ABSTRACT
BACKGROUND: Cancer care has evolved rapidly, increasing the demand on healthcare resources. While many non-oral cancer treatments are administered in the hospital, not all necessitate complex medical care. Treatments that can be administered subcutaneously, intramuscularly, or as short intravenous infusions with a low risk of extravasation can be safely administered in the community. PATIENTS AND METHODS: Since 2017, the National University Cancer Institute, Singapore (NCIS) has operated a program called NCIS on-the-go (NOTG) comprising a network of community cancer treatment clinics located within 20 km of the hospital. NOTG provides 17 low-risk treatments and nursing services run by oncology-trained nurses without on-site physicians. Patients who receive their first dose of cancer treatment uneventfully in the cancer centre can opt-in to receive subsequent doses at any NOTG clinic. RESULTS: Treatment at NOTG has become more mainstream over the years, with its workload increasing by over sevenfold since 2017, and is now responsible for â¼10% of the total main cancer centre workload. The program is sustainable and financially viable to operate. A survey of 155 patients revealed a 96.8% user satisfaction rate, with the majority reporting tangible savings in travelling time, waiting time, and travelling costs. The diversion of low-risk treatments to NOTG has indirectly increased capacity and reduced waiting times at the main cancer centre for patients requiring complex cancer treatments, resulting in a win-win situation. CONCLUSIONS: NOTG represents an innovative model of care to deliver low-risk cancer treatments safely in the community and can be easily replicated in other countries.
Subject(s)
Neoplasms , Tertiary Care Centers , Humans , Singapore , Neoplasms/therapy , Tertiary Care Centers/organization & administration , Delivery of Health Care , Cancer Care Facilities/organization & administrationABSTRACT
OBJECTIVES: Long working hour is a known risk factor for metabolic diseases. We explored the association between working hours and metabolic dysfunction-associated steatotic liver disease (MASLD). STUDY DESIGN: Data on working hours among 22,818 workers (11,999 females) from the Korea National Health and Nutrition Examination Survey (2013-2021) were used for this study. METHODS: MASLD was defined as a combination of hepatic steatosis combined with one or more of cardiometabolic risk factors (overweight/obesity, prediabetes/diabetes, raised blood pressure, hypertriglyceridemia, low high-density lipoprotein cholesterol). Hepatic steatosis was assessed using the hepatic steatosis index. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The overall prevalence of MASLD was 30.4% in men and 18.1% in women. Among male workers, 20.2% worked ≥55 h/week, whereas among female workers, 10.1% worked ≥55 h/week. Compared with working 35-40 h/week, working ≥55 h/week was positively associated with overweight/obesity (OR: 1.21; 95% CI: 1.05-1.40), pre-diabetes mellitus (pre-DM)/DM (OR: 1.20; 95% CI: 1.04-1.38), raised blood pressure (OR: 1.17; 95% CI: 1.02-1.35), and presence of any cardiometabolic risk factors (OR: 1.56; 95% CI: 1.21-2.02). The adjusted OR (95% CI) of the association between working hours and MASLD was 1.27 (1.09-1.47) for ≥55 h/week compared with working 35-40 h/week in male workers. In female workers, long working hours were not clearly associated with cardiometabolic risk factors and MASLD. CONCLUSION: Long working hours are positively associated with MASLD among Korean male workers. Policy interventions are needed to mitigate the adverse metabolic effects of prolonged working hours.
