Efficacy of Aminolevulinic Acid Mediated Photodynamic Therapy in the Treatment of Oral Premalignant Lesions: A Systematic Review.

BACKGROUND: Aminolevulinic acid (ALA) mediated photodynamic therapy (PDT) is considered as an effective treatment option for oral premalignant lesions. ALA is a Food and Drug Administration (FDA) approved second-generation photosensitizer (PS) used both orally as well as topically. OBJECTIVE: This systematic review aims to evaluate the efficacy of ALA-PDT for the treatment of oral premalignant lesions. METHODS: The focused question was, "Is ALA-PDT effective in the treatment of oral premalignant lesions?"A literature search was made in PubMed/Medline and GoogleScholar using different combinations of the following keywords: photodynamic therapy, oral premalignant lesions, oral leukoplakia (OL), erythroplakia, oral erythroleukoplakia (OEL), oral verrucous hyperplasia (OVH); and oral lichen planus (OLP). Review articles, preclinical studies, case-reports, commentaries, letters to the Editor, unpublished articles, studies on photodynamic therapy used in areas other than the oral cavityand, articles published in languages other than English were excluded. The relevant information was summarized. RESULTS: There were initially 64 results for the above parameters; 47 studies were excluded, leaving 17 studies for analysis. Characteristics of the included studies, PS, and PDT protocol were summarized. CONCLUSION: The outcome of the included studies suggested that ALA-PDT is an effective, easy to perform technique, well tolerated treatment with encouraging achievements in the treatment of oral premalignant lesions. No systemic side effects and skin photosensitivity were reported with topical ALA even within initial 48 hours after PDT, and patients were not required to avoid exposure to light following treatment. The clinical outcome of the ALA-PDT application, as reported in the studies, was also very promising, with either diminution in the size of the lesion or complete remission or improvement in signs and symptoms as well as reduced recurrence.

Structural Modelling of Platelet Activating Factor Acetyl Hydrolase in Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei: Implications on Therapeutics for Leishmaniasis, Chagas Disease, and Sleeping Sickness.

Purpose: Leishmaniasis, Chagas disease, and sleeping sickness are caused by protozoa Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, respectively. Platelet activating factor acetyl hydrolase (PAF-AH) is an inflammatory protein implicated in pathogenesis of these three infections, thereby making them attractive drug targets. Methods: PAF-AH sequences were retrieved from UniProt and aligned using Clustal Omega. Homologous models of parasitic proteins were built based on crystal structure of human PAF-AH and validated using PROCHECK server. Volumes of substrate-binding channel were calculated using the ProteinsPlus program. High throughput virtual screening using Glide program in Schrodinger was done with ZINC drug library against parasitic PAF-AH enzymes. Complexes with best hits were energy-minimized and subjected to 100 ns molecular dynamic simulation and analyzed. Results: PAF-AH enzyme sequences from protozoa Leishmania donovani, Trypanosoma cruzi, Trypanosoma brucei, and human have a minimum of 34% sequence similarity with each other. Corresponding structures show a globular conformation consisting of twisted ß-pleated sheets, flanked by α-helices on either side. Catalytic triad of serine-histidine-aspartate is conserved. Substrate-binding channel residues are conserved to an extent, with a lower channel volume in human as compared to target enzymes. Drug screening resulted in identification of three molecules that had better affinities than the substrate to the target enzymes. These molecules fulfill Lipinski's rules for drug likeness and also bind with less affinity to the human counterpart, thereby establishing a high selective index. Conclusion: Structures of PAF-AH from protozoan parasites and humans belong to the same family of enzymes and have a similar three-dimensional fold. However, they show subtle variations in residue composition, secondary structure composition, substrate-binding channel volume, and conformational stability. These differences result in certain specific molecules being potent inhibitors of the target enzymes while simultaneously having weaker binding to human homologue.

Comparative Structural Analysis of Human ACE2 Receptor with Spike Protein of SARS-CoV-2 Variants: Implications to Understand Infectivity of the Virus.

Purpose: Spike protein on SARS-CoV-2 virus plays an integral part during infection as cell entry depends on binding of this protein to human ACE2 receptor. Understanding of infectivity by these variants necessitates a comparative structural analysis of complexes of spike protein-receptor binding domain (RBD) of these variants to receptor. Methodology: Wild type SARS-CoV-2 spike protein sequence was retrieved from the UniProt database, and mutations of five variants at receptor binding domain were manually incorporated and aligned using Clustal Omega. Crystal structure complexes of human ACE2 receptor with spike protein RBD domain of SARS-CoV-2 variants of wild type, α, ß, and δ were extracted from the RCSB database. Wild type SARS-CoV-2 complex with receptor was used as template to generate model complexes of receptor with spike protein RBD of γ and omicron variants through WinCoot program. These were energy minimized and validated and molecular dynamic simulation was performed using Desmond simulation program. Results: Mutations are distributed across the entire length of RBD, but the maximum number of mutations are seen at 11 positions within binding interface motifs of six variant sequences. Interface of spike protein RBDs with human ACE2-receptor shows different mix of hydrogen bonded and ionic interactions. Alpha and ß variants have few interactions, while γ and δ variants have higher number of interactions compared to wild type variant. Omicron variant, with 10 polar interactions including two ionic bonds, has the highest binding energy. Conclusion: Different mutations on RBD of spike protein results in varying quantity and quality of interactions, thereby affecting potency of each variant. Variations in binding are due to interactions of mutant residues and induced conformational changes on loops of RBDs. Variants α and ß have a low potency, while, γ, δ, and omicron have a higher potency. These results correlate with viral infectivity and place clinical observations in the right perspective.

