Effective drug delivery by PEGylated drug conjugates

The current review presents an update of drug delivery using poly(ethylene glycol) (PEG), that focuses on recent developments in both protein and organic drugs. Certainly the past 10 years has resulted in a renaissance of the field of PEG drug conjugates, initiated by the use of higher molecular weight PEGs (M(w)>20,000), especially 40,000 which is estimated to have a plasma circulating t(1/2) of approximately 10 h in mice. This recent resuscitation of small organic molecule delivery by high molecular weight PEG conjugates was founded on meaningful in vivo testing using established tumor models, and has led to a clinical candidate, PEG-camptothecin (PROTHECAN), an ester based prodrug currently in phase II trials. Additional applications of high molecular weight PEG prodrug strategies to amino containing drugs are presented: similar tripartate systems based on lower M(w) PEG and their use with proteins is expounded on. The modification of a benzyl elimination tripartate prodrug specific for mercaptans is presented, and its successful application to 6-mercaptopurine giving a water soluble formulation is discussed. Recent novel PEG oligonucleotides and immunoconjugates are also covered. Clinical results of FDA approved PEGylated proteins are also presented.     

The Influence of Face Shields on the Quality of Colonoscopy in the Era of the COVID-19 Pandemic

Background/AimsThe worldwide coronavirus disease 2019 pandemic has led endoscopists to use personal protective equipment (PPE) for infection prevention. This study aimed to investigate whether wearing a face shield as PPE affects the quality of colonoscopy.MethodsWe reviewed the medical records and colonoscopy findings of patients who underwent colonoscopies at Asan Medical Center, Korea from March 10 to May 31, 2020. The colonoscopies in this study were performed by five gastroenterology fellows and four expert endoscopists. We compared colonoscopy quality indicators, such as withdrawal time, adenoma detection rate (ADR), mean number of adenomas per colonoscopy (APC), polypectomy time, and polypectomy adverse events, both before and after face shields were added as PPE on April 13, 2020.ResultsOf the 1,344 colonoscopies analyzed, 715 and 629 were performed before and after the introduction of face shields, respectively. The median withdrawal time was similar between the face shield and no-face shield groups (8.72 minutes vs 8.68 minutes, p=0.816), as was the ADR (41.5% vs 39.8%, p=0.605) and APC (0.72 vs 0.77, p=0.510). Polypectomy-associated quality indicators, such as polypectomy time and polypectomy adverse events were also not different between the groups. Quality indicators were not different between the face shield and no-face shield groups of gastroenterology fellows, or of expert endoscopists.ConclusionsColonoscopy performance was not unfavorably affected by the use of a face shield. PPE, including face shields, can be recommended without a concern about colonoscopy quality deterioration.     

Difficulty in distinguishing malignant gastric lymphoma from advanced gastric cancer: Focusing on endoscopic findings of the Borrmann type

Malignant gastric lymphoma (MGL) accounts for a small proportion (upto 5%) of gastric malignancies. However, unlike for advanced gastric cancer (AGC) that requires surgical treatment, the standard treatments for MGL are chemotherapy and radiotherapy. Hence, the initial impression of the endoscopist is critical for the differential diagnosis and for planning future treatment. The purpose of this study was to assess the endoscopic diagnostic accuracy and the possibility of distinguishing between AGC and MGL depending on the endoscopist''s experience.A total of 48 patients who had MGL, and 48 age and sex-matched patients who had AGC were assessed by endoscopic review at a tertiary referral hospital between June 2008 and February 2017. Two endoscopic specialists reviewed the endoscopic findings and divided these diagnoses into 5 groups: Borrmann type (1, 2, 3, and 4) and early gastric cancer-like type. After this, 7 experts and 8 trainees were asked to complete a quiz that was comprised of 6 images for each of the 96 cases and to provide an endoscopic diagnosis for each case. The test results were analyzed to assess the diagnostic accuracy according to the pathologic results, endoscopic subgroups, and endoscopists’ experience. For inter-observer agreement was calculated with Fleiss kappa values.The overall diagnostic accuracy of endoscopic findings by the experts was 0.604 and that by the trainees was 0.493 (P = .050). There was no significant difference in the diagnosis according to the final pathology (lymphoma cases, 0.518 vs 0.440, P = .378; AGC cases, 0.690 vs 0.547, P = .089, respectively). In the subgroup analysis, the experts showed significantly higher diagnostic accuracy for the endoscopic Borrmann type 4 subgroup, including lymphoma or AGC cases, than the trainees (P = .001). Inter-observer agreement of final diagnosis (Fleiss kappa, 0.174) and endoscopic classification groups (Fleiss kappa, 0.123–0.271) was slightly and fair agreement.The experts tended to have a higher endoscopic diagnostic accuracy. Distinguishing MGL from AGC based on endoscopic findings is difficult, especially for the beginners. Even if the endoscopic impression is AGC, it is important to consider MGL in the differential diagnosis.     