Subject(s)
Nutrition Surveys , Humans , Republic of Korea/epidemiology , Male , Female , Adult , Middle Aged , Risk Factors , Prevalence , Metabolic Diseases/epidemiology , Fatty Liver/epidemiology , Work Schedule Tolerance , Obesity/epidemiologyABSTRACT
PURPOSE OF THE STUDY: Laminectomy with fusion (LF) is commonly performed with laminoplasty (LP) for cervical myelopathy. Foraminal stenosis is important in the surgical treatment of cervical myelopathy. LF and LP can affect foraminal size in different ways. This study aimed to compare foraminal dimensions after LF and LP using a medical computer-assisted design (CAD) program. MATERIAL AND METHODS: Computed tomography (CT) scans of the cervical vertebrae of 16 patients with cervical myelopathy were retrospectively viewed in the Digital Imaging and Communications in Medicine format on a CAD program. CT images were reformatted in an oblique plane perpendicular to the long axis of each foramen from C2-C3 to C6-C7. The narrowest foraminal crosssectional dimension (FCD) was measured and compared between the LF and LP groups at the operated, non-operated, and C4-C5 levels. The difference between the preoperative and postoperative FCDs was also calculated and compared between the operated and C4-C5 levels. Intra- and interobserver reliabilities for FCD measurements were evaluated using intraclass correlation coefficients. RESULTS AND DISCUSSION: At the operated spinal levels, the LF and LP groups showed decreased and increased mean FCDs, respectively. At the adjacent non-operated levels, the mean FCD slightly increased in both the groups. In the LF group, the difference between the preoperative and postoperative FCDs in the C4-C5 levels was larger than that in the other operated levels, but this difference was insignificant. CONCLUSIONS: LF and LP showed contrary results for FCD. Therefore, FCD and kyphosis should be considered for LF and LP. KEY WORDS: three-dimensional, foraminal cross-sectional dimension, laminoplasty, laminectomy fusion, computer-aided design, drafting system, preoperative-postoperative comparison.
Subject(s)
Cervical Vertebrae , Imaging, Three-Dimensional , Laminectomy , Laminoplasty , Spinal Fusion , Tomography, X-Ray Computed , Humans , Laminectomy/methods , Cervical Vertebrae/surgery , Cervical Vertebrae/diagnostic imaging , Laminoplasty/methods , Spinal Fusion/methods , Female , Male , Tomography, X-Ray Computed/methods , Retrospective Studies , Imaging, Three-Dimensional/methods , Middle Aged , Spinal Cord Diseases/surgery , Spinal Cord Diseases/diagnostic imaging , AgedABSTRACT
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has influenced hospital infection control practices. AIM: To evaluate the impact of the COVID-19 pandemic on healthcare-associated infections (HAIs) in intensive care units (ICUs). METHODS: A retrospective analysis using data from the Korean National Healthcare-Associated Infections Surveillance System was conducted. Comparisons between incidence rates and micro-organism distributions of bloodstream infection (BSI), central line-associated bloodstream infections (CLABSI), catheter-associated urinary tract infection (CAUTI), and ventilator-associated pneumonia (VAP) before and during the COVID-19 pandemic were performed according to hospital size. FINDINGS: The incidence rate of BSI significantly decreased during the COVID-19 pandemic compared to the pre-COVID-19 period (1.38 vs 1.23 per 10,000 patient-days, relative change -11.5%; P < 0.001). The incidence rate of VAP (1.03 vs 0.81 per 1000 device-days, relative change -21.4%; P < 0.001) significantly decreased during the COVID-19 pandemic compared to the pre-COVID-19 period, whereas rates of CLABSI (2.30 vs 2.23 per 1000 device-days; P = 0.19) and CAUTI (1.26 vs 1.26 per 1000 device-days; P = 0.99) were similar between the two periods. The rates of BSI and CLABSI significantly increased during the COVID-19 pandemic compared to the pre-COVID-19 period in large-sized hospitals, whereas these rates significantly decreased in small-to-medium-sized hospitals. The rates of CAUTI and VAP significantly decreased in small-sized hospitals. There were no significant changing trends in the rates of multidrug-resistant pathogens isolated from patients with HAI between the two periods. CONCLUSION: The incidence rates of BSI and VAP in ICUs decreased during the COVID-19 pandemic compared to the pre-COVID-19 period. This decrease was mainly seen in small-to-medium-sized hospitals.
Subject(s)
COVID-19 , Catheter-Related Infections , Cross Infection , Pneumonia, Ventilator-Associated , Sepsis , Urinary Tract Infections , Humans , Catheter-Related Infections/epidemiology , COVID-19/epidemiology , Cross Infection/epidemiology , Intensive Care Units , Pandemics , Pneumonia, Ventilator-Associated/epidemiology , Republic of Korea/epidemiology , Retrospective Studies , Sepsis/epidemiology , Urinary Tract Infections/epidemiologyABSTRACT
A new, to the best of our knowledge, output coupler (OC) with enhancement of the cavity reflectivity is proposed to remarkably elevate the output powers and efficiencies of diode-pumped Nd:GdVO4/KGW Raman yellow-orange lasers. The cavity reflectivity is effectively increased by using the double-sided dichroic coating on the OC. In comparison with the conventional single-sided coating, the conversion efficiency can be boosted from 15% to 26.3% in the experiment of a yellow laser at 578.8 nm, and the maximum output power can be increased from 5.7 to 10.5 W in the quasi-continuous-wave mode with 50% duty cycle and frequency of 500 Hz. Furthermore, in the operation of an orange laser at 588 nm, the maximum output power can be improved from 5.6 to 7.0 W by replacing the conventional OC with the new one.
