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Purpose: The management of pain following cancer-related surgeries involves the use of opioid analgesics. Nevertheless, there is little evidence characterizing the utility and prescription patterns of opioids after these procedures. Our primary aim was to identify patients from three types of cancer surgery who were overprescribed with opioids. The secondary aim was to determine the potential predictors of overprescribing in the same period., Methods: We conducted the study at a single cancer referral hospital. Opioid-naïve patients with breast, gynecologic, or head and neck cancer were studied. Patients were considered opioid-naïve if they had a history of opioid use ≤ 30 mg oral morphine equivalent daily dose for less than seven days in the preceding three months before surgery. We recruited eligible participants by convenience sampling on the wards until at least 102 patients were included in the final analysis. After discharge, we followed up on the participants on day 7 via telephone using a structured proforma including questions to identify the last date and amount of opioid dose taken. The equivalent days of opioid use were calculated by their 24-hr use before discharge and the number of doses prescribed for discharge. Our primary outcome was the prevalence of overprescribing in the three surgical specialties defined as the number of patients taking less than 50% of discharge opioids within the first seven days after discharge. We examined the predictors on incidents of overprescribing using multivariable Poisson regression as the secondary outcome., Results: We recruited 119 patients, and 107 patients were included in the final analysis. There were 59/107 (55%) patients found to be overprescribed with opioids. At discharge, they exhibited lower mean numerical rating scale pain scores, lower mean pain severity scores, higher equivalent days of opioids prescribed, and not used opioids in the last 24 hr before discharge. The incidence of overprescribing was 2.4 times greater for patients prescribed with opioids without 24-hr opioid use (relative risk [RR], 2.38; 95% confidence interval [CI], 1.30 to 4.35; P = 0.005). Similarly, the incidence of overprescribing was 1.7 times greater for patients who had opioids 24 hr before discharge and were supplied with opioids for five equivalent days or more at the time of discharge (RR, 1.67; 95% CI, 1.09 to 2.56; P = 0.02)., Conclusion: Our study shows that the majority of recruited patients undergoing breast, gynecologic, or head and neck cancer surgery were overprescribed opioids. Individualized assessments on patients' 24-hr opioid requirements before discharge and supplying for less than five days are important considerations to reduce overprescribing in opioid-naïve patients after cancer surgery., (© 2024. The Author(s).)

Abstract: To scale and sustain successful quality improvement (QI) interventions, it is recommended for health system leaders to calculate the economic and financial sustainability of the intervention. Many methods of economic evaluation exist, and the type of method depends on the audience: providers, researchers, and hospital executives. This is a primer to introduce cost-effectiveness analysis, budget impact analysis, and return on investment calculation as 3 distinct methods for each stakeholder needing a measurement of the value of QI at the health system level. Using cases for the QI of hospital-acquired condition rates (e.g., pressure injuries), this primer proceeds stepwise through each method beginning from the same starting point of constructing a model so that the repetition of steps is minimized and thereby capturing the attention of all intended audiences., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.)

The benefits and long-term effects of extracurricular scientific research on undergraduate students in many countries have been intensively investigated, but it remains obscure for Chinese medical students. In this study, we investigated the outcome of 60 medical students who have participated in extracurricular scientific research at Jinan University Medical School over a period of 7 years (2011-2018). The results revealed that these students have contributed to 31 biomedical science articles in reputable academic journals, as first- or co-authors. Furthermore, they also independently procured various funding based on their research achievements, and smaller awards for achievements in conferences and competitions. Assessment of the grade point average score of these students revealed that conducting extracurricular scientific research did not affect their routine medical study and exam grades (P>0.05). The students benefited from participating in extracurricular research, by acquiring the ability to think scientifically and enhancing their communication skills. In addition, the medical students were motivated to enlist for postgraduate studies so that they could further embark in scientific research. In sum, Chinese medical students are capable of participating in scientific research and make a significant contribution to science., (© 2021 International Union of Biochemistry and Molecular Biology.)