Antiobesity effects of the water-soluble fraction of the ethanol extract of Smilax china L. leaf in 3T3-L1 adipocytes

BACKGROUND/OBJECTIVESSeveral medicinal properties of Smilax china L. have been studied including antioxidant, anti-inflammatory, and anti-cancer effects. However, the antiobesity activity and mechanism by which the water-soluble fraction of this plant mediates its effects are not clear. In the present study, we investigated the lipolytic actions of the water-soluble fraction of Smilax china L. leaf ethanol extract (wsSCLE) in 3T3-L1 adipocytes.MATERIALS/METHODSThe wsSCLE was identified by measuring the total polyphenol and flavonoid content. The wsSCLE was evaluated for its effects on cell viability, lipid accumulation, glycerol, and cyclic adenosine monophosphate (cAMP) contents. In addition, western blot analysis was used to evaluate the effects on protein kinase A (PKA), PKA substrates (PKAs), and hormone-sensitive lipase (HSL). For the lipid accumulation assay, 3T3-L1 adipocytes were treated with different doses of wsSCLE for 9 days starting 2 days post-confluence. In other cell experiments, mature 3T3-L1 adipocytes were treated for 24 h with wsSCLE.RESULTSResults showed that treatment with wsSCLE at 0.05, 0.1, and 0.25 mg/mL had no effect on cell morphology and viability. Without evidence of toxicity, wsSCLE treatment decreased lipid accumulation compared with the untreated adipocyte controls as shown by the lower absorbance of Oil Red O stain. The wsSCLE significantly induced glycerol release and cAMP production in mature 3T3-L1 cells. Furthermore, protein levels of phosphorylated PKA, PKAs, and HSL significantly increased following wsSCLE treatment.CONCLUSIONThese results demonstrate that the potential antiobesity activity of wsSCLE is at least in part due to the stimulation of cAMP-PKA-HSL signaling. In addition, the wsSCLE-stimulated lipolysis induced by the signaling is mediated via activation of the β-adrenergic receptor.     

Hypoglycemic and antioxidant effects of Daraesoon (Actinidia arguta shoot) in animal models of diabetes mellitus

BACKGROUND/OBJECTIVES

The primary objective of the treatment of diabetes mellitus is the attainment of glycemic control. Hyperglycemia increases oxidative stress which contributes to the progression of diabetic complications. Thus, the purpose of this study was to investigate the hypoglycemic and antioxidant effects of Daraesoon (Actinidia arguta shoot) in animal models of diabetes mellitus.

MATERIALS/METHODS

Rats with streptozotocin-induced diabetes received an oral administration of a starch solution (1 g/kg) either with or without a 70% ethanol extract of Daraesoon (400 mg/kg) or acarbose (40 mg/kg) after an overnight fast and their postprandial blood glucose levels were measured. Five-week-old C57BL/6J mice were fed either a basal or high-fat/high-sucrose (HFHS) diet with or without Daraesoon extract (0.4%) or acarbose (0.04%) for 12 weeks after 1 week of adaptation to determine the effects of the chronic consumption of Daraesoon on fasting hyperglycemia and antioxidant status.

RESULTS

Compared to the control group, rats that received Daraesoon extract (400 mg/kg) or acarbose (40 mg/kg) exhibited a significant reduction in the area under the postprandial glucose response curve after the oral ingestion of starch. Additionally, the long-term consumption of Daraesoon extract or acarbose significantly decreased serum glucose and insulin levels as well as small intestinal maltase activity in HFHS-fed mice. Furthermore, the consumption of Daraesoon extract significantly reduced thiobarbituric acid reactive substances and increased glutathione levels in the livers of HFHS-fed mice compared to HFHS-fed mice that did not ingest Daraesoon.

CONCLUSIONS

Daraesoon effectively suppressed postprandial hyperglycemia via the inhibition of α-glucosidase in STZ-induced diabetic rats. Chronic consumption of Daraesoon alleviated fasting hyperglycemia and oxidative stress in mice fed a HFHS diet.     

The Extent of Late Gadolinium Enhancement Can Predict Adverse Cardiac Outcomes in Patients with Non-Ischemic Cardiomyopathy with Reduced Left Ventricular Ejection Fraction: A Prospective Observational Study

ObjectiveThe clinical course of an individual patient with heart failure is unpredictable with left ventricle ejection fraction (LVEF) only. We aimed to evaluate the prognostic value of cardiac magnetic resonance (CMR)-derived myocardial fibrosis extent and to determine the cutoff value for event-free survival in patients with non-ischemic cardiomyopathy (NICM) who had severely reduced LVEF.Materials and MethodsOur prospective cohort study included 78 NICM patients with significantly reduced LV systolic function (LVEF < 35%). CMR images were analyzed for the presence and extent of late gadolinium enhancement (LGE). The primary outcome was major adverse cardiac events (MACEs), defined as a composite of cardiac death, heart transplantation, implantable cardioverter-defibrillator discharge for major arrhythmia, and hospitalization for congestive heart failure within 5 years after enrollment.ResultsA total of 80.8% (n = 63) of enrolled patients had LGE, with the median LVEF of 25.4% (19.8–32.4%). The extent of myocardial scarring was significantly higher in patients who experienced MACE than in those without any cardiac events (22.0 [5.5–46.1] %LV vs. 6.7 [0–17.1] %LV, respectively, p = 0.008). During follow-up, 51.4% of patients with LGE ≥ 12.0 %LV experienced MACE, along with 20.9% of those with LGE ≤ 12.0 %LV (log-rank p = 0.001). According to multivariate analysis, LGE extent more than 12.0 %LV was independently associated with MACE (adjusted hazard ratio, 6.71; 95% confidence interval, 2.54–17.74; p < 0.001).ConclusionIn NICM patients with significantly reduced LV systolic function, the extent of LGE is a strong predictor for long-term adverse cardiac outcomes. Event-free survival was well discriminated with an LGE cutoff value of 12.0 %LV in these patients.     

Improved Survival with Anti-VEGF Therapy in the Treatment of Unresectable Appendiceal Epithelial Neoplasms

Annals of Surgical Oncology - Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms....