modes. A systematic workflow has been established to distinguish between type III and type I/II inhibitors. A selection of 66 compounds was tested for Mnk1 and Mnk2 inhibition, and 9 out of 20 active compounds showed type III interaction with an allosteric site of the proteins. Most of the type III inhibitors exhibited dual Mnk1 and Mnk2 activities and demonstrated potent antiproliferative properties against the MV4-11 acute myeloid leukemia cell line. Interestingly, ATP-/substrate-competitive inhibitors were found to be highly selective for Mnk2, with little or no activity for Mnk1. Our study suggests that Mnk1 and Mnk2 share a common structure of the allosteric inhibitory binding site but possess different structural features of the ATP catalytic domain. The findings will assist in the future design and development of Mnk targeted anticancer therapeutics.

Efficient deprotection of F-BODIPY derivatives: removal of BF2 using Brønsted acids.

The effective and efficient removal of the BF2 moiety from F-BODIPY derivatives has been achieved using two common Brønsted acids; treatment with trifluoroacetic acid (TFA) or methanolic hydrogen chloride (HCl) followed by work-up with Ambersep(®) 900 resin (hydroxide form) effects this conversion in near-quantitative yields. Compared to existing methods, these conditions are relatively mild and operationally simple, requiring only reaction at room temperature for six hours (TFA) or overnight (HCl).

Lactating nurses' experiences of return to work after lifting COVID-19 lockdown: A qualitative study.

Aim: To explore the lactating nurses' experiences of return to work after lifting COVID-19 lockdown. Background: Return to work is a key reason for the low rates of breastfeeding. Especially after lifting COVID-19 lockdown, case counts reached recorded highs. So lactating nurses face more challenges when they return to work. Method: The empirical phenomenology method was used to conduct a qualitative study. Lactating nurses were recruited in a tertiary hospital through purposive and snowball sampling, and participated in semi-structured video interviews. Colaizzi's method was used to analyze the data. Results: Three themes and 10 sub-themes emerged from the interview data of 15 participants. The first theme was "preparation for return to work", which helped lactating nurses adapt to return to work quickly. The second was "experiences of return to work". The inconvenience of pumping was mentioned repeatedly. In addition, the flexible work schedule was highlighted. The third was "experiences of infection". The attitudes toward breastfeeding differed due to different perceptions of COVID-19. Conclusions: Lactation nurses easily interrupted or stopped breastfeeding when they returned to work after lifting COVID-19 lockdown. Recommendations include the further provision of longer periods of leave, flexible working arrangements, separate facilities for breast pumping, and breastfeeding strategies for epidemics.

A fluorescent "allosteric scorpionand" complex visualizes a biological recognition event.

We describe a new class of fluorescent reporter and its employment to visualize the biotin/avidin binding interaction. Derivatives of the azamacrocycle cyclam that contain a pendant naphthalimide dye are inherently fluorescent when zinc(II) is coordinated. Introducing a second pendant group--biotin--affords an unsymmetrical bis-triazole-scorpionand ligand that interacts specifically with avidin. This ligand has been assembled by using a one-pot "double-click" strategy and complexed with copper(II) and zinc(II). The zinc(II) complex is fluorescent, and its fluorescence output changes in the presence of avidin. Upon avidin binding, the fluorescence output is diminished by interaction with the protein, at [complex]/[avidin] ratios of up to 4:1. The observed change might arise from a specific quenching effect in the biotin binding pocket or from a binding-induced change in the coordination geometry of the complex.

Anti-Leukaemic Activity of Rilpivirine Is Mediated by Aurora A Kinase Inhibition.

