Fabrication of versatile poly(xylitol sebacate)-co-poly(ethylene glycol) hydrogels through multifunctional crosslinkers and dynamic bonds for wound healing.

Poly(polyol sebacate) (PPS) polymer family has been recognized as promising biomaterials for biomedical applications with their characteristics of easy production, elasticity, biodegradation, and cytocompatibility. Poly(xylitol sebacate)-co-poly(ethylene glycol) (PXS-co-PEG) has been developed to fabricate PPS-based hydrogels; however, current PXS-co-PEG hydrogels presented limited properties and functions due to the limitations of the crosslinkers and crosslinking chemistry used in the hydrogel formation. Here, we fabricate a new type of PXS-co-PEG hydrogels through the use of multifunctional crosslinkers as well as dynamic bonds. In our design, polyethyleneimine-polydopamine (PEI-PDA) macromers are utilized to crosslink aldehyde-functionalized PXS-co-PEG (APP) through imine bonds and hydrogen bonds. PEI-PDA/APP hydrogels present multiple functional properties (e.g., fluorescent, elastomeric, biodegradable, self-healing, bioadhesive, antioxidant, and antibacterial behaviors). These properties of PEI-PDA/APP hydrogels can be fine-tuned by changing the PDA grafting degrees in the PEI-PDA crosslinkers. Most importantly, PEI-PDA/APP hydrogels are considered promising wound dressings to promote tissue remodeling and prevent bacterial infection in vivo. Taken together, PEI-PDA/APP hydrogels have been demonstrated as versatile biomaterials to provide multiple tailorable properties and desirable functions to expand the utility of PPS-based hydrogels for advanced biomedical applications. STATEMENT OF SIGNIFICANCE: Various strategies have been developed to fabricate poly(polyol sebacate) (PPS)-based hydrogels. However, current PPS-based hydrogels present limited properties and functions due to the limitations of the crosslinkers and crosslinking chemistry used in the hydrogel formation. This work describes that co-engineering crosslinkers and interfacial crosslinking is a promising approach to synthesizing a new type of poly(xylitol sebacate)-co-poly(ethylene glycol) (PXS-co-PEG) hydrogels as multifunctional hydrogels to expand the utility of PPS-based hydrogels for advanced biomedical applications. The fabricated hydrogels present multiple functional properties (e.g., fluorescent, biodegradable, elastomeric, self-healing, bioadhesive, antioxidative, and antibacterial), and these properties can be fine-tuned by the defined crosslinkers. The fabricated hydrogels are also used as promising wound dressing biomaterials to exhibit promoted tissue remodeling and prevent bacterial infection in vivo.

Ultrasonic interfacial crosslinking of TiO2-based nanocomposite hydrogels through thiol-norbornene reactions for sonodynamic antibacterial treatment.

Nanocomposite (NC) hydrogels used for sonodynamic therapy (SDT) face challenges such as lacking interfacial interactions between the polymers and nanomaterials as well as presenting uneven dispersion of nanomaterials in the hydrogel network, reducing their mechanical properties and treatment efficiency. Here, we demonstrate a promising approach of co-engineering nanomaterials and interfacial crosslinking to expand the materials construction and biomedical applications of NC hydrogels in SDT. In this work, mesoporous silica-coated titanium dioxide nanoparticles with thiolated surface functionalization (TiO2@MS-SH) are utilized as crosslinkers to react with norbornene-functionalized dextran (Nor-Dex) through ultrasound-triggered thiol-norbornene reactions, forming TiO2@MS-SH/Nor-Dex NC hydrogels. The TiO2@MS-SH nanoparticles act not only as multivalent crosslinkers to improve the mechanical properties of hydrogels under ultrasound irradiation but also as reactive oxygen species (ROS) generators to allow the use of TiO2@MS-SH/Nor-Dex NC hydrogels in SDT applications. Particularly, the TiO2@MS-SH/Nor-Dex NC hydrogels present tailorable microstructures, properties, and sonodynamic killing of bacteria through the modulation of the ultrasound frequency. Taken together, a versatile TiO2-based NC hydrogel platform prepared under ultrasonic interfacial crosslinking reactions is developed for advancing the applications in SDT.