Reversine, or 2-(4-morpholinoanilino)-6cyclohexylaminopurine, is a 2,6-disubstituted purine derivative. This small molecule exhibits tumor-suppressive activities through different molecular mechanisms. In this study, in vitro and in vivo angiogenic models were used to elucidate the effect of Reversine on angiogenesis in the tumor suppression. Firstly, we grafted osteosarcoma-derived MNNG/HOS cell aggregates onto chick embryonic chorioallantoic membrane (CAM) to examine the vascularization of these grafts following Reversine treatment. Following culture, it was determined that Reversine inhibited MNNG/HOS grafts growth, and decreased the density of blood vessels in the chick CAM. We then used CAM and chick embryonic yolk-sac membrane (YSM) to investigate the effects of Reversine on angiogenesis. The results revealed Reversine inhibited the proliferation of endothelial cells, where cells were mainly arrested at G 1 /S phase of the cell cycle. Scratch-wound assay with HUVECs revealed that Reversine suppressed cell migration in vitro. Furthermore, endothelial cells tube formation assay and chick aortic arch sprouting assay demonstrated Reversine inhibited the sprouting, migration of endothelial cells. Lastly, qPCR and western blot analyses showed BMP-associated Smad1/5/8 signaling expressions were up-regulated by Reversine treatment. Our results showed that Reversine could suppress tumor growth by inhibiting angiogenesis through BMP signaling, and suggests a potential use of Reversine as an anti-tumor therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Baicalin is a flavone glycoside that possesses numerous pharmacological properties. but its protective mode of action in kidney injury induced by diabetes mellitus remains incompletely understood. Using a streptozotocin (STZ)-induced diabetic mouse model, we found that baicalin could ameliorate diabetes-induced the pathological changes of the kidney function and morphology through suppressing inflammation and oxidative stress. Furthermore, baicalin treatment could alleviate interstitial fibrosis in the diabetic kidney via inhibiting epithelial-to-mesenchymal transition (EMT), which was accompanied by a sharp upregulation of Klotho, the endogenous inhibitor of renal fibrosis. We further verified that baicalin-rescued expression of Klotho was associated with Klotho promoter hypomethylation due to aberrant methyltransferase 3a expressions. Klotho knockdown via RNA interferences largely abrogated the anti-renal fibrotic effects of Baicalin in HK2 cells. These findings suggested that baicalin could alleviate renal injury-induced by diabates through partly modulating Klotho promoter methylation, which provides new insights into the treatment of diabetic nephropathy.

BRISC and BRCA1-A complex member 2 ( Babam2 ) plays an essential role in promoting cell cycle progression and preventing cellular senescence. Babam2 -deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of Babam2 in ESCs would enable us to understand the mechanism of Babam2 in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated Babam2 knockout ( Babam2 -/- ) mESCs to investigate the function of Babam2 in mESCs. We demonstrated that the loss of Babam2 in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, CDC25A and CDK2, were found to be degraded in Babam2 -/- mESCs following gamma irradiation. In addition, Babam2 -/- mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in Babam2 -/- mESCs. In summary, Babam2 maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.

The incidence of gestational diabetes mellitus (GDM) has increased dramatically amongst multiethnic population. However, how gestational diabetes mellitus damages the developing embryo is still unknown. In this study, we used yolk sac membrane (YSM) model to investigate angiogenesis in the developing chick embryo. We determined that in the presence of high glucose, it retarded the growth and extension of the embryonic vascular plexus and it also reduced the density of the vasculature in yolk sac membrane model. Using the same strategy, we used the chorioallantoic membrane (CAM) as a model to investigate the influence of high glucose on the vasculature. We established that high glucose inhibited development of the blood vessel plexus and the blood vessels formed had a narrower diameter than control vessels. Concurrent with the abnormal angiogenesis, we also examined how it impacted cardiogenesis. We determined the myocardium in the right ventricle and left atrium were significantly thicker than the control and also there was a reduction in glycogen content in cardiomyocytes. The high glucose also induced excess reactive oxygen species (ROS) production in the cardiomyocytes. We postulated that it was the excess reactive oxygen species that damaged the cardiomyocytes resulting in cardiac hyperplasia., Competing Interests: No conflict of interest has been declared by the authors., (© Georg Thieme Verlag KG Stuttgart · New York.)