Acute myeloid leukaemia (AML) affects predominantly elderly people and has an incidence of 1% of all cancers and 2% of all cancer deaths. Despite using intensive chemotherapy and allogeneic stem cell transplantation, the treatment options for AML remain open for innovation. Thus, there is a need to explore alternative therapies such as less toxic targeted therapies in AML. Aurora A kinase is a well-established target for the treatment of various cancers, including AML. This kinase plays a pivotal role in the cell-division cycle, particularly in different stages of mitosis, and is also involved in many other cellular regulatory processes. In a previous study, we demonstrated that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In the current study, we have further explored the selectivity of rilpivirine for Aurora A kinase inhibition by testing this drug against a panel of 429 kinases. Concurrently, we demonstrated that rilpivirine significantly inhibited the proliferation of AML cells in a time- and concentration-dependent manner that was preceded by G2/M cell-cycle arrest leading to the induction of apoptosis. Consistent with its kinase inhibitory role, rilpivirine modulated the expression of critical proteins in the Aurora A kinase-signalling pathway. Importantly, orally administered rilpivirine significantly inhibited tumour growth in an HL-60 xenograft model without showing body weight changes or other clinical signs of toxicity. Furthermore, rilpivirine enhanced the anti-proliferative efficacy of the conventional anti-leukaemic chemotherapeutic agent cytarabine. Collectively, these findings provide the stimulus to explore further the anti-leukaemic activity of the anti-viral drug rilpivirine.

Disaster Preparedness Among Nurses in China: A Cross-Sectional Study.

BACKGROUND: Increasingly frequent global disasters such as coronavirus disease 2019 pose a threat to human health and life. The World Health Organization has called on countries to formulate detailed plans to prepare for disasters. It is critical to investigate and evaluate the disaster preparedness of nurses. PURPOSE: This study was designed to investigate the disaster preparedness and psychological condition of nurses in China and analyze the significant factors influencing their disaster preparedness. METHODS: A cross-sectional survey was conducted in 2020, and 1,313 nurses were enrolled using convenience sampling. The study questionnaires were distributed and collected via a networking platform equivalent to Amazon Mechanical Turk. The disaster preparedness of the respondents was measured using the Disaster Preparedness Evaluation Tool, the Hospital Anxiety and Depression Scale was used to evaluate anxiety and depression status, and a self-designed questionnaire developed based on a review of the literature was used to explore the potential factors of influence on disaster preparedness. RESULTS: The average score for disaster preparedness among the participants was 186.34 ( SD = 40.80), which corresponded with a moderate level, especially in skill (mean score = 42.01, SD = 12.39). Items with higher scores included support for the government, personal protection, and health education, whereas items with lower scores included nursing leadership in the community, capacity to cope with chemical or biological attacks, and assessment of posttraumatic stress disorder. Disaster preparedness was negatively related with mental health, including depression and anxiety. The main factors affecting disaster preparedness included educational background, nursing specialty, prior disaster training, prior disaster rescue experience, and depression level. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The disaster preparedness of Chinese nurses must be improved. More attention should be paid to disaster preparedness in nurses, and future tailored interventions are urgently needed to promote nursing leadership in the community, the ability to cope with chemical or biological attacks, and posttraumatic stress disorder assessments. Moreover, relieving negative emotions to promote the mental health of nurses should receive greater attention.

Discovery of Potent Inhibitors of Cyclin-Dependent Kinases 7 and 9: Design, Synthesis, Structure-Activity Relationship Analysis and Biological Evaluation.

Cyclin-dependent kinases (CDKs) 7 and 9 are deregulated in various types of human cancer and are thus viewed as therapeutic targets. Accordingly, small-molecule inhibitors of both CDKs are highly sought-after. Capitalising on our previous discovery of CDKI-73, a potent CDK9 inhibitor, medicinal chemistry optimisation was pursued. A number of N-pyridinylpyrimidin-2-amines were rationally designed, chemically synthesised and biologically assessed. Among them, N-(6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl)-4-(imidazo[1,2-a]pyrimidin-3-yl)pyrimidin-2-amine was found to be one of the most potent inhibitors of CDKs 7 and 9 as well as the most effective anti-proliferative agent towards multiple human cancer cell lines. The cellular mode of action of this compound was investigated in MV4-11 acute myeloid leukaemia cells, revealing that the compound dampened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub-G1 phase and induced apoptosis.

Optimization and validation of voxel size-related radiomics variability by combatting batch effect harmonization in pulmonary nodules: a phantom and clinical study.

