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1.
Front Oncol ; 14: 1448333, 2024.
Article in English | MEDLINE | ID: mdl-39114305

ABSTRACT

Objectives: This study aimed to construct prediction models based on computerized tomography (CT) signs, histogram and morphology features for the diagnosis of micropapillary or solid (MIP/SOL) components of stage IA lung adenocarcinoma (LUAC) and to evaluate the models' performance. Methods: This clinical retrospective study included image data of 376 patients with stage IA LUAC based on postoperative pathology, admitted to Putian First Hospital from January 2019 to June 2023. According to the presence of MIP/SOL components in postoperative pathology, patients were divided into MIP/SOL+ and MIP/SOL- groups. Cases with tumors ≤ 3 cm and ≤ 2 cm were separately analyzed. Each subgroup of patients was then randomly divided into a training set and a test set in a ratio of 7:3. The training set was used to build the prediction model, and the test set was used for internal validation. Results: For tumors ≤ 3 cm, ground-glass opacity (GGO) [odds ratio (OR) = 0.244; 95% confidence interval (CI): 0.103-0.569; p = 0.001], entropy (OR = 1.748; 95% CI: 1.213-2.577; p = 0.004), average CT value (OR = 1.002; 95% CI: 1.000-1.004; p = 0.002), and kurtosis (OR = 1.240; 95% CI: 1.023-1.513; p = 0.030) were independent predictors of MIP/SOL components of stage IA LUAC. The area under the ROC curve (AUC) of the nomogram prediction model for predicting MIP/SOL components was 0.816 (95% CI: 0.756-0.877) in the training set and 0.789 (95% CI: 0.689-0.889) in the test set. In contrast, for tumors ≤ 2 cm, kurtosis was no longer an independent predictor. The nomogram prediction model had an AUC of 0.811 (95% CI: 0.731-0.891) in the training set and 0.833 (95% CI: 0.733-0.932) in the test set. Conclusion: For tumors ≤ 3 cm and ≤ 2 cm, GGO, average CT value, and entropy were the same independent influencing factors in predicting MIP/SOL components of stage IA LUAC. The nomogram prediction models have potential diagnostic value for identifying MIP/SOL components of early-stage LUAC.

2.
Nano Lett ; 24(33): 10186-10195, 2024 Aug 21.
Article in English | MEDLINE | ID: mdl-39136297

ABSTRACT

Despite its significant clinical efficacy as a first-line treatment for advanced bladder cancer, cisplatin-based chemotherapy provides a limited benefit for patients with lymphovascular invasion (LVI), which is characterized by the presence of tumor emboli within blood vessels and associated with enhanced cisplatin resistance and metastatic potential. Notably, platelets, a critical component of LVI, hinder the delivery of chemotherapeutic agents to tumors and facilitate metastasis. Consequently, platelet function inhibition holds the potential to disrupt LVI formation, as well as augment the antitumor activity of cisplatin. Herein, we developed a tumor microenvironment-targeted nanodrug with lipid-coated mesoporous silica nanoparticles (silicasomes) that synergistically combines cisplatin with an antiplatelet agent, tirofiban, for bladder cancer treatment. The customized nanodrug can concurrently prevent LVI formation and enhance the chemotherapeutic efficacy without significant adverse effects. This study supports the integration of chemotherapy and antiplatelet therapy via a silicasome-based nanosystem as a highly promising strategy for bladder cancer management.


Subject(s)
Cisplatin , Nanoparticles , Silicon Dioxide , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Humans , Silicon Dioxide/chemistry , Cisplatin/pharmacology , Cisplatin/chemistry , Cisplatin/therapeutic use , Nanoparticles/chemistry , Cell Line, Tumor , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Tumor Microenvironment/drug effects , Mice , Neoplasm Invasiveness/prevention & control , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , Oligopeptides
3.
Comput Struct Biotechnol J ; 24: 322-333, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38690549