Dual Dynamic Covalently Crosslinked Alginate Hydrogels with Tunable Properties and Multiple Stimuli-Responsiveness.

Alginate is a biopolymer that can be crosslinked with calcium ions to fabricate cytocompatible hydrogels. However, using calcium ions to crosslink alginate provides limited properties and functions to alginate hydrogels, restricting their biomedical applications. Here, phenylboronic acid-functionalized polyethyleneimine (PBA-PEI) was developed to introduce two orthogonal dynamic covalent crosslinks in the alginate hydrogels, where PBA-PEI was used to crosslink alginate dialdehyde (ADA) through imine bonds and boronate ester bonds. The grafting degree of PBA in the PEI structure was applied to fine-tune the properties of PBA-PEI/ADA hydrogels, including the rheological property, mechanical strength, swelling behavior, and antibacterial activity. In particular, the highly sensitive boronate ester bonds in the network enabled PBA-PEI/ADA hydrogels to be responsive to several stimuli, such as glucose, fructose, and hydrogen peroxide. Taken together, PBA-PEI/ADA hydrogels with tunable properties and multiple stimuli-responsiveness have been demonstrated as smart biomaterials for advanced biomedical applications.

Risk of Peripheral Arterial Occlusive Disease with Periodontitis and Dental Scaling: A Nationwide Population-Based Cohort Study.

Periodontitis (PD) is a common oral disease associated with various other diseases, particularly those affecting the cardiovascular system. This study explored whether peripheral artery occlusive disease (PAOD) is associated with PD and dental scaling. This study was a retrospective cohort study design from 2000 to 2018. The study population was newly diagnosed with periodontitis. The comparison group was defined as never diagnosed with periodontitis. The outcome variable was defined with the diagnosis of peripheral arterial occlusive disease (PAOD). The propensity score matching was performed by age, sex, comorbidities, and dental scaling between the two groups. Kaplan-Meier analysis was used to calculate the cumulative incidence of PAOD among the two groups. To perform the independent risk of the PAOD group, the multivariate Cox proportional hazard model was used to estimate the hazard ratios. First, 792,681 patients with PD and 458,521 patients with no history of PD were selected from Taiwan's Longitudinal Health Insurance Database, which comprises the data of two million beneficiaries. After propensity score matching between the PD and non-PD groups for age, sex, comorbidities, and dental scaling, 357,106 patients in each group were analyzed for PAOD risk. The incidence density, relative risk, and cumulative incidence of PAOD were higher in the PD group than in the non-PD group. After adjusting for all variables, the risk of PAOD for the PD group was greater than for the non-PD group (adjusted hazard ratio = 1.03; 95% CI, 1.01-1.06). Undergoing at least one dental scaling procedure reduced the risk of PAOD. Age over 65 years was also a risk factor. In conclusion, patients with PD have an increased risk of PAOD. In addition, our results can lead to increased attention to oral hygiene, as dental scaling has a trend towards a lower risk of PAOD.

Association Between Aortic Aneurysm and Aortic Dissection With Fluoroquinolones Use in Patients With Urinary Tract Infections: A Population-Based Cohort Study.

Background Fluoroquinolones are first-line antibiotics recommended for the treatment of complicated urinary tract infections (UTIs), with frequent reports of adverse effects of aortic aneurysm (AA) and aortic dissection (AD). We examined whether fluoroquinolones can increase the risk of AA and AD in patients with UTIs in the Taiwanese population. Methods and Results We used the National Health Insurance Research Database to identify patients diagnosed with UTIs under single antibiotic treatment of fluoroquinolones and first-, second-, or third-generation cephalosporins. An AA and AD diagnosis within a year constituted the study event. Multivariable analysis with a multiple Cox regression model was applied for comparing the hazard risk of AA and AD between fluoroquinolones and first- or second-generation cephalosporins. Propensity score matching was performed to reduce the potential for bias caused by measured confounding variables. Among 1 249 944 selected patients with UTIs, 28 568 patients were assigned to each antibiotic group after propensity score matching. The incidence of AA and AD was not significantly different between the fluoroquinolones and first- or second-generation cephalosporins (adjusted HR [aHR], 0.86 [95% CI, 0.59-1.27]). However, the mortality increased in the fluoroquinolones group (aHR, 1.10 [95% CI, 1.04-1.16]). Conclusions Compared with first- or second-generation cephalosporins, fluoroquinolones were not associated with increased risk of AA and AD in patients with UTI. However, a significant risk of mortality was still found in patients treated with fluoroquinolones. The priority is to control infections with adequate antibiotics rather than exclude fluoroquinolones considering the risk of AA and AD for patients with UTI.

