Colorectal cancer (CRC) remains one of the major causes of death worldwide, despite steady improvement in early detection and overall survival over the past decade. Current treatment paradigms, with chemotherapy and biologics, appear to have reached their maximum benefit. Immunotherapy, especially with checkpoint inhibitors, has shown considerable clinical benefit in various cancers, including mismatch-repair-deficient CRC. This has led to the planning and initiation of several clinical trials evaluating novel immunotherapy agents—as single agents, combinations and in conjunction with chemotherapy—in patients with CRC. This article reviews biological and preclinical data for checkpoint inhibitors and discusses various immunotherapy trials in CRC, as well as current efforts in CRC immunotherapy.

Poor skin permeability limits the application of peptides to the skin. Enhanced skin permeation could facilitate the development of new therapies for dermatologic and cosmeceutical applications. The aim of this study was to investigate the application of iontophoresis to the delivery of small peptide model compounds (5-aminolevulinic acid and L-alanine-L-tryptophan) across human skin. Under the conditions tested, iontophoresis increased the in vitro permeability coefficient of ALA.HCl across human epidermis from 7 X 10(-5) cm/h with passive diffusion to 110 x 10(-5) cm/h with iontophoresis. D-Glucose permeation elucidated the iontophoretic electrotransport of ALA.HCl to have contributions of both electrorepulsion and electroosmosis. The L-alanine-L-tryptophan permeability coefficient was increased from 1.5 x 10(-5) cm/h to 35 x 10(-5) cm/h with iontophoretic application. Iontophoretic delivery of the dipeptide increased markedly at lower pH because of an increase in electrorepulsive transport. The study demonstrates that iontophoresis can enhance epidermal permeation of a small peptide and peptide-like drug by up to 15- and 22-fold under the conditions tested.

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The transdermal route offers advantages for delivery of peptides and proteins. However, these polar and large molecules do not permeate the skin barrier well. Various enhancement methods have been employed to address this problem. Iontophoresis is one of the methods that shows promise but its application to peptide delivery has yet to be fully explored. This study investigates the effects of different molecular properties and iontophoretic conditions on the skin permeation of peptides. In this study, the permeation of alanine-tryptophan dipeptide (MW 276 Da), alanine-alanine-proline-valine tetrapeptide (MW 355 Da), Argireline® (Acetyl hexapeptide-3, MW 889 Da) and Triptorelin acetate (decapeptide, MW 1311 Da) through excised human skin under passive or iontophoretic current of 0.4 mA was investigated. The effects of pH change (3.0-7.4, to provide different net negative, neutral, and positive charges) to the peptide, donor concentration (1-10 mg/ml), background electrolyte (34-137 mM NaCl and/or 5-20 mM HEPES) and current direction (anodal vs cathodal) were also studied. Peptides were analysed by high-performance liquid chromatography or liquid scintillation counting. Iontophoresis led up to a 30 times increase in peptide permeation relative to passive permeation for the peptides. Electroosmosis was an important determinant of the total flux for the high molecular weight charged peptides. Electrorepulsion was found to be considerable for low molecular weight charged moieties. Permeation was decreased at lower pH, possibly due to decreased electroosmosis. Results also showed that 10 times increase in donor peptide concentration increases permeation of peptides by about 2-4 times and decreases iontophoretic permeability coefficients by about 2.5-5 times. The addition of extra background electrolyte decreased the iontophoretic permeation coefficient of peptides by 2-60 times. This study shows that iontophoretic permeation of peptides is affected by a number of parameters that can be optimized for effective transdermal peptide delivery.

Our study supports the use of ultrasound for improved ALA delivery by showing significant improvements in the cumulative drug load and flux via combined ultrasound and ALA treatment.

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Background and Objectives Studies of gum or periodontal disease have focused mainly on bacterial pathogens. However, information related to fungal species in the saliva and subgingival mileu is particularly lacking in smokers with periodontitis. This cross-sectional study compared the prevalence of various Candida species in saliva and subgingival plaque samples of smokers and non-smokers with periodontal disease. Methodology Study subjects were recruited into three group—Group 1: Smokers with chronic periodontitis (N = 30), Group 2: Non-smokers with chronic periodontitis (N = 30) and Group 3: Healthy controls (N = 30). Clinical parameters recorded included plaque index (PI), gingival index (GI), periodontal probing depth (PPD) and clinical attachment loss (CAL). Saliva and subgingival plaque samples were collected from subjects from the above groups. The collected samples were processed for isolation and identification of various Candida species using CHROMagar chromogenic media. Additionally, antifungal susceptibility tests were performed for the isolated Candida species in order to assess antifungal drug resistance to fluconazole and voriconazole. Results Prevalence of Candida species in saliva samples was quantified as 76.6% in Group 1, 73.3% in Group 2 and 36.6% in Group 3 and statistically significant differences were observed between groups 1 & 3. Prevalence of Candida species in subgingival plaque samples was quantified as 73.3% in Group 1, 66.6% in Group 2 and 60% in Group 3 and no statistically significant differences were observed between groups. Candida albicans was the most frequently isolated species followed by Candida krusei and Candida tropicalis. A positive correlation was observed for smoking exposure, pack years and Candida colonization. A marginally significant positive correlation was observed between Candida colonization and increasing pocket depth and attachment loss. Antifungal drug resistance was mainly observed for Candida krusei in both saliva and subgingival plaque samples. Conclusion Based on the results we can conclude that oral candidal carriage is significantly increased in smokers with periodontal disease. Mechanistic studies are needed to understand the importance of Candida species in periodontal disease.

Administration with a novel magnetic film array technology provided enhanced skin penetration of urea and increased epidermal hydration when compared with administration under an occlusive film only.