ABSTRACT

Data curation for a hospital-based cancer registry heavily relies on the labor-intensive manual abstraction process by cancer registrars to identify cancer-related information from free-text electronic health records. To streamline this process, a natural language processing system incorporating a hybrid of deep learning-based and rule-based approaches for identifying lung cancer registry-related concepts, along with a symbolic expert system that generates registry coding based on weighted rules, was developed. The system is integrated with the hospital information system at a medical center to provide cancer registrars with a patient journey visualization platform. The embedded system offers a comprehensive view of patient reports annotated with significant registry concepts to facilitate the manual coding process and elevate overall quality. Extensive evaluations, including comparisons with state-of-the-art methods, were conducted using a lung cancer dataset comprising 1428 patients from the medical center. The experimental results illustrate the effectiveness of the developed system, consistently achieving F1-scores of 0.85 and 1.00 across 30 coding items. Registrar feedback highlights the system's reliability as a tool for assisting and auditing the abstraction. By presenting key registry items along the timeline of a patient's reports with accurate code predictions, the system improves the quality of registrar outcomes and reduces the labor resources and time required for data abstraction. Our study highlights advancements in cancer registry coding practices, demonstrating that the proposed hybrid weighted neural-symbolic cancer registry system is reliable and efficient for assisting cancer registrars in the coding workflow and contributing to clinical outcomes.

4.
Sleep Med ; 118: 81-87, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38626648

ABSTRACT

BACKGROUND: Evening-type and insomnia symptoms are significantly related to each other and independently associated with depressive symptoms, yet few studies have examined the potential interaction between these two conditions. Therefore, we aimed to examine the associations of evening-type and insomnia symptoms with depressive symptoms among Chinese youths, with a specific focus on the joint effects of the two conditions on depressive symptoms. METHODS: Participants aged between 12 and 25 were invited to participate in an online survey from December 15, 2022, to May 26, 2023. Multivariate logistic regression models and additive interaction models were used to examine the independent and joint effects of chronotypes and insomnia symptoms on depressive symptoms, respectively. RESULTS: Of the 6145 eligible youths, the prevalence of evening-type and insomnia symptoms were 24.9 % and 29.6 %, respectively. Both evening-type (adjusted OR, [AdjOR]: 3.21, 95 % CI: 2.80-3.67) and insomnia symptoms (AdjOR: 10.53, 95 % CI: 9.14-12.12) were associated with an increased risk of depressive symptoms. In addition, the additive interaction models showed that there is an enhanced risk of depression related to interaction between evening-type and insomnia symptoms (relative excess risk due to interaction, [RERI]: 11.66, 95 % CI: 7.21-16.11). CONCLUSIONS: The present study provided additional evidence demonstrating the presence of interaction between evening-type and insomnia symptoms, which can lead to a higher risk of depressive symptoms. Our findings argue the need for addressing both sleep and circadian factors in the management of depressive symptoms in young people.


Subject(s)
Depression , Sleep Initiation and Maintenance Disorders , Humans , Sleep Initiation and Maintenance Disorders/epidemiology , Sleep Initiation and Maintenance Disorders/psychology , Male , Female , Adolescent , Depression/epidemiology , Surveys and Questionnaires , Prevalence , Circadian Rhythm/physiology , China/epidemiology , Child , Adult , Young Adult , Risk Factors
5.
Nat Rev Cancer ; 24(1): 72-87, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38040850

ABSTRACT

Systemic antiplatelet treatment represents a promising option to improve the therapeutic outcomes and therapeutic efficacy of chemotherapy and immunotherapy due to the critical contribution of platelets to tumour progression. However, until recently, targeting platelets as a cancer therapeutic has been hampered by the elevated risk of haemorrhagic and thrombocytopenic (low platelet count) complications owing to the lack of specificity for tumour-associated platelets. Recent work has advanced our understanding of the molecular mechanisms responsible for the contribution of platelets to tumour progression and metastasis. This has led to the identification of the biological changes in platelets in the presence of tumours, the complex interactions between platelets and tumour cells during tumour progression, and the effects of platelets on antitumour therapeutic response. In this Review, we present a detailed picture of the dynamic roles of platelets in tumour development and progression as well as their use in diagnosis, prognosis and monitoring response to therapy. We also provide our view on how to overcome challenges faced by the development of precise antiplatelet strategies for safe and efficient clinical cancer therapy.