Suspension spheroid cultures of anchorage-dependent cell types have been widely used in cancer and stem cell research, as well as for producing organoids. It is believed that the 3-dimensional spheroid presents cells with a more physiological microenvironment to grow so that they behave more like cells in vivo, which is lacking in conventional 2-dimensional monolayer cultures. Recently, it has been reported that cancer cells grown as spheroids could express stem cell-associated genes. Hence, it is investigated whether normal mouse and human fibroblasts cultured as spheroids could also be induced to express stem cell-associated genes. The transcriptomes of human fibroblasts cultured as a monolayer and spheroids are compared and analyzed using real-time RT-qPCR, RNA-sequencing, and bioinformatics. The results reveal that the spheroid transcriptome resemble somatic cells being reprogramed into stem cells, including the induced expression of stemness-associated genes, increased expression of mesenchymal-to-epithelial transition-associated genes, and decreased expression of epithelial-to-mesenchymal transition-associated genes. In this context, it is hypothesized that during the process of spheroid formation, matrix-cell signaling is lost in favor of cell-cell contact signaling and that this subsequently increases the activity of the PI3K/Akt pathway that then upregulates Tbdx3 and stemness-associated genes., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The functions of microRNA-1 (miR-1) in cardiac hypertrophy, and cardiomyocyte differentiation have been investigated. However, the mechanism on how miR-1 could repress cardiomyocyte proliferation has not been fully elucidated., Methods: We address this issue by investigating whether miR-1 affected the proliferation of neonatal cardiomyocyte and identify some of the genes targeted by miR-1. miR-1 was over-expressed in neonatal cardiomyocytes and the effect on cell cycle and growth were analyzed by flow cytometry and Brdu-incorporation assay. Relevant vectors carrying the luciferase reporter were constructed for validation of miR-1 binding to its matching sites on the 3'-untranslated region of the predicated target mRNAs. Cardiomyocytes were co-transfected with the vectors and miR-1 mimics, then luciferase reporter assay was performed. Lastly, we examined the expression of target genes in cardiomyocytes after transfection with miR-1 mimics, as well as their normal expression pattern in 2- and 13-day-old mice hearts., Results: We have demonstrated that miR-1 was the most significantly upregulated miRNA in 13-day-old mouse hearts compared with 2-day-old hearts. We also showed that miR-1 could repress cardiomyocyte G1/S phase transition, proliferation and viability. IGF1 and CCND1 were identified as candidate target genes regulated by miR-1. In addition, overexpression of miR-1 could suppress the expression of these two genes at the mRNA level. It could also correspondingly inhibit CCND1 expression at the protein level but not for IGF1., Conclusions: Our results suggest that miR-1 plays an important role in inhibiting cardiomyocyte proliferation in the developing neonatal mouse heart by directly suppressing the cell-cycle regulator, CCND1., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

SummaryFibroblast growth factor (FGF) signalling acts as one of modulators that control neural crest cell (NCC) migration, but how this is achieved is still unclear. In this study, we investigated the effects of FGF signalling on NCC migration by blocking this process. Constructs that were capable of inducing Sprouty2 (Spry2) or dominant-negative FGFR1 (Dn-FGFR1) expression were transfected into the cells making up the neural tubes. Our results revealed that blocking FGF signalling at stage HH10 (neurulation stage) could enhance NCC migration at both the cranial and trunk levels in the developing embryos. It was established that FGF-mediated NCC migration was not due to altering the expression of N-cadherin in the neural tube. Instead, we determined that cyclin D1 was overexpressed in the cranial and trunk levels when Sprouty2 was upregulated in the dorsal neural tube. These results imply that the cell cycle was a target of FGF signalling through which it regulates NCC migration at the neurulation stage.

Antimicrobial resistance of disease-related microorganisms is considered a worldwide prevalent and serious issue which increases the failure of treatment outcomes and leads to high mortality. Considering that the increased resistance to systemic antimicrobial therapy often needs of the use of more toxic agents, topical antimicrobial therapy emerges as an attractive route for the treatment of infectious diseases. The topical antimicrobial therapy is based on the absorption of high drug doses in a readily accessible skin surface, resulting in a reduction of microbial proliferation at infected skin sites. Topical antimicrobials retain the following features: (a) they are able to escape the enzymatic degradation and rapid clearance in the gastrointestinal tract or the first-pass metabolism during oral administration; (b) alleviate the physical discomfort related to intravenous injection; (c) reduce possible adverse effects and drug interactions of systemic administrations; (d) increase patient compliance and convenience; and (e) reduce the treatment costs. Novel antimicrobials for topical application have been widely exploited to control the emergence of drug-resistant microorganisms. This review provides a description of antimicrobial resistance, common microorganisms causing skin and soft tissue infections, topical delivery route of antimicrobials, safety concerns of topical antimicrobials, recent advances, challenges and future prospective in topical antimicrobial development.