ABSTRACT
BACKGROUND: The effects of subinhibitory concentrations (sub-MICs) of antibacterial agents on the biofilm-forming ability of Staphylococcus aureus require further study. AIM: To investigate the effects of sub-MICs of chlorhexidine and mupirocin on biofilm formation in clinical meticillin-resistant Staphylococcus aureus (MRSA) isolates. METHODS: MRSA isolates were collected from patients with bloodstream infections at a tertiary care hospital. The basal level of biofilm formation and biofilm induction by sub-MICs of chlorhexidine and mupirocin were evaluated by measuring biofilm mass stained with Crystal Violet. FINDINGS: Of the 112 MRSA isolates tested, 63 (56.3%) and 44 (39.3%) belonged to sequence type (ST)5 and ST72 lineages, respectively, which are the predominant healthcare- and community-associated clones in South Korea. ST5 isolates were more likely to have chlorhexidine MIC ≥4 (73.0% vs 29.5%), resistance to mupirocin (23.8% vs 0%), agr dysfunction (73.0% vs 9.1%), and qacA/B gene (58.7% vs 2.3%) compared to ST72 isolates. The basal level of biofilm formation ability was frequently stronger in ST72 isolates compared to ST5 isolates (77.3% vs 12.7%). Sub-MICs of chlorhexidine and mupirocin promoted biofilm formation in 56.3% and 53.6%, respectively, of all isolates. Biofilm induction was more prevalent in ST5 isolates (85.7% for chlorhexidine, 69.8% for mupirocin) than in ST72 isolates (15.9% for chlorhexidine, 27.3% for mupirocin). CONCLUSION: Sub-MICs of chlorhexidine and mupirocin promoted biofilm formation in half of the clinical MRSA isolates. Our results suggest that ST5 MRSA biofilm can be induced together with some other bacterial virulent factors following exposure to chlorhexidine, which might confer a survival advantage to this clone in the healthcare environment.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Chlorhexidine/pharmacology , Disinfectants/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Mupirocin/pharmacology , Carrier State/microbiology , Humans , Microbial Sensitivity Tests , Republic of Korea , Staphylococcal Infections/blood , Staphylococcal Infections/microbiology , Tertiary Care CentersABSTRACT
BACKGROUND: The effects of early central venous catheter (CVC) removal on the clinical outcomes of patients with candidaemia remain controversial. This study evaluated the impact of delayed CVC removal on mortality according to the severity of comorbidities in patients with candidaemia. METHODS: Patients with candidaemia in a tertiary care hospital between January 2010 and December 2017 were included retrospectively. The severity of comorbidities was classified as low [Charlson Comorbidity Index (CCI) score ≤3] or high (CCI score ≥4). Cases with removal of CVC >2 days after the onset of candidaemia or without CVC removal were classified as having delayed CVC removal. RESULTS: In total, 239 patients with candidaemia were included, excluding 18 who died within 2 days of onset of candidaemia. Of these, 149 had low CCI scores and 90 had high CCI scores. Septic shock [adjusted odds ratio (aOR)=9.5] and delayed CVC removal (aOR=4.7) were significantly associated with increased 30-day mortality, whereas Candida parapsilosis infection (aOR=0.2) and cerebrovascular disease (aOR=0.3) were associated with decreased 30-day mortality, in patients with low CCI scores. Septic shock (aOR=13.0) was the only risk factor for 30-day mortality in those with high CCI scores. Delayed CVC removal was associated with increased 30-day mortality in patients with low CCI scores (50.0% vs 20.3%; P=0.001), but not in those with high CCI scores (50.0% vs 47.9%; P=0.87). CONCLUSION: Early CVC removal may improve the survival of patients with candidaemia and low CCI scores, but no such protective effect was evident in those with high CCI scores.