Background: Broad generalization of radiomics-assisted models may be impeded by concerns about variability. This study aimed to evaluate the merit of combatting batch effect (ComBat) harmonization in reducing the variability of voxel size-related radiomics in both phantom and clinical study in comparison with image resampling correction method. Methods: A pulmonary phantom with 22 different types of nodules was scanned by computed tomography (CT) with different voxel sizes. The variability of voxel size-related radiomics features was evaluated using concordance correlation coefficient (CCC), dynamic range (DR), and intraclass correlation coefficient (ICC). ComBat and image resampling compensation methods were used to reduce variability of voxel size-related radiomics. The percentage of robust radiomics features was compared before and after optimization. Pathologically differential diagnosis of invasive adenocarcinoma (IAC) from adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) (AIS-MIA group) was used for clinical validation in 134 patients. Results: Before optimization, the number of excellent features in the phantom and clinical data was 26.12% and 32.31%, respectively. The excellent features were increased after image resampling and ComBat correction. For clinical optimization, the effect of the ComBat compensation method was significantly better than that of image resampling, with excellent features reaching 90.96% and poor features only amounting to 4.96%. In addition, the hierarchical clustering analysis showed that the first-order and shape features had better robustness than did texture features. In clinical validation, the area under the curve (AUC) of the testing set was 0.865 after ComBat correction. Conclusions: The ComBat harmonization can optimize voxel size-related CT radiomics variability in pulmonary nodules more efficiently than image resampling harmonization.

Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer.

Tankyrases are multifunctional poly(adenosine diphosphate-ribose) polymerases that regulate diverse biological processes including telomere maintenance and cellular signaling. These processes are often implicated in a number of human diseases, with cancer being the most prevalent example. Accordingly, tankyrase inhibitors have gained increasing attention as potential therapeutics. Since the discovery of XAV939 and IWR-1 as the first tankyrase inhibitors over two decades ago, tankyrase-targeted drug discovery has made significant progress. This review starts with an introduction of tankyrases, with emphasis placed on their cancer-related functions. Small-molecule inhibitors of tankyrases are subsequently delineated based on their distinct modes of binding to the enzymes. In addition to inhibitors that compete with oxidized nicotinamide adenine dinucleotide (NAD+) for binding to the catalytic domain of tankyrases, non-NAD+-competitive inhibitors are detailed. This is followed by a description of three clinically trialled tankyrase inhibitors. To conclude, some of challenges and prospects in developing tankyrase-targeted cancer therapies are discussed.

Circulating tumor DNA integrating tissue clonality detects minimal residual disease in resectable non-small-cell lung cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has been proven as a marker for detecting minimal residual diseases following systemic therapies in mid-to-late-stage non-small-cell lung cancers (NSCLCs) by multiple studies. However, fewer studies cast light on ctDNA-based MRD monitoring in early-to-mid-stage NSCLCs that received surgical resection as the standard of care. METHODS: We prospectively recruited 128 patients with stage I-III NSCLCs who received curative surgical resections in our Lung Cancer Tempo-spatial Heterogeneity prospective cohort. Plasma samples were collected before the surgery, 7 days after the surgery, and every 3 months thereafter. Targeted sequencing was performed on a total of 628 plasma samples and 645 matched tumor samples using a panel covering 425 cancer-associated genes. Tissue clonal phylogeny of each patient was reconstructed and used to guide ctDNA detection. RESULTS: The results demonstrated that ctDNA was more frequently detected in patients with higher stage diseases pre- and postsurgery. Positive ctDNA detection at as early as 7 days postsurgery identified high-risk patients with recurrence (HR = 3.90, P < 0.001). Our results also show that longitudinal ctDNA monitoring of at least two postsurgical time points indicated a significantly higher risk (HR = 7.59, P < 0.001), preceding radiographic relapse in 73.5% of patients by a median of 145 days. Further, clonal ctDNA mutations indicated a high-level specificity, and subclonal mutations informed the origin of tumor recurrence. CONCLUSIONS: Longitudinal ctDNA surveillance integrating clonality information may stratify high-risk patients with disease recurrence and infer the evolutionary origin of ctDNA mutations.