The Role of Aldehyde-Functionalized Crosslinkers on the Property of Chitosan Hydrogels.

Chitosan has been utilized as a popular biopolymer to fabricate hydrogels for biomedical applications. However, chitosan hydrogels are generally too brittle to mimic the deformability of the extracellular matrix in many tissues and organs. In particular, the role of the varied crosslinkers in determining the elasticity of chitosan hydrogels is lack of discussion. Here, three aldehyde-functionalized crosslinkers (i.e., aldehyde-modified poly(xylitol sebacate)-co-poly(ethylene glycol) (APP), glutaraldehyde (GA), and polydextran aldehyde (PDA)) are used to react with quaternized chitosan (QCS) through imine bonds to form hydrogels. The microstructures, mechanical performances, and cytocompatibility of the three hydrogels are systematically investigated. The APP/QCS hydrogels presented the best compressive and stretch properties among the three hydrogels. The mechanical property and antibacterial activity of APP/QCS hydrogels can be further modulated using varied QCS amounts, where more QCS contributed higher stiffness and stretchability as well as better bacterial inhibition to the APP/QCS hydrogels. Taken together, it is demonstrated that the inherent elastomeric characteristic of APP crosslinker provides the desirable elasticity and stretchability to QCS hydrogels compared to the other aldehyde-functionalized crosslinkers of GA and PDA. This strategy of using multivalent elastomeric crosslinkers to fabricate deformable chitosan hydrogels can expand the use of chitosan hydrogels in tissue engineering applications.

Ultrasound-triggered hydrogel formation through thiol-norbornene reactions.

An ultrasound-initiated thiol-norbornene reaction has been applied to fabricate hydrogels, and the ultrasound conditions in determining the properties of hydrogels have been systematically investigated.

The acute paraquat poisoning mortality (APPM) score to predict the risk of death in paraquat-poisoned patients.

CONTEXT: Mortality prediction in paraquat poisoning is a major issue since most prediction rules are inapplicable if the exact ingestion time cannot be determined and/or the serum paraquat concentration is not readily available, as in most countries. Therefore, we aimed to develop and validate a new prediction rule not requiring these two parameters. METHODS: We designed a 10-year observational cohort study including all consecutive paraquat-poisoned patients managed in two Taiwanese hospitals. We built one cohort to define and one cohort to validate this prediction rule. Parameters independently related to mortality determined using a multivariate analysis were used to formulate the Acute Paraquat Poisoning Mortality (APPM) score. RESULTS: Overall, 321 paraquat-poisoned patients were included, 156 in the derivation and 165 in the validation cohort. Mortality rates in the derivation and validation cohorts were 73% and 81%, respectively (p = 0.20). The three parameters chosen of 28-day mortality at presentation were urine paraquat level >10 ppm (using a colorimetric sodium dithionite-based test; odds ratio (OR), 12.70; 95% confidence interval (CI), 2.64-61.24), white blood cells >13.0 G/L (OR, 5.50; CI, 1.41-21.48) and blood glucose >140 mg/dL [7.8 mmol/L] (OR, 7.45; CI, 1.70-32.86). In the derivation cohort, the area under the ROC curve (AUC-ROC) of the APPM score did not significantly differ from AUC-ROCs of serum paraquat (0.95, p = 0.25) and the Severity Index of Paraquat Poisoning (0.95, p = 0.33). AUC-ROCs of the APPM score in the derivation and validation cohorts were 0.91 and 0.94, respectively. CONCLUSION: We built and validated a reliable score to predict 28-day mortality in paraquat-poisoned patients at presentation, independently from the ingestion time and serum paraquat measurement.