Subject(s)
Candidemia/mortality , Catheter-Related Infections/mortality , Catheterization, Central Venous/methods , Aged , Candidemia/complications , Catheter-Related Infections/complications , Comorbidity , Female , Humans , Male , Middle Aged , Retrospective Studies , Survival Analysis , Tertiary Care Centers , Time FactorsABSTRACT
Since publication of the original article, the authors have noticed that there were errors in the labelling of Figures 6D and 6E. The correct figure and its legend are reproduced here. The authors wish to apologise for any inconvenience caused.
ABSTRACT
Candida albicans, a major opportunistic fungal pathogen, is frequently found together with Streptococcus mutans in dental biofilms associated with severe childhood caries (tooth decay), a prevalent pediatric oral disease. However, the impact of this cross-kingdom relationship on C. albicans remains largely uncharacterized. Here, we employed a novel quantitative proteomics approach in conjunction with transcriptomic profiling to unravel molecular pathways of C. albicans when cocultured with S. mutans in mixed biofilms. RNA sequencing and iTRAQ (isobaric tags for relative and absolute quantitation)-based quantitative proteomics revealed that C. albicans genes and proteins associated with carbohydrate metabolism were significantly enhanced, including sugar transport, aerobic respiration, pyruvate breakdown, and the glyoxylate cycle. Other C. albicans genes and proteins directly and indirectly related to cell morphogenesis and cell wall components such as mannan and glucan were also upregulated, indicating enhanced fungal activity in mixed-species biofilm. Further analyses revealed that S. mutans-derived exoenzyme glucosyltransferase B (GtfB), which binds to the fungal cell surface to promote coadhesion, can break down sucrose into glucose and fructose that can be readily metabolized by C. albicans, enhancing growth and acid production. Altogether, we identified key pathways used by C. albicans in the mixed biofilm, indicating an active fungal role in the sugar metabolism and environmental acidification (key virulence traits associated with caries onset) when interacting with S. mutans, and a new cross-feeding mechanism mediated by GtfB that enhances C. albicans carbohydrate utilization. In addition, we demonstrate that comprehensive transcriptomics and quantitative proteomics can be powerful tools to study microbial contributions which remain underexplored in cross-kingdom biofilms.
Subject(s)
Biofilms/growth & development , Candida albicans/genetics , Gene Expression Regulation, Bacterial , Gene Expression Regulation, Fungal , Streptococcus mutans/genetics , Transcriptome , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Candida albicans/metabolism , Candida albicans/pathogenicity , Carbohydrate Metabolism , Cell Wall/metabolism , Child , Coculture Techniques , Dental Caries/microbiology , Dental Caries/pathology , Glucans/metabolism , Glucosyltransferases/genetics , Glucosyltransferases/metabolism , Humans , Proteomics , Streptococcus mutans/metabolism , Streptococcus mutans/pathogenicity , Symbiosis/geneticsABSTRACT
Numerous depth extraction techniques have been proposed in the past. However, the utility of these techniques is limited as they typically require multiple imaging units, bulky platforms for computation, cannot achieve high speed and are computationally expensive. To counter the above challenges, a sensor with Offset Pixel Apertures (OPA) has been recently proposed. However, a working system for depth extraction with the OPA sensor has not been discussed. In this paper, we propose the first such system for depth extraction using the OPA sensor. We also propose a dedicated hardware implementation for the proposed system, named as the Depth Map Processor (DMP). The DMP can provide depth at 30 frames per second at 1920 × 1080 resolution with 31 disparity levels. Furthermore, the proposed DMP has low power consumption as for the aforementioned speed and resolution it only requires 290.76 mW. The proposed system makes it an ideal choice for depth extraction systems in constrained environments.