Background: Physical variables like mortality or cardiac events were used to evaluate the requirement of red blood cell (RBC) transfusion. However, patient-reported outcomes (PROs) of blood transfusion recipients were seldom assessed. The health-related quality of life (HRQoL) of patients before and after RBC transfusion was compared in this study., Study Design and Methods: The study period was February to June 2016. Standardized generic and anemia symptom-specific HRQoL instruments were administered to patients receiving RBC transfusion in the medical unit of a single center. The primary outcome was the change in HRQoL scores on Days 1 and 7 posttransfusion from baseline values on the day of transfusion (Day 0). Multiple linear regression analysis was performed to study the effect of transfusion strategy and other factors on PRO., Results: The analysis included 99 general medical patients. The median (interquartile range) pretransfusion hemoglobin level was 72 (66-78) g/L. Two or more units of RBCs were prescribed to 45 patients (45%) on Day 0. Functional Assessment of Cancer Therapy-Anemia Subscale improved significantly on Days 1 and 7 by effect sizes of 0.41 and 0.38, respectively (p < 0.001). Regression analysis showed that lower baseline HRQoL scores were associated with better PRO on both Day 1 and Day 7 (p < 0.001). Transfusion trigger and number of RBC units transfused did not affect the change in HRQoL., Conclusion: Worse pretransfusion HRQoL is a predictor of improvement in PRO after blood transfusion. There is no evidence that a restrictive transfusion or single-unit policy jeopardizes PRO., (© 2017 AABB.)

Excess alcohol consumption during pregnancy could lead to fetal alcohol syndrome (FAS). However, the molecular mechanism leading to craniofacial abnormality, a feature of FAS, is still poorly understood. The cranial neural crest cells (NCCs) contribute to the formation of the craniofacial bones. Therefore, NCCs exposed to ethanol was investigated - using chick embryos and in vitro explant culture as experimental models. We demonstrated that exposure to 2% ethanol induced craniofacial defects, which includes parietal defect, in the developing chick fetus. Immunofluorescent staining revealed that ethanol treatment downregulated Ap-2ɑ, Pax7 and HNK-1 expressions by cranial NCCs. Using double-immunofluorescent stainings for Ap-2ɑ/pHIS3 and Ap-2ɑ/c-Caspase3, we showed that ethanol treatment inhibited cranial NCC proliferation and increased NCC apoptosis, respectively. Moreover, ethanol treatment of the dorsal neuroepithelium increased Laminin, N-Cadherin and Cadherin 6B expressions while Cadherin 7 expression was repressed. In situ hybridization also revealed that ethanol treatment up-regulated Cadherin 6B expression but down-regulated slug, Msx1, FoxD3 and BMP4 expressions. In summary, our experimental results demonstrated that ethanol treatment interferes with the production of cranial NCCs by affecting the proliferation and apoptosis of these cells. In addition, ethanol affected the delamination, epithelial-mesenchymal transition (EMT) and cell migration of cranial NCCs, which may have contributed to the etiology of the craniofacial defects., (Copyright © 2017. Published by Elsevier B.V.)