Subject(s)
Neoplasms , Humans , Neoplasms/pathology , Blood Platelets/pathology , Blood Platelets/physiology , Immunotherapy
6.
Zhongguo Dang Dai Er Ke Za Zhi ; 25(7): 697-704, 2023 Jul 15.
Article in Chinese | MEDLINE | ID: mdl-37529951

ABSTRACT

OBJECTIVES: To investigate the risk factors for neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture and establish a nomogram model for predicting the risk of neonatal asphyxia. METHODS: A retrospective study was conducted with 613 cases of neonatal asphyxia treated in 20 cooperative hospitals in Enshi Tujia and Miao Autonomous Prefecture from January to December 2019 as the asphyxia group, and 988 randomly selected non-asphyxia neonates born and admitted to the neonatology department of these hospitals during the same period as the control group. Univariate and multivariate analyses were used to identify risk factors for neonatal asphyxia. R software (4.2.2) was used to establish a nomogram model. Receiver operator characteristic curve, calibration curve, and decision curve analysis were used to assess the discrimination, calibration, and clinical usefulness of the model for predicting the risk of neonatal asphyxia, respectively. RESULTS: Multivariate logistic regression analysis showed that minority (Tujia), male sex, premature birth, congenital malformations, abnormal fetal position, intrauterine distress, maternal occupation as a farmer, education level below high school, fewer than 9 prenatal check-ups, threatened abortion, abnormal umbilical cord, abnormal amniotic fluid, placenta previa, abruptio placentae, emergency caesarean section, and assisted delivery were independent risk factors for neonatal asphyxia (P<0.05). The area under the curve of the model for predicting the risk of neonatal asphyxia based on these risk factors was 0.748 (95%CI: 0.723-0.772). The calibration curve indicated high accuracy of the model for predicting the risk of neonatal asphyxia. The decision curve analysis showed that the model could provide a higher net benefit for neonates at risk of asphyxia. CONCLUSIONS: The risk factors for neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture are multifactorial, and the nomogram model based on these factors has good value in predicting the risk of neonatal asphyxia, which can help clinicians identify neonates at high risk of asphyxia early, and reduce the incidence of neonatal asphyxia.


Subject(s)
Asphyxia Neonatorum , Nomograms , Infant, Newborn , Humans , Male , Pregnancy , Female , Retrospective Studies , Cesarean Section , Risk Factors , Asphyxia Neonatorum/epidemiology , Asphyxia Neonatorum/etiology
7.
Cancer Res ; 83(17): 2924-2937, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37326467

ABSTRACT

Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)-positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer. SIGNIFICANCE: A smart nanomedicine encapsulating fulvestrant to improve its half-life, bioavailability, and tumor-targeting and coloaded with CDK4/6 inhibitor abemaciclib to block resistance is a safe and effective therapy for ER-positive breast cancer.


Subject(s)
Neoplasms , Receptors, Estrogen , Animals , Mice , Swine , Fulvestrant/pharmacology , Fulvestrant/therapeutic use , Receptors, Estrogen/metabolism , Aminopyridines/pharmacology , Neoplasms/drug therapy , Drug Resistance, Neoplasm , Cell Line, Tumor
8.
Pediatr Neonatol ; 64(5): 562-569, 2023 09.
Article in English | MEDLINE | ID: mdl-37105821

ABSTRACT

BACKGROUND: Birth asphyxia causes hypoxia or inadequate perfusion to the organs of newborns, leading to metabolism dysfunctions including blood glucose disorders. METHODS: Neonates with and without birth asphyxia were retrospectively recruited from 53 hospitals in Hubei Province from January 1 to December 31, 2018. In summary, 875, 1139, and 180 cases in the control group, the mild asphyxia group, and the severe asphyxia group were recruited, respectively. Neonatal blood glucose values at postnatal 1, 2, 6, and 12 h (time error within 0.5 h was allowed) were gathered from the medical records. RESULTS: The incidence rates of hyperglycemia in the control group, the mild asphyxia group and the severe asphyxia group were 2.97%, 7.90%, and 23.33%, respectively (p < 0.001). Additionally, the incidence rates of hypoglycemia in the three groups above were 3.66%, 4.13%, and 7.78%, respectively (p = 0.042). The blood glucose values of neonates with hypoglycemia in the asphyxia group were lower than in the control group (p = 0.003). Furthermore, the blood glucose values of neonates with hyperglycemia were highest in the severe asphyxia group (p < 0.001). There were 778 and 117 cases with blood glucose records at four predefined time points in the mild and severe asphyxia group, respectively. The incidence of blood glucose disorders in the mild asphyxia group significantly decreased from postnatal 6 h (p<0.05). However, we found no obvious changes of the incidence of glucose disorders within postnatal 12 h in the severe asphyxia group (p = 0.589). CONCLUSION: Birth asphyxia is likely to cause neonatal blood glucose disorders, both hypoglycemia and hyperglycemia, during the early postnatal life. The neonates with severe asphyxia have higher incidence, worse severity and longer duration of blood glucose disorders than neonates with mild asphyxia.