ABSTRACT
This study evaluated potential changes in antischistosome immune responses in children from schools that received 4 rounds of annual mass drug administration (MDA) of praziquantel (PZQ). In a repeated cross-sectional study design, 210 schistosome egg-positive children were recruited at baseline from schools in western Kenya (baseline group). Another 251 children of the same age range were recruited from the same schools and diagnosed with schistosome infection by microscopy (post-MDA group). In-vitro schistosome-specific cytokines and plasma antibody levels were measured by ELISA and compared between the 2 groups of children. Schistosome soluble egg antigen (SEA) and soluble worm antigen preparation (SWAP) stimulated higher IL-5 production by egg-negative children in the post-MDA group compared to the baseline group. Similarly, anti-SEA IgE levels were higher in egg-negative children in the post-MDA group compared to the baseline group. Anti-SEA and anti-SWAP IgG4 levels were lower in egg-negative children in the post-MDA group compared to baseline. This resulted in higher anti-SEA IgE/IgG4 ratios for children in the post-MDA group compared to baseline. These post-MDA immunological changes are compatible with the current paradigm that treatment shifts immune responses to higher antischistosome IgE:IgG4 ratios in parallel with a potential increase in resistance to reinfection.
Subject(s)
Anthelmintics/therapeutic use , Antibodies, Helminth/blood , Mebendazole/therapeutic use , Praziquantel/therapeutic use , Schistosoma mansoni/drug effects , Schistosoma mansoni/immunology , Schistosomiasis mansoni/drug therapy , Adolescent , Animals , Child , Cross-Sectional Studies , Cytokines/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immune System Phenomena , Immunoglobulin E/blood , Immunoglobulin G/blood , Kenya , Male , Schistosomiasis mansoni/prevention & controlABSTRACT
AIMS: This study investigated the association of persistent organic pollutants (POPs), an emerging new risk factor for type 2 diabetes and the metabolic syndrome, with the presence of opposite phenotypes of glucose and lipid metabolism among normal-weight Koreans of similar body composition. METHODS: Fifty subjects, randomly selected from an ongoing community-based cohort study, from two opposite phenotype groups - metabolically unhealthy normal weight (MUHNW) and metabolically healthy normal weight (MHNW) - were matched for waist circumference, visceral fat mass and demographic variables, then compared for serum concentrations of POPs. RESULTS: Most POPs (10 out of 13 compounds) were present in higher serum concentrations in the MUHNW than in the MHNW. In particular, serum concentrations of all compounds of the organochlorine pesticide class were 2.2 to 4.7 times higher in cases than in controls. Compared with the lowest tertile of summary measures of POPs, Odds ratios (95% confidence interval) for the second and third tertiles were 7.4 (1.9-29.4) and 10.4 (2.6-41.2), respectively. Adjusting for possible confounders did not change the results. CONCLUSION: Taken altogether, these findings from the present and previous studies suggest that increased serum POP concentrations may play an important role in the development of unhealthy metabolic phenotypes in lean people.
Subject(s)
Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Environmental Pollutants/blood , Metabolic Syndrome/blood , Metabolic Syndrome/epidemiology , Adult , Case-Control Studies , Female , Humans , Ideal Body Weight/physiology , Male , Phenotype , Republic of Korea/epidemiology , Risk FactorsABSTRACT
BACKGROUND: Gram-negative bacteria are increasingly the cause of catheter-related bloodstream infection (CRBSI), and the prevalence of multi-drug-resistant strains is rising rapidly. This study evaluated the impact of delayed central venous catheter (CVC) removal on clinical outcomes in patients with Gram-negative CRBSI. METHODS: Between January 2007 and December 2016, patients with Gram-negative bacteraemia and CVC placement, from two tertiary care hospitals, were included retrospectively. Cases with CVC removal more than three days after onset of bacteraemia or without CVC removal were classified as having delayed CVC removal. RESULTS: In total, 112 patients were included. Of these, 78 had CRBSI (43 definite and 35 probable) and 34 had Gram-negative bacteraemia from another source (non-CRBSI). Enterobacteriaceae were less common pathogens in patients with CRBSI than in patients with non-CRBSI (11.5% vs 41.3%; P<0.001). Delayed CVC removal was associated with increased 30-day mortality (40.5% vs 11.8%; P=0.01) in patients with Gram-negative CRBSI; this was not seen in patients with non-CRBSI (25.0% vs 14.3%; P>0.99). Delayed CVC removal [odds ratio (OR) 6.8], multi-drug-resistant (MDR) Gram-negative bacteraemia (OR 6.3) and chronic renal failure (OR 11.1) were associated with 30-day mortality in patients with CRBSI. The protective effect of early CVC removal on mortality was evident in the MDR group (48.3% vs 18.2%; P=0.03), but not in the non-MDR group (11.1% vs 0%; P=0.43). CONCLUSION: CVCs should be removed early to improve clinical outcomes in patients with Gram-negative CRBSI, especially in settings where MDR isolates are prevalent.
Subject(s)
Bacteremia/epidemiology , Catheter-Related Infections/complications , Catheter-Related Infections/epidemiology , Central Venous Catheters/adverse effects , Device Removal/methods , Gram-Negative Bacterial Infections/epidemiology , Adult , Aged , Aged, 80 and over , Bacteremia/mortality , Bacteremia/therapy , Catheter-Related Infections/mortality , Catheter-Related Infections/therapy , Female , Gram-Negative Bacterial Infections/mortality , Gram-Negative Bacterial Infections/therapy , Humans , Male , Middle Aged , Retrospective Studies , Survival Analysis , Tertiary Care Centers , Time Factors , Treatment OutcomeABSTRACT
This corrects the article DOI: 10.1038/oncsis.2017.87.
ABSTRACT
Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2), epithelial cell-specific regulators of alternative splicing, are downregulated during the epithelial-mesenchymal transition (EMT). These factors have roles in tumor progression and metastasis in some cancers; however, their expression and function in ovarian cancer (OC) remain unclear. We found that ESRP1 and ESRP2 mRNAs were expressed at higher levels in OC cells than in immortalized ovarian surface epithelial (IOSE) cells, and confirmed their overexpression in OC tissues at the protein level. The Cancer Genome Atlas (TCGA) data analysis revealed frequent gene amplification of ESRP1 in OC tissues; however, we detected no significant correlation between ESRP1 gene copy number and gene expression in OC cells. Importantly, expression of ESRP1 and ESRP2 was inversely correlated with DNA methylation in OC cells, and ESRP2 overexpression in OC tissues was significantly associated with DNA hypomethylation. Notably, survival analysis using TCGA data from 541 OC tissues revealed that high ESRP1 expression was significantly associated with shorter 5-year survival of patients. Ectopic ESRP1 expression in mesenchymal OC cells promoted cell proliferation but suppressed cell migration. Furthermore, we found that ESRP1 drives a switch from mesenchymal to epithelial phenotype characterized by reduced cell migration in association with induction of epithelial cell-specific variant of CD44 and ENAH. Taken together, our findings suggest that an epigenetic mechanism is involved in ESRP1 overexpression, and that ESRP1 has a role in OC progression.
ABSTRACT
Autophagy is an intracellular degradation process activated by stress factors such as nutrient starvation to maintain cellular homeostasis. There is emerging evidence demonstrating that de novo protein synthesis is involved in the autophagic process. However, up-to-date characterizing of these de novo proteins is technically difficult. In this chapter, we describe a novel method to identify newly synthesized proteins during starvation-mediated autophagy by bioorthogonal noncanonical amino acid tagging (BONCAT), in conjunction with isobaric tagging for relative and absolute quantification (iTRAQ)-based quantitative proteomics. l-azidohomoalanine (AHA) is an analog of methionine, and it can be readily incorporated into the newly synthesized proteins. The AHA-containing proteins can be enriched with avidin beads after a "click" reaction between alkyne-bearing biotin and the azide moiety of AHA. The enriched proteins are then subjected to iTRAQ™ labeling for protein identification and quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). By using this technique, we have successfully profiled more than 700 proteins that are synthesized during starvation-induced autophagy. We believe that this approach is effective in identification of newly synthesized proteins in the process of autophagy and provides useful insights to the molecular mechanisms and biological functions of autophagy.