Structural modeling of Omicron spike protein and its complex with human ACE-2 receptor: Molecular basis for high transmissibility of the virus.

Omicron is a new variant of SARS-CoV-2, which is currently infecting people around the world. Spike glycoprotein, an important molecule in pathogenesis of infection has been modeled and the interaction of its Receptor Binding Domain with human ACE-receptor has been analysed by simulation studies. Structural analysis of Omicron spike glycoprotein shows the 30 mutations to be distributed over all domains of the trimeric protein, wherein the mutant residues are seen to be participating in higher number of intra-molecular interactions including two salt bridges emanating from mutant residues thereby stabilizing their conformation, as compared to wild type. Complex of Receptor Binding Domain (RBD) with human ACE-2 receptor shows seven mutations at interacting interface comprising of two ionic interactions, eight hydrogen bonds and seven Van der Waals interactions. The number and quality of these interactions along with other binding biophysical parameters suggests more potency of RBD domain to the receptor as compared to the wild type counterpart. Results of this study explains the high transmissibility of Omicron variant of SARS-CoV-2 that is currently observed across the world.

Shear bond strength comparison of moisture-insensitive primer and self-etching primer.

CONTEXT: The detrimental effect of moisture on orthodontic bonding has long been known. Hydrophilic bonding materials have been introduced suggesting the possibility of obtaining successful orthodontic bonding to a moisture contaminated enamel surface. AIMS: This study has been performed with an aim to compare the in vitro shear bond strength (SBS) and debonding characteristic of moisture-insensitive primer (MIP) (Transbond MIP) (3M Unitek, South Peck Road, Monrovia, California, USA) and self-etching primer (SEP) (Transbond Plus SEP) (3M Unitek, South Peck Road, Monrovia, California, USA) in combination with a color changing adhesive system (Transbond Plus Color Change) (3M Unitek, South Peck Road, Monrovia, California, USA) under both dry and contaminated condition. SETTINGS AND DESIGN: Randomized controlled clinical study. SUBJECTS AND METHODS: One hundred and twenty freshly extracted teeth for the purpose of orthodontic treatment were collected. Teeth were randomly assigned into four groups, each consisting of 30 specimen and stainless steel brackets were bonded using each primer-adhesive combination under different enamel conditions, that is, dry and enamel contaminated with natural saliva. SBS and adhesive remnant index were calculated for each group. RESULTS: Analysis of variance of SBS for both MIP and SEP under dry and contaminated condition showed no statistical significance (P = 0.5). Chi-square test showed significant difference in debonding characteristics among the test groups (P < 0.001). All the groups showed typical debonding characteristics of separation either at the bracket-adhesive interface or within the adhesive itself. CONCLUSIONS: Moisture contamination did not affect the SBS and adhesive remaining on tooth for both MIP and SEP.

Utility of the "harmless acute pancreatitis score" in predicting a non-severe course of acute pancreatitis: a pilot study in an Indian cohort.

BACKGROUND: Several severity predictors have been tested for assessing acute pancreatitis (AP). The recently described harmless acute pancreatitis score (HAPS) could be an ideal predictor for Indian patients at the community level. We validate this system in the current study. METHODS: This was a prospective pilot study conducted at a tertiary center from July 2010 to December 2011. Consecutive directly admitted patients over 18 years with a documented first episode of AP were enrolled and followed for at least 12 months after discharge/till death. HAPS was defined as absence of rebound abdominal tenderness, serum creatinine of <2 mg/dL, and hematocrit of <43 for male and <39.6 for female patients at the time of admission; and it was considered positive if the patient fulfilled all three criteria. Study outcomes included total hospital stay, need for intensive care unit (ICU), ICU stay, development of local complications, organ failure, hospital-acquired infections (including infected necrosis), and in-hospital mortality. RESULTS: There were a total of 103 patients directly admitted with AP during the study period, out of which, 23 were excluded. Forty-seven (58.8 %) patients were positive for HAPS. Of these, 44 (93.6 %) had an eventual non-severe (mild) clinical course with odds ratio 17.6 (95 % CI 4.5-68.3). Sensitivity, specificity, positive and negative predictive value, and receiver operating characteristics area under the curve of HAPS as a predictor of non-severe disease were 76.3 (66.9-86.4), 85.7 (78.0-96.8), 93.8 (88.5-98.6), 56.6 (45.4-73.6), and 84.8 (76.9-92.7) respectively. CONCLUSION: This study validated the utility of HAPS for directly admitted patients with AP in India. Large-scale multicenter community-based studies need to be performed.