Subject(s)
Asphyxia Neonatorum , Hyperglycemia , Hypoglycemia , Infant, Newborn, Diseases , Humans , Infant, Newborn , Blood Glucose , Asphyxia , Retrospective Studies , Asphyxia Neonatorum/epidemiology , Infant, Newborn, Diseases/epidemiology , Hypoglycemia/epidemiology , Hypoglycemia/etiology , Hyperglycemia/epidemiology , China/epidemiology
9.
Exp Ther Med ; 24(6): 748, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36561967

ABSTRACT

Since ferroptosis is considered to be a notable cause of cardiomyocyte death, inhibiting ferroptosis has become a novel strategy in reducing cardiac cell death and improving cardiopathic conditions. Therefore, the aim of the present study was to search for ferroptosis-related hub genes and determine their diagnostic value in myocardial infarction (MI) to aid in the diagnosis and treatment of the disease. A total of 10,286 DEGs were identified, including 6,822 upregulated and 3.464 downregulated genes in patients with MI compared with healthy controls. After overlapping with ferroptosis-related genes, 128 ferroptosis-related DEGs were obtained. WGCNA successfully identified a further eight functional modules, from which the blue module had the strongest correlation with MI. Blue module genes and ferroptosis-related differentially expressed genes were overlapped to obtain 20 ferroptosis-related genes associated with MI. Go and KEGG analysis showed that these genes were mainly enriched in cellular response to chemical stress, trans complex, transferring, phosphorus-containing groups, protein serine/threonine kinase activity, FoxO signaling pathway. Hub genes were obtained from 20 ferroptosis-related genes through the PPI network. The expression of hub genes was found to be down-regulated in the MI group. Finally, the miRNAs-hub genes and TFs-hub genes networks were constructed. The GSE141512 dataset and the use of RT-qPCR assays on patient blood samples were used to confirm these results. The results showed that ATM, PIK3CA, MAPK8, KRAS and SIRT1 may play key roles in the development of MI, and could therefore be novel markers or targets for the diagnosis or treatment of MI.

10.
Transl Psychiatry ; 12(1): 390, 2022 09 17.
Article in English | MEDLINE | ID: mdl-36115840

ABSTRACT

Bipolar disorder (BD) is a complex psychiatric disorder with strong heritability. Identification of new BD risk genes will help determine the mechanism underlying disease pathogenesis. In the present study, we carried out whole genome sequencing for a Chinese BD family with three affected members and three unaffected members, and identified multiple candidate causal variations, including a frameshift mutation in the GOLGB1 gene. Since a GOLGB1 missense mutation was also found in another BD pedigree, we carried out functional studies by downregulating Golgb1 expression in the brain of neonatal mice. Golgb1 deficiency had no effect on anxiety, memory, and social behaviors in young adult mice. However, we found that young adult mice with Golgb1 deficiency exhibited elevated locomotor activity and decreased depressive behaviors in the tail suspension test and the sucrose preference test, but increased depressive behaviors in the forced swim test, resembling the dual character of BD patients with both mania and depression. Moreover, Golgb1 downregulation reduced PSD93 levels and Akt phosphorylation in the brain. Together, our results indicate that GOLGB1 is a strong BD risk gene candidate whose deficiency may result in BD phenotypes possibly through affecting PSD93 and PI3K/Akt signaling.


Subject(s)
Bipolar Disorder , Animals , Bipolar Disorder/metabolism , Humans , Mice , Pedigree , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Sucrose
11.
Adv Sci (Weinh) ; 9(20): e2200477, 2022 07.
Article in English | MEDLINE | ID: mdl-35524631