Continuous Wave Laser Nanowelding Process of Ag Nanowires on Flexible Polymer Substrates.

In this paper we present the laser nanowelding process of silver nanowires (AgNWs) deposited on flexible polymer substrates by continuous wave (CW) lasers. CW lasers are cost-effective and can provide moderate power density, somewhere between nanosecond pulsed lasers and flash lamps, which is just enough to perform the nanowelding process efficiently and does not damage the nanowires on the polymer substrates. Here, an Nd:YAG CW laser (wavelength 532 nm) was used to perform the nanowelding of AgNWs on polyethylene terephthalate (PET) substrates. Key process parameters such as laser power, scan speed, and number of scans were studied and optimized, and mechanisms of observed phenomena are discussed. Our best result demonstrates a sheet resistance of 12 ohm/squ with a transmittance at λ = 550 nm of 92% for AgNW films on PET substrates. A transparent resistive heater was made, and IR pictures were taken to show the high uniformity of the CW laser nanowelded AgNW film. Our findings show that highly effective and efficient nanowelding can be achieved without the need of expensive pulse lasers or light sources, which may contribute to lower the cost of mass producing AgNWs on flexible substrates.

A novel flowchart to predict mortality and analyse effectiveness of routinely used pharmacological regimens in paraquat poisoning.

Paraquat is responsible for an extremely high case-fatality rate poisoning. Mortality prediction remains a major issue since evidence to support benefits of routinely used treatments is lacking. We aimed to develop an easy-to-use prediction flowchart not requiring the ingestion time, for which accuracy is frequently questionable, and to evaluate the effectiveness of routinely used pharmacological therapies on mortality. We designed a two-centre cohort study including consecutive paraquat-poisoned adults with confirmed diagnosis based on serum/urine paraquat measurement. We built a flowchart using a multivariate analysis of death predictors and analysed the outcome according to the administered therapies. Overall, 256 patients were enrolled. Mortality rate was 75%. Independent death predictors on admission were serum creatinine (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.97-13.05) and serum paraquat concentration (OR, 2.26; CI, 1.66-3.09). The area-under-the flowchart curve was 0.91. Overall sensitivity and specificity were 81.5% and 94.8%, respectively. More survivors than non-survivors of severe poisoning received methylprednisolone (P = 0.04). While not significantly differing in severity, methylprednisolone-treated patients had better survival (P = 0.04). To conclude, we defined an efficient flowchart to predict mortality in paraquat poisoning at presentation, even if ingestion time is undetermined. Methylprednisolone seems effective to improve the outcome, especially in the most severe cases.

Deep Venous Thrombosis and Risk of Consequent Sepsis Event: A Retrospective Nationwide Population-Based Cohort Study.

Deep vein thrombosis causes several acute and chronic vessel complications and puts patients at risk of subsequent sepsis development. This unique study aimed to estimate the risk of sepsis development in DVT patients compared with non-DVT patients. This population-based cohort study used records of a longitudinal health insurance database containing two million patients defined in Taiwan's National Health Insurance Research Database (NHIRD). Our study included patients aged over 20 years with a new diagnosis of DVT with at least two outpatient department visits or an admission between 2001 and 2014. Patients with a diagnosis of sepsis before the index date were excluded. Propensity score matching (PSM) was used to homogenize the baseline characteristics between the two groups. To define the independent risk of the DVT group, a multivariate Cox proportional hazard model was used to estimate the hazard ratios. After PSM, the DVT group (n = 5753) exhibited a higher risk of sepsis (adjusted hazard ratio, aHR, 1.74; 95% CI, 1.59-1.90) compared with non-DVT group (n = 5753). Patients with an increased risk of sepsis were associated with being elderly aged, male, having diabetes, chronic kidney disease, chronic obstructive pulmonary disease, stroke, malignancy, and use of antibiotics. In conclusion, this population-based cohort study demonstrated an increased risk of sepsis in DVT patients compared with non-DVT patients. Thus, early prevention and adequate treatment of DVT is necessary in clinical practice.

Risk of Mortality and Readmission among Patients with Pelvic Fracture and Urinary Tract Infection: A Population-Based Cohort Study.

