Technique to prevent fracture of a partial auricular prosthesis mold.

One of the difficulties faced during the essential and demanding step of fabricating a mold for a partial auricular prosthesis is the fracture of its most elevated part, which engages the remnant concha and triangular fossa region, because of the presence of excessive convolutions and undercuts. This technique describes a 4-part mold for a partial auricular prosthesis in which the most elevated portion is poured separately, thereby preventing mold fracture.

Rare diseases and pyruvate kinase M2: a promising therapeutic connection.

Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that regulates proliferating cell metabolism. The role of PKM2 in common diseases has been well established, but its role in rare diseases (RDs) is less understood. Over the past few years, PKM2 has emerged as a crucial player in RDs, including, neoplastic, respiratory, metabolic, and neurological disorders. Herein, we summarize recent findings and developments highlighting PKM2 as an emerging key player in RDs. We also discuss the current status of PKM2 modulation in RDs with particular emphasis on preclinical and clinical studies in addition to current challenges in the field.

Imidazopyrimidine: from a relatively exotic scaffold to an evolving structural motif in drug discovery.

Nitrogen-fused heterocycles are of immense importance in modern drug discovery and development. Among them, imidazopyrimidine is a highly versatile scaffold with vast pharmacological utility. These compounds demonstrate a broad spectrum of pharmacological actions, including antiviral, antifungal, anti-inflammatory, and anticancer. Their adaptable structure allows for extensive structural modifications, which can be utilized for optimizing pharmacological effects via structure-activity relationship (SAR) studies. Additionally, imidazopyrimidine derivatives are particularly noteworthy for their ability to target specific molecular entities, such as protein kinases, which are crucial components of various cellular signaling pathways associated with multiple diseases. Despite the evident importance of imidazopyrimidines in drug discovery, there is a notable lack of a comprehensive review that outlines their role in this field. This review highlights the ongoing interest and investment in exploring the therapeutic potential of imidazopyrimidine compounds, underscoring their pivotal role in shaping the future of drug discovery and clinical medicine.

Half sphere and single clip-bar retained implant supported silicone auricular prosthesis.

Implant supported auricular prosthesis can be retained by several mechanical means, one of them being the Hader bar and clip system. Conventionally two or more rider clips are used. This technique describes a modified Hader bar design to maintain retention while eliminating the requirement of a second clip, significantly bringing down cost.

Roadmap to Pyruvate Kinase M2 Modulation - A Computational Chronicle.

Pyruvate kinase M2 (PKM2) has surfaced as a potential target for anti-cancer therapy. PKM2 is known to be overexpressed in the tumor cells and is a critical metabolic conduit in supplying the augmented bioenergetic demands of the recalcitrant cancer cells. The presence of PKM2 in structurally diverse tetrameric as well as dimeric forms has opened new avenues to design novel modulators. It is also a truism to state that drug discovery has advanced significantly from various computational techniques like molecular docking, virtual screening, molecular dynamics, and pharmacophore mapping. The present review focuses on the role of computational tools in exploring novel modulators of PKM2. The structural features of various isoforms of PKM2 have been discussed along with reported modulators. An extensive analysis of the structure-based and ligand- based in silico methods aimed at PKM2 modulation has been conducted with an in-depth review of the literature. The role of advanced tools like QSAR and quantum mechanics has been established with a brief discussion of future perspectives.

PROTACting the kinome with covalent warheads.

The dawn of targeted degradation using proteolysis-targeting chimeras (PROTACs) against recalcitrant proteins has prompted numerous efforts to develop complementary drugs. Although many of these are specifically directed against undruggable proteins, there is increasing interest in small molecule-based PROTACs that target intracellular pathways, and some have recently entered clinical trials. Concurrently, small molecule-based PROTACs that target protumorigenic pathways in cancer cells, the tumor microenvironment (TME), and angiogenesis have been found to have potent effects that synergize with the action of antibodies. This has led to the augmentation of PROTACs with variable substitution patterns. Several combinations with small molecules targeting undruggable proteins are now under clinical investigation. In this review, we discuss the recent milestones achieved as well as challenges encountered in this area of drug development, as well as our opinion on the best path forward.

Cognitive Skills and DNA Methylation Are Correlating in Healthy and Novice College Students Practicing Preksha Dhyana Meditation.

The impact of different meditation protocols on human health is explored at the cognitive and cellular levels. Preksha Dhyana meditation has been observed to seemingly affect the cognitive performance, transcriptome, and methylome of healthy and novice participant practitioners. In this study, we performed correlation analyses to investigate the presence of any relationships in the changes in cognitive performance and DNA methylation in a group of college students practicing Preksha Dhyana (N = 34). Nine factors of cognitive performance were assessed at baseline and 8 weeks postintervention timepoints in the participants. Statistically significant improvements were observed in six of the nine assessments, which were predominantly relating to memory and affect. Using Illumina 850 K microarray technology, 470 differentially methylated sites (DMS) were identified between the two timepoints (baseline and 8 weeks), using a threshold of p-value < 0.05 and methylation levels beyond -3% to 3% at every site. Correlation analysis between the changes in performance on each of the nine assessments and every DMS unveiled statistically significant positive and negative relationships at several of these sites. The identified DMS were in proximity of essential genes involved in signaling and other important metabolic processes. Interestingly, we identified a set of sites that can be considered as biomarkers for Preksha meditation improvements at the genome level.

Remdesivir: Mechanism of Metabolic Conversion from Prodrug to Drug.

BACKGROUND: Remdesivir (GS-5734) has emerged as a promising drug during the challenging times of COVID-19 pandemic. Being a prodrug, it undergoes several metabolic reactions before converting to its active triphosphate metabolite. It is important to establish the atomic level details and explore the energy profile of the prodrug to drug conversion process. METHODS: In this work, Density Functional Theory (DFT) calculations were performed to explore the entire metabolic path. Further, the potential energy surface (PES) diagram for the conversion of prodrug remdesivir to its active metabolite was established. The role of catalytic triad of Hint1 phosphoramidase enzyme in P-N bond hydrolysis was also studied on a model system using combined molecular docking and quantum mechanics approach. RESULTS: The overall energy of reaction is 11.47 kcal/mol exergonic and the reaction proceeds through many steps requiring high activation energies. In the absence of a catalyst, the P-N bond breaking step requires 41.78 kcal/mol, which is reduced to 14.26 kcal/mol in a catalytic environment. CONCLUSION: The metabolic pathways of model system of remdesivir (MSR) were explored completely and potential energy surface diagrams at two levels of theory, B3LYP/6-311++G(d, p) and B3LYP/6-31+G(d), were established and compared. The results highlight the importance of an additional water molecule in the metabolic reaction. The PN bond cleavage step of the metabolic process requires the presence of an enzymatic environment.

Speech intelligibility, nasal resonance, and swallowing ability of maxillectomy patients with customized obturator: A non randomized controlled study.

Aim: To compare speech intelligibility (SI), nasal resonance, and swallowing ability in maxillectomy patients with a customized obturator to the conventional obturator. Settings and Design: Non-randomized controlled study. Materials and Methods: Forty-eight maxillectomy patients were recruited and assessment of SI, nasal resonance, and swallowing ability was done at three situations: without obturator, with conventional obturator, and with customized obturator. Recordings of unrehearsed conversation, counting from number 1-20 and four sets of Chapel Hill Multilingual Intelligibility Test in the Hindi language were used to assess SI and nasal resonance. SI was evaluated by untrained listeners and graded according to a 6-point scale. Nasal resonance was evaluated by speech pathologists on a 7-point scale of severity. Swallowing ability was evaluated by water drinking test. Statistical Analysis Used: One-way ANOVA, Post hoc Bonferroni and Chi square test. Results: SI and nasal resonance showed a statistically significant difference between any two groups (P < 0.001). Water drinking time was significantly different between without obturator and with customized obturator (P < 0.001), but the difference was not statistically significant between without obturator and with obturator (P < 0.004). Conclusion: SI, nasal resonance, and swallowing ability improved with customized obturator in comparison to the conventional obturator.

Prevalence of maxillectomy defects among patients visiting in an institutionalized hospital setting: A prospective, single-institute study.

INTRODUCTION: The rehabilitation of a patient undergone maxillectomy requires a prosthesis that provides with the optimum appearance and functional results. Scarce literature has been published regarding the prevalence of maxillary defects related to palatal obturator prosthesis. This study evaluates the incidence of the maxillectomy defects among different age groups, gender, side involved, and etiology. MATERIALS AND METHODS: This is a prospective study of maxillectomy defects cases which reported and were treated in the department over a period of 2 years (2015-2017). Information regarding general identification, gender, and age at which the patient was operated for surgical resection of the maxilla or diagnosis of the tumor, affected side and etiology, and the time lag between surgical resection and rehabilitation was recorded from the clinical records of the patients. RESULTS: A total of 30 patients reported to the department in the 2 years. However, the detailed data were available for only 22 patients, and these patients were treated in the department. Information regarding general identification, gender, and age at which the patient was operated for surgical resection of maxilla or diagnosis of the tumor, affected side and etiology, and the time lag between surgical resection and rehabilitation was recorded from the clinical records of the patients. CONCLUSION: The finding of the study revealed a predominance of the males being more affected, with the predominance of the left side involvement over the right side, with most frequently involved the age group of 21-40 years, and the etiology revealed the predominance of carcinoma of the maxilla for its resection.

Comparison of the effect of different surface treatments on the bond strength of different cements with nickel chromium metal alloy: An in vitro study.

BACKGROUND: For success of any indirect metal restoration, a strong bond between cement and the intaglio surface of metal is imperative. The aim of this study is to evaluate and compare the effect of different surface treatment on the tensile and shear bond strength of different cements with nickel-chromium alloy. MATERIAL AND METHODS: 120 premolars were sectioned horizontally parallel to the occlusal surface to expose the dentin. Wax patterns were fabricated for individual tooth followed by casting them in nickel chromium alloy. 60 samples were tested for tensile bond strength, and the remaining 60 for shear bond strength. The samples were divided into three groups (of 20 samples each) as per the following surface treatment: oxidation only, oxidation and sandblasting, or oxidation, sandblasting followed by application of alloy primer. Each group was subdivided into 2 subgroups of 10 samples each, according to the bonding cement i.e RM-GIC and resin cement. Samples were subjected to thermocycling procedure followed by evaluation of bond strength. RESULTS: Two-way analyses of variance (ANOVA) was performed to compare the means of tensile and shear bond strength across type of surface treatment and cement, followed by post hoc parametric analysis. For all tests 'p' value of less than 0.05 was considered statistically significant. CONCLUSIONS: The surface treatment of oxidation and sandblasting followed by application of alloy primer offered the maximum tensile and shear bond strength for both RM GIC and resin cement. Resin cement exhibited greater tensile and shear bond strength than RM-GIC for all the three surface treatment methods. Key words:Resin cement, resin modified glass ionomer cement, oxidation, sandblasting, alloy primer, tensile bond strength, shear bond strength, universal testing machine.