ABSTRACT

New strategies to decrease risk of relapse after surgery are needed for improving 5-year survival rate of hepatocellular carcinoma (HCC). To address this need, a wound-targeted nanodrug is developed, that contains an immune checkpoint inhibitor (anti-PD-L1)and an angiogenesis inhibitor (sorafenib)). These nanoparticles consist of highly biocompatible mesoporous silica (MSNP) that is surface-coated with platelet membrane (PM) to achieve surgical site targeting in a self-amplified accumulation manner. Sorafenib is introduced into the MSNP pores while covalently attaching anti-PD-L1 antibody on the PM surface. The resulting nano-formulation, abbreviated as a-PM-S-MSNP, can effectively target the surgical margin when intraperitoneally (IP) administered into an immune competent murine orthotopic HCC model. Multiple administrations of a-PM-S-MSNP generate potent anti-HCC effect and significantly prolong overall mice survival. Immunophenotyping and immunochemistry staining reveal the signatures of favorable anti-HCC immunity and anti-angiogenesis effect at tumor sites. More importantly, microscopic inspection of a-PM-S-MSNP treated mice shows that 2 out 6 are histologically tumor-free, which is in sharp contrast to the control mice where tumor foci can be easily identified. The data suggest that a-PM-S-MSNP can efficiently inhibit post-surgical HCC relapse without obvious side effects and holds considerable promise for clinical translation as a novel nanodrug.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Nanoparticles , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/surgery , Cell Line, Tumor , Liver Neoplasms/drug therapy , Liver Neoplasms/surgery , Mice , Nanoparticles/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Sorafenib/pharmacology , Sorafenib/therapeutic use
12.
Eur J Med Chem ; 229: 114043, 2022 Feb 05.
Article in English | MEDLINE | ID: mdl-34929581

ABSTRACT

Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.


Subject(s)
Amides/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Amides/metabolism , Animals , Binding Sites , Cell Line, Tumor , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Half-Life , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Mice , Mice, Inbred ICR , Molecular Docking Simulation , Neoplasms/drug therapy , Structure-Activity Relationship , Thiophenes/chemistry , Transplantation, Heterologous
13.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(12): 1208-1213, 2021 Dec 15.
Article in English, Chinese | MEDLINE | ID: mdl-34911602

ABSTRACT

OBJECTIVES: To study the effect of glucose metabolism disorders on the short-term prognosis in neonates with asphyxia. METHODS: A retrospective analysis was performed on the medical data of the neonates with asphyxia who were admitted to 52 hospitals in Hubei Province of China from January to December, 2018 and had blood glucose data within 12 hours after birth. Their blood glucose data at 1, 2, 6, and 12 hours after birth (with an allowable time error of 0.5 hour) were recorded. According to the presence or absence of brain injury and/or death during hospitalization, the neonates were divided into a poor prognosis group with 693 neonates and a good prognosis group with 779 neonates. The two groups were compared in the incidence of glucose metabolism disorders within 12 hours after birth and short-term prognosis. RESULTS: Compared with the good prognosis group, the poor prognosis group had a significantly higher proportion of neonates from secondary hospitals (48.5% vs 42.6%, P<0.05) or with severe asphyxia (19.8% vs 8.1%, P<0.05) or hypothermia therapy (4.8% vs 1.5%, P<0.05), as well as a significantly higher incidence rate of disorder of glucose metabolism (18.8% vs 12.5%, P<0.05). Compared with the good prognosis group, the poor prognosis group had a significantly higher incidence rate of disorder of glucose metabolism at 1, 2, and 6 hours after birth (P<0.05). The multivariate logistic regression analysis showed that recurrent hyperglycemia (adjusted odds ratio=2.380, 95% confidence interval: 1.275-4.442, P<0.05) was an independent risk factor for poor prognosis in neonates with asphyxia. CONCLUSIONS: Recurrent hyperglycemia in neonates with asphyxia may suggest poor short-term prognosis, and it is necessary to strengthen the early monitoring and management of the nervous system in such neonates.


Subject(s)
Asphyxia Neonatorum , Hyperglycemia , Asphyxia , Asphyxia Neonatorum/complications , Asphyxia Neonatorum/epidemiology , Humans , Infant, Newborn , Prognosis , Retrospective Studies
14.
Front Psychol ; 12: 736277, 2021.
Article in English | MEDLINE | ID: mdl-34970184

ABSTRACT

There exists a lack of an understanding of how to facilitate knowledge sharing (KS) behaviors in healthcare organizations. This study is among the first to specifically address this issue through synthesizing psychological ownership (PO), self-determination theory, and psychological empowerment (PE) theory. This study developed a research model that described the impact of the psychological and motivational facilitating factors, including autonomous motivation, user PE, and PO on knowledge sharing intention (KSI) and knowledge sharing behavior (KSB). Data collected from 343 healthcare professionals were analyzed using the technique of partial least squares (PLS) to validate the research model. The results indicated that user PE, organization-based PO, and autonomous motivation all had significant direct/indirect positive effects on KSI and KSB as we hypothesized. Surprisingly, knowledge-based PO had a significant positive effect on KSI, which contradicted our original hypothesis. The implications for theory and for practice, limitations, and future research directions are discussed accordingly.

15.
J Inflamm Res ; 14: 3697-3706, 2021.
Article in English | MEDLINE | ID: mdl-34377007

ABSTRACT

PURPOSE: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis. METHODS: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9-42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2. RESULTS: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age. CONCLUSION: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.

16.
J Med Chem ; 64(15): 11288-11301, 2021 08 12.
Article in English | MEDLINE | ID: mdl-34337952

ABSTRACT

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays an important role in one-carbon metabolism. The MTHFD2 gene is upregulated in various cancers but very low or undetectable in normal proliferating cells, and therefore a potential target for cancer treatment. In this study, we present the structure of MTHFD2 in complex with xanthine derivative 15, which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by 15. Allosteric inhibitors often provide good selectivity and, indeed, xanthine derivatives are highly selective for MTHFD2. Moreover, several conformational changes were observed upon the binding of 15, which impeded the binding of the cofactor and phosphate to MTHFD2. To the best of our knowledge, this is the first study to identify allosteric inhibitors targeting the MTHFD family and our results would provide insights on the inhibition mechanism of MTHFD proteins and the development of novel inhibitors.


Subject(s)
Aminohydrolases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Methylenetetrahydrofolate Dehydrogenase (NADP)/antagonists & inhibitors , Multifunctional Enzymes/antagonists & inhibitors , Xanthine/pharmacology , Allosteric Site/drug effects , Aminohydrolases/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism , Models, Molecular , Molecular Structure , Multifunctional Enzymes/metabolism , Structure-Activity Relationship , Xanthine/chemical synthesis , Xanthine/chemistry
17.
J Org Chem ; 2021 Jun 16.
Article in English | MEDLINE | ID: mdl-34132097

ABSTRACT

A straightforward and novel controllable site-selective construction of 2- and 4-substituted pyrimido[1,2-b]indazole from 3-aminoindazoles and ynals has been developed. The high regioselectivity of this reaction could be easily switched by converting different catalytic systems. In this way, a series of 2- and 4-substituted pyrimido[1,2-b]indazole derivatives were obtained in moderate to good yields. In addition, the photophysical properties of compound 3a prepared by the present method were discussed.

18.
Med Educ Online ; 26(1): 1913785, 2021 Dec.
Article in English | MEDLINE | ID: mdl-33849405

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic has brought unprecedented challenges to medical education systems and medical students. The aim of this study was to investigate the effects of COVID-19 pandemic on medical career and specialty choices among medical students. An online cross-sectional survey of Chinese medical students was conducted during the COVID-19 pandemic from February to April 2020. The students' willingness to be a doctor before and after the COVID-19 pandemic and changed willingness to specialize in respiratory medicine and infectious diseases were investigated. Multiple linear regression and binary logistic regression was used to explore factors that were associated with changes of willingness. A total of 1,837 medical students, including 1,227 females (66.8%), with a median age of 21.0 years, were recruited. Of the participants, 10.6% and 6.9% showed increased and decreased willingness to be a doctor after the COVID-19 outbreak, respectively. Moreover, 11.7% showed increased willingness and 9.5% showed decreased willingness to major in respiratory medicine and infectious diseases. Students with younger age, lower household income, fewer depressive symptoms, less exposure to negative pandemic information and more satisfaction with their own major after the pandemic were associated with increased willingness to be a doctor. Students who engaged in regular exercise, were males and undergraduate level, were interested in medicine, paid more attention to positive information, were satisfied with their majors, and had increased willingness to be a doctor after the pandemic were more likely to choose to specialize in respiratory medicine and infectious disease. However, the severity of anxiety symptoms was associated with decreased willingness to work in the specialties of respiratory medicine and infectious diseases. Psychological problems and professional satisfaction appear to be independent factors that affect medial career and specialty choices. The impacts of the COVID-19 pandemic on medical students require further research.