Patients with pelvic fractures could encounter various complications during or after treatments. This cohort study investigated the risk of mortality and readmissions in patients with pelvic fractures, with or without urinary tract infections (UTIs), within 30 days following the pelvic fractures. This retrospective cohort study examined claim records from the Longitudinal Health Insurance Database 2000 (LHID2000). We selected patients hospitalized with pelvic fractures between 1997 and 2013 for study. Patients who had index data before 2000 or after 2010 (n = 963), who died before the index date (n = 64), who were aged <18 years (n = 94), or who had a pelvic injury (n = 31) were excluded. In total, the study cohort comprised 1623 adult patients; 115 had UTIs, and 1508 patients without UTIs were used as a comparison cohort. Multivariate analysis with a multiple Cox regression model and Kaplan-Meier survival analysis were performed to analyze the data. Our results showed that the 1-year mortality rate (adjusted hazard ratio [HR]: 2.32; 95% CI: 1.25-4.29) and readmission rate (adjusted HR: 1.72; 95% CI: 1.26-3.34) of the UTI group were significantly higher than those of the non-UTI group. Moreover, the Kaplan-Meier curve for the 1-year follow-up indicated that the UTI group had a higher cumulative risk of both mortality and hospital readmission compared with the non-UTI group. In conclusion, among patients with pelvic fracture, patients with UTI were associated with increased risks of mortality and readmission. Physicians must pay more attention to such patients to prevent UTIs among patients with pelvic fractures during hospitalization and conduct a follow-up after discharge within at least 1 year.

Functions and therapeutic targets of Siglec-mediated infections, inflammations and cancers.

Siglecs, sialic acid (SA)-binding immunoglobulin (Ig)-like lectins, belong to a family of Ig-like lectins. All Siglecs have at least two domains including an extracellular domain with variable (V) and constant (C)-set immunoglobulin (Ig) regions, and a transmembrane domain. Some of the Siglecs (Siglec-2-12, -17, -E, -F and -G) with three domains including immunoreceptor tyrosine-based inhibitory motif associated with Src homology 2 (SH2) tyrosine phosphatases (SHP1/2) usually deliver an inhibitory signal. Certain Siglecs (Siglec-14, -15, -16 and -H) containing no intracellular domain carry certain basic amino acid in transmembrane domain coupled with immunoreceptor tyrosine-based activating motif for cell activation. The number of Siglec-encoding genes has been correlated to lifespan of mammals, indicating its evolutional advantage on acquisition of Siglecs in humans. Certain polymorphisms of Siglecs have been associated with premature delivery, infection, schizophrenia, allergy, dementia or chronic obstructive pulmonary disease. Siglecs mainly expressing on leukocytes could interact with cis- or trans-SA ligands for cell-cell and host-organism interactions on infections, inflammations and cancers. Amplifying or eliminating the SA-Siglec interactions is a promising strategy to treat cancers, infections and inflammations, based on SA modifications in different linkages or nanoparticle decoration, and on the antibodies in conjugation of chimeric receptor design or toxins.

Effect of Periodontitis and Scaling and Root Planing on Risk of Pharyngeal Cancer: A Nested Case-Control Study.

This study investigated the association between periodontitis and the risk of pharyngeal cancer in Taiwan. For this population-based nested case-control study using the Longitudinal Health Insurance Database derived from Taiwan's National Health Insurance Research Database, we identified patients (n = 1292) who were newly diagnosed with pharyngeal cancer between 2005 and 2013 and exactly paired them with propensity score matched control subjects (n = 2584). Periodontitis and scaling and root planing (SRP) were identified before the index date. Pharyngeal cancer was subdivided into 3 subgroups on the basis of anatomic location: nasopharyngeal cancer, oropharyngeal cancer, and hypopharyngeal cancer. A multiple conditional logistic regression model was applied to analyze the adjusted odds ratio (aOR). Periodontitis was associated with an increased risk of pharyngeal cancer (aOR, 1.57; 95% confidence interval (CI), 1.17 to 2.10), especially oropharyngeal cancer (aOR, 2.22; 95% CI, 1.07 to 4.60). We found a decreased risk of pharyngeal cancer in patients who had undergone SRP (aOR, 0.77; 95% CI, 0.61 to 0.96). In conclusion, this study showed that periodontitis was associated with an increased risk of pharyngeal cancer and SRP exerted a protective effect against pharyngeal cancer. Our results suggest that treating periodontitis and performing SRP, which are modifiable factors in oral health, in clinical practice may provide an opportunity to decrease the disease burden of pharyngeal cancer in Taiwan.