Subject(s)
Amino Acids/metabolism , Autophagy , Protein Biosynthesis , Proteins/metabolism , Proteomics/methods , Alanine/analogs & derivatives , Alanine/analysis , Alanine/metabolism , Amino Acids/analysis , Animals , Cell Culture Techniques/methods , Chromatography, Ion Exchange/methods , Click Chemistry/methods , HeLa Cells , Humans , Proteins/chemistry , Spectrometry, Mass, Electrospray Ionization/methodsABSTRACT
Identifying the cellular binding targets of drugs and other bioactive small molecules is a crucial step for understanding their molecular mechanisms of action as well as potential off-target effects. The field of chemical proteomics is an emerging discipline in chemical biology using synthetic chemistry and high-throughput detection techniques to study small molecule-protein interactions. In this chapter, we describe a quantitative chemical proteomics protocol combining bioorthogonal click chemistry and quantitation by isobaric tags for relative and absolute quantification (iTRAQ) to identify the specific binding targets of drugs and bioactive small molecules such as natural products. A modified drug probe with a click chemistry-enabling addition is synthesized and used in live cell treatments where it undergoes covalent interactions with its cognate cellular targets. The probes are then ligated to biotin through click chemistry and enriched with avidin beads, followed by iTRAQ labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for protein identification and relative quantitation discriminating specific targets from nonspecific binding proteins. The presented protocol has been used to successfully profile prominent drugs and natural products including andrographolide, aspirin, curcumin, etc., and can be a powerful tool to study the molecular mechanisms of bioactive small molecules.
Subject(s)
Alkynes/chemistry , Diterpenes/chemistry , Proteome/isolation & purification , Chromatography, Liquid , Click Chemistry , HCT116 Cells , Humans , Protein Binding , Proteome/chemistry , Proteomics , Staining and Labeling , Tandem Mass SpectrometryABSTRACT
Although low doses of persistent organic pollutants (POPs), strong lipophilic chemicals with long half-lives, have been linked to various endocrine, immune, nervous and reproductive system diseases, few obesity studies have considered adipose tissue as an important POPs exposure source. Because the toxicodynamics of POPs relate directly to the dynamics of adiposity, POPs might explain puzzling findings in obesity research. In two people exposed to the same amounts of environmental POPs, the one having more adipose tissue may be advantaged because POPs storage in adipose tissue can reduce burden on other critical organs. Therefore, adipose tissue can play a protective role against the POPs effects. However, two situations increase the POPs release from adipose tissue into the circulation, thereby increasing the risk that they will reach critical organs: (i) weight loss and (ii) insulin resistance. In contrast, weight gain reduces this possibility. Therefore, avoiding harmful health effects of POPs may mostly contradict conventional judgments about obesity and weight change. These contradictory situations can explain the obesity paradox, the adverse effects of intensive intentional weight loss and the protective effects of obesity against dementia. Future studies should consider that adipose tissue is widely contaminated with POPs in modern society.
Subject(s)
Adiposity/drug effects , Environmental Pollutants/adverse effects , Obesity/epidemiology , Body Weight , Environmental Pollutants/analysis , Humans , Insulin Resistance , Obesity/chemically induced , Risk FactorsABSTRACT
We fabricated C-doped (1.5 wt.%) In3Sb1Te2 (CIST) thin films with amorphous phase (a-CIST) using a sputter method. Two electrical-phase-changes at 250 and 275 °C were observed in the sheet resistance measurement. In order to understand the origin of these electrical-phase-changes, all samples were characterized by XRD, TEM, and HRXPS with synchrotron radiation. In a-CIST, only weak Sb-C bonding was observed. In the first electrical-phase-change at 250 °C, strong Sb-C bonding occurred without an accompanying structural/phase change (still amorphous). On the other hand, the second electrical-phase-change at 275 °C was due to the structural/phase change from amorphous to crystalline without a chemical state change.
ABSTRACT
This study aimed to investigate the role of PIN1 on the hepatic differentiation of human dental pulp stem cells (hDPSCs) and its signaling pathway, as well as the potential therapeutic effects of hDPSC transplantation and PIN1 inhibition on CCl4 (carbon tetrachloride)-induced liver fibrosis in mice. The in vitro results showed that hepatic differentiation was suppressed by infection with adenovirus-PIN1 and promoted by PIN1 inhibitor juglone via the downregulation of Wnt3a and ß-catenin. Compared with treatment with either hDPSC transplantation or juglone alone, the combination of hDPSCs and juglone into CCl4-injured mice significantly suppressed liver fibrosis and restored serum levels of alanine transaminase, aspartate transaminase, and ammonia. Collectively, the present study shows for the first time that PIN1 inhibition promotes hepatic differentiation of hDPSCs through the Wnt/ß-catenin pathway. Furthermore, juglone in combination with hDPSC transplantation effectively treats liver fibrosis, suggesting that hDPSC transplantation with PIN1 inhibition may be a novel therapeutic candidate for the treatment of liver injury.