Activation of osteoblasts in bone formation and osteoclasts in bone resorption is important during the bone fracture healing process. There has been a long interest in identifying and developing a natural therapy for bone fracture healing. In this study, we investigated the regulation of osteoclast differentiation by baicalin, which is a natural molecule extracted from Eucommiaulmoides (small tree native to China). It was determined that baicalin enhanced osteoclast maturation and bone resorption activity in a dose-dependent manner. Moreover, this involves the activation of MAPK, increased Mitf nuclear translocation and up-regulation of downstream osteoclast-related target genes expression. The baicalin-induced effect on osteoclast differentiation can be mimicked by specific inhibitors of p-ERK (U0126) and the Mitf-specific siRNA, respectively. Protein-ligand docking prediction identified that baicalin might bind to RANK, which is the upstream receptor of p-ERK/Mitf signalling in osteoclasts. This indicated that RANK might be the binding target of baicalin. In sum, our findings revealed baicalin increased osteoclast maturation and function via p-ERK/Mitf signalling. In addition, the results suggest that baicalin can potentially be used as a natural product for the treatment of bone fracture., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Bag1 transcribes a multifunctional protein that participates in many important biological processes such as cell apoptosis, proliferation, differentiation and embryo development. Despite numerous published studies, the role of Bag1 in the context of embryonic stem (ES) cells, has not been explored. To investigate the function of Bag1 in ES cells, we generated mutant Bag1 -/- ES cells using the CRISPR/Cas9 system. We established that the Bag1 double knockout ES cell line maintained their pluripotency, possessed a normal karyotype and the ability to differentiate into all three germ layers., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Deep tissue pressure ulcers, a serious clinical challenge originating in the muscle layer, are hardly detectable at the beginning. The challenge apparently occurs in aged subjects more frequently. As the ulcer propagates to the skin surface, it becomes very difficult to manage and can lead to fatal complications. Preventive measures are thus highly desirable. Although the complex pathological mechanisms have not been fully understood, prolonged and excessive physical challenges and oxidative stress are believed to be involved in the ulcer development. Previous reports have demonstrated that oxidative stress could compromise the mechanical properties of muscle cells, making them easier to be damaged when physical challenges are introduced. In this study, we used senescence accelerated (SAMP8) mice and its control breed (SAMR1) to examine the protective effects of intermittent vibration on aged and control muscle tissues during prolonged epidermal compression under 100mmHg for 6h. Results showed that an application of 35Hz, 0.25g intermittent vibration during compression decreased the compression-induced muscle breakdown in SAMP8 mice, as indicated histologically in terms of number of interstitial nuclei. The fact that no significant difference in muscle damage could be established in the corresponding groups in SAMR1 mice suggests that SAMR1 mice could better accommodate the compression insult than SAMP8 mice. Compression-induced oxidative damage was successfully curbed using intermittent vibration in SAMP8 mice, as indicated by 8-OHdG. A possible explanation is that the anti-oxidative defense could be maintained with intermittent vibration during compression. This was supported by the expression level of PGC-1-alpha, catalase, Gpx-1 and SOD1. Our data suggested intermittent vibration could serve as a preventive measure for deep tissue ulcer, particularly in aged subjects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The BRE gene, alias BRCC45, produces a 44 kDa protein that is normally distributed in both cytoplasm and nucleus. In this study, we used adult fibroblasts isolated from wild-type (WT) and BRE knockout (BRE(-/-)) mice to investigate the functional role of BRE in DNA repair and cellular senescence. We compared WT with BRE(-/-) fibroblasts at different cell passages and observed that the mutant fibroblasts entered replicative senescence earlier than the WT fibroblasts. With the use of gamma irradiation to induce DNA damage in fibroblasts, the percentage of SA-β-Gal(+) cells was significantly higher in BRE(-/-) fibroblasts compared with WT cells, suggesting that BRE is also associated with DNA damage-induced premature senescence. We also demonstrated that the gamma irradiation induced γ-H2AX foci, a DNA damage marker, persisted significantly longer in BRE(-/-) fibroblasts than in WT fibroblasts, confirming that the DNA repair process is impaired in the absence of BRE. In addition, the BRCA1-A complex recruitment and homologous recombination (HR)-dependent DNA repair process upon DNA damage were impaired in BRE(-/-) fibroblasts. Taken together, our results demonstrate a role for BRE in both replicative senescence and DNA damage-induced premature senescence. This can be attributed to BRE being required for BRCA1-A complex-driven HR DNA repair.

Background: Hair bulge progenitor cells (HBPCs) are multipotent stem cells derived from the bulge region of mice vibrissal hairs. The purified HBPCs express CD34, K15 and K14 surface markers. It has been reported that HBPCs could be readily induced to transdifferentiate into adipocytes and osteocytes. However, the ability of HBPCs to transdifferentiate into cardiomyocytes has not yet been investigated., Methodology/principal Findings: The cardiomyogenic potential of HBPCs was investigated using a small cell-permeable molecule called Cardiogenol C. We established that Cardiogenol C could induce HBPCs to express transcription factors GATA4, Nkx2.5 and Tbx5, which are early specific markers for pre-cardiomyogenic cells. In prolonged cultures, the Cardiogenol C-treated HBPCs can also express muscle proteins, cardiac-specific troponin I and sarcomeric myosin heavy chain. However, we did not observe the ability of these cells to functionally contract. Hence, we called these cells cardiomyocyte-like cells rather than cardiomyocytes. We tried to remedy this deficiency by pre-treating HBPCs with Valproic acid first before exposing them to Cardiogenol C. This pretreatment inhibited, rather than improved, the effectiveness of Cardiogenol C in reprogramming the HBPCs. We used comparative proteomics to determine how Cardiogenol C worked by identifying proteins that were differentially expressed. We identified proteins that were involved in promoting cell differentiation, cardiomyocyte development and for the normal function of striated muscles. From those differentially expressed proteins, we further propose that Cardiogenol C might exert its effect by activating the Wnt signaling pathway through the suppression of Kremen1. In addition, by up-regulating the expression of chromatin remodeling proteins, SIK1 and Smarce1 would initiate cardiac differentiation., Conclusions/significance: In conclusion, our CD34+/K15+ HBPCs could be induced to transdifferentiate into cardiomyocyte-like cells using a small molecule called Cardiogenol C. The process involves activation of the Wnt signaling pathway and altered expression of several key chromatin remodeling proteins. The finding is clinically significant as HBPCs offer a readily accessible and autologous source of progenitor cells for cell-based therapy of heart disease, which is one of major killers in developed countries.