Hysterectomies are associated with an increased risk of osteoporosis and bone fracture: A population-based cohort study.

AIM: This study investigated the risk of osteoporosis or bone fractures (vertebrae, hip and others) in hysterectomized women in Taiwan. MATERIALS AND METHODS: This is a retrospective population-based cohort study from 2000 to 2013. Women aged ≥30 years who underwent hysterectomy between 2000 and 2012 were included in this study. The comparison group was randomly selected from the database with a 1:4 matching with age and index year. Incidence rate and hazard ratios of osteoporosis and bone fracture between hysterectomized women and the comparison group were calculated. Cox proportional hazard regressions were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 9,189 hysterectomized women and 33,942 age-matched women without a hysterectomy. All women were followed for a median time of about 7 years. The adjusted hazard ratio (aHR) of subsequent osteoporosis or bone fracture was higher in the hysterectomy women (2.26, 95% confidence interval [CI] = 2.09-2.44) than in the comparison group. In the subgroup analysis, oophorectomy and estrogen therapy increase the risk of osteoporosis or fracture in both groups. Regarding the fracture site, the aHR of vertebral fracture (4.92, 95% CI = 3.78-6.40) was higher in the hysterectomized women than in the comparison group. As follow-up time increasing, the aHR of vertebral fracture in hysterectomized women were 4.33 (95% CI = 2.99-6.28), 3.89 (95% CI = 2.60-5.82) and 5.42 (95% CI = 2.66-11.01) for <5, 5-9 and ≥9 years of follow-up, respectively. CONCLUSIONS: In conclusion, we found that hysterectomized women might be associated with increased risks of developing osteoporosis or bone fracture.

Does Hemoperfusion Increase Survival in Acute Paraquat Poisoning? A Retrospective Multicenter Study.

The efficacy of hemoperfusion (HP) in patients with acute paraquat poisoning (PQ) remains controversial. We conducted a multi-center retrospective study to include acute PQ-poisoned patients admitted to two tertiary medical centers between 2005 and 2015. We used the Severity Index of Paraquat Poisoning (SIPP) to stratify the severity of PQ-poisoned patients. The indication to start HP was a positive result for the semiquantitative urine PQ test and presentation to the hospital was within 24 h. Early HP was defined as the first session of HP performed within five hours of PQ ingestion. A total of 213 patients (100 HP group, 113 non-HP group) were eligible for the study. The overall 60-day mortality of poisoned patients was 75.6% (161/213). Multivariate Cox regression analysis showed no statistically significant difference in 60-day survival between HP and non-HP groups (95% confidence interval (CI): 0.84-1.63, p = 0.363). Further subgroup analysis in the HP group showed early HP (95%CI: 0.54-1.69, p = 0.880), and multiple secessions of HP (95%CI: 0.56-1.07, p = 0.124) were not significantly related to better survival. Among acute PQ-poisoned patients, this study found that HP was not associated with increased 60-day survival. Furthermore, neither early HP nor multiple secessions of HP were associated with survival.

Increased risk of knee osteoarthritis in patients using oral N-acetylcysteine: a nationwide cohort study.