Subject(s)
COVID-19 , Career Choice , Specialization , Students, Medical , Anxiety/epidemiology , China/epidemiology , Cross-Sectional Studies , Female , Humans , Linear Models , Male , Pandemics , SARS-CoV-2 , Students, Medical/psychology , Surveys and Questionnaires , Young Adult
19.
Transl Cancer Res ; 10(1): 1-9, 2021 Jan.
Article in English | MEDLINE | ID: mdl-35116234

ABSTRACT

BACKGROUND: To explore the clinical value of energy spectrum curves of dual-energy computer tomography (CT) in quantitative evaluation of different pathological grades of gastric adenocarcinoma. METHODS: A total of 62 patients with 36 poorly, 25 moderately and 1 well differentiated gastric adenocarcinomas confirmed pathologically were collected. Dual-energy CT plain and enhanced scanning were undergone before operation. Dual-Energy software was used to measure the slope of the energy spectrum curves (λ) in arterial and venous phases (VPs) after image reconstruction. Patients were divided into two groups according to the pathological results, including well and moderately differentiated gastric adenocarcinoma group and poorly differentiated gastric adenocarcinoma group. Data of each group were analyzed by independent sample t-test. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficiency of the corresponding parameters. RESULTS: There were significant differences in λ values of 40-50, 40-60, 40-80, 40-90, 40-100, 40-120, 40-130, 40-140 and 40-150 keV energy ranges in VP between the well and moderately differentiated group and poorly differentiated group (P<0.05), but no significant differences in λ values of different energy ranges in arterial phase (AP) between the two groups (P>0.05). And the area under curve in 40-120 keV energy range was the largest in VP. λ40-120keV=2.69 was selected as the diagnostic threshold with the maximum Youden index, the sensitivity and specificity were 61.1% and 76%, respectively. CONCLUSIONS: The energy spectrum curve of dual-energy CT had certain diagnostic value in the quantitative evaluation of pathological grading of gastric adenocarcinoma.

20.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(9): 942-947, 2020 Sep.
Article in Chinese | MEDLINE | ID: mdl-32933623

ABSTRACT

OBJECTIVE: To investigate the clinical features and outcome of neonatal acute respiratory distress syndrome (ARDS) in southwest Hubei, China. METHODS: According to the Montreux definition of neonatal ARDS, a retrospective clinical epidemiological investigation was performed on the medical data of neonates with ARDS who were admitted to Department of Neonatology/Pediatrics in 17 level 2 or level 3 hospitals in southwest Hubei from January to December, 2017. RESULTS: A total of 7 150 neonates were admitted to the 17 hospitals in southwest Hubei during 2017 and 66 (0.92%) were diagnosed with ARDS. Among the 66 neonates with ARDS, 23 (35%) had mild ARDS, 28 (42%) had moderate ARDS, and 15 (23%) had severe ARDS. The main primary diseases for neonatal ARDS were perinatal asphyxia in 23 neonates (35%), pneumonia in 18 neonates (27%), sepsis in 12 neonates (18%), and meconium aspiration syndrome in 10 neonates (15%). Among the 66 neonates with ARDS, 10 neonates (15%) were born to the mothers with an age of ≥35 years, 30 neonates (45%) suffered from intrauterine distress, 32 neonates (49%) had a 1-minute Apgar score of 0 to 7 points, 24 neonates (36%) had abnormal fetal heart monitoring results, and 21 neonates (32%) experienced meconium staining of amniotic fluid. Intraventricular hemorrhage was the most common comorbidity (12 neonates), followed by neonatal shock (9 neonates) and patent ductus arteriosus (8 neonates). All 66 neonates with ARDS were treated with mechanical ventilation in addition to the treatment for primary diseases. Among the 66 neonates with ARDS, 10 died, with a mortality rate of 15% (10/66), and 56 neonates were improved or cured, with a survival rate of 85% (56/66). CONCLUSIONS: Neonatal ARDS in southwest Hubei is mostly mild or moderate. Perinatal asphyxia and infection may be the main causes of neonatal ARDS in this area. Intraventricular hemorrhage is the most common comorbidity. Neonates with ARDS tend to have a high survival rate after multimodality treatment.


Subject(s)
Respiratory Distress Syndrome, Newborn , China , Female , Humans , Infant, Newborn , Meconium Aspiration Syndrome , Pregnancy , Retrospective Studies
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