BACKGROUND: Knee osteoarthritis (OA) is known to be a progressive degenerative disorder; however, recent evidence suggests that inflammatory mediators contribute to cartilage degradation. Studies have reported that N-acetylcysteine (NAC) had a promising effect on the reduction of the synthesis of proinflammatory and structural mediators by synovial cells. Given the lack of relevant clinical trials, we conducted this study to determine the relationship between NAC use and risk of knee OA. METHODS: We designed a retrospective cohort study from 2000 to 2013. Patients who received oral NAC over 28 days within 1 year after the first prescription were defined as the case group, whereas those without NAC use were considered as candidates of the control group. We adopted 1:4 propensity-score matching by age, sex, index year, and comorbidities to obtain the control group. The primary outcome was a new diagnosis of knee OA during the follow-up period. RESULTS: Our study sample comprised 12,928 people who used NAC and 51,715 NAC nonusers. NAC users had a significantly higher incidence of osteoarthritis (adjusted hazard ratio: 1.42, P < .001) than did NAC nonusers. Also, in analyses stratified by age group and sex, all subgroups exhibited a significantly higher incidence of knee osteoarthritis (P < .0001) among NAC users than among NAC nonusers. The use of oral NAC was associated with nearly four-fold increased the risk of knee OA in the young age group. CONCLUSIONS: Long-term use of oral NAC is associated with a higher risk of knee OA.

CD133 Targeted PVP/PMMA Microparticle Incorporating Levamisole for the Treatment of Ovarian Cancer.

Levamisole (LEVA) is used to treat worm infections, but it can also inhibit cancer cell growth by inhibiting the aldehyde dehydrogenase pathway. Therefore, here, we developed a drug carrier targeting CD133, a biomarker overexpressed in ovarian cancer cells. The particle structure and cytotoxicity of the prepared LEVA-containing particles-called LEVA/PVP/PMMA microparticles (MPs) (because it used matrix material polyvinylpyrrolidone (PVP) and poly(methylmethacrylate) (PMMA))-were investigated in the ovarian cancer cell lines SKOV-3 and CP70. The particle size of the MPs was determined to be 1.0-1.5 µm and to be monodispersed. The hydrophilic property of PVP created a porous MP surface after the MPs were soaked in water for 20 min, which aided the leaching of the hydrophilic LEVA out of the MPs. The encapsulation efficiency of LEVA/PVP/PMMA MPs could reach up to 20%. Free-form LEVA released 50% of drugs in <1 h and 90% of drugs in 1 day, whereas the drug release rate of LEVA/PVP/PMMA MPs was much slower; 50% released in 4 h and only 70% of drugs released in 1 day. In the in vitro cell model test, 5 mM free-form LEVA and 0.1 g/mL CD133 targeted LEVA/PVP/PMMA MPs reduced SKOV-3 cell viability by 60%; 0.1 g/mL LEVA/PVP/PMMA MPs was equivalent to a similar dosage of the free drug. In addition, the cytotoxicity of CD133-conjugated LEVA/PVP/PMMA MPs shows a different cytotoxicity response toward cell lines. For SKOV-3 cells, treatment with free-form LEVA or CD133-conjugated LEVA/PVP/PMMA MPs exerted dose-dependent cytotoxic effects on SKOV-3 cell viability. However, CD133-conjugated LEVA/PVP/PMMA MPs demonstrated no significant dose-dependent cytotoxic efficacy toward CP70 cells.

Candida albicans Aro1 affects cell wall integrity, biofilm formation and virulence.

BACKGROUND: Candida albicans is an opportunistic pathogen capable of causing life-threatening systemic infections. The C. albicans ARO1 gene encodes an arom multifunctional enzyme, which can possibly catalyze reactions of the shikimate pathway to synthesize aromatic amino acids. However, the functions of C. albicans Aro1 have not been extensively characterized. METHODS: ARO1 knockdown mutant strain was constructed, using a tetracycline-regulated (TR) expression system. Cell growth of the mutant strain was compared with wild type. Effects of the ARO1 gene knockdown on cell wall properties, adhesion to polystyrene and biofilm formation were further investigated. Finally, Galleria mellonella was used as a model host to study the role of ARO1 in virulence of C. albicans. RESULTS: We showed that defective growth in the ARO1 knockdown strain was rescued by supplemental aromatic amino acids. In addition, the ARO1 knockdown strain was easily aggregated and precipitated. The knockdown of ARO1 also caused changes in cell wall properties and compositions and promoted C. albicans cell adhesion to polystyrene and biofilm formation. Finally, the ARO1 knockdown strain showed attenuation of C. albicans virulence. CONCLUSION: This work provides new insights into C. albicans metabolism, cell wall and virulence.