Coarse grained MD simulation of bulk and interfacial behavior of mixture of CTAB/SDS surfactants.

CONTEXT: This study involves simulating the process of inhibiting corrosion through the formation of micelles by surfactants and their deposition on iron (Fe) surfaces. The primary focus is on examining CTAB/SDS mixtures in aqueous solutions with different concentrations. Micelle properties, including size, shape, aggregation number, cluster size, and surfactant diffusion, were calculated and validated with experimental data. The coarse-grained Fe surface was modeled and validated against experimental water contact-angle data. Subsequently, the deposition of CTAB/SDS mixtures on the Fe surface and air-water interface was studied systematically. We found that the relative ratio of CTAB/SDS in the solution directly influences surfactant deposition behavior, which might impact the corrosion inhibition efficiency. METHODS: All the MD simulations were performed using the GROMACS software with MARTINI2 force field and Martini polar water. The molecules are packed using PACKMOL software. Both NVT and NPT simulations are caried out at temperature and pressure of 303 K and 1 bar respectively, with a nonbonded interaction cut-off (rcut) of 1.1 nm. The LJ potential was shifted from 0.9 nm to rcut, while the electrostatic potential was shifted from 0.0 nm to rcut. For electrostatics, reaction-field coulomb type is used, relative dielectric constant (epsilon-r) and the reaction field dielectric constant (epsilon-rf) are equal to 2.5 and infinity respectively. The dielectric constant below rcut is epsilon-r, and beyond the cut-off is epsilon-rf. Coulomb-modifier used as potential-shift which leads to shift in the coulomb potential by a constant such that it is zero at the rcut. This makes the potential of the integral of the force . The neighbor list was updated every 10 steps, employing a neighbor list cut-off equal to rcut. Using a polar water model, we used a constant time step of 0.02 ps throughout the simulation. The used epsilon-r = 2.5, is recommended for polar water.

Design, optimization, and evaluation of topical gel of Cardiospermum halicacabum and Ricinus communis L. leaves extract for the treatment of rheumatoid arthritis.

This research aims to develop and assess the anti-arthritic properties of a topically herbal gel including leaf extracts from Cardiospermum halicacabum and Ricinus communis L. in rats. Utilizing gelling agents carbopol 940 (2.5, 5, 7.5 g), nine herbal gel compositions were created. Prepared formulations were then assessed for physical appearance, spreadability, viscosity, net content, pH, extrudability, in vitro diffusion profile, and main skin irritant tests. According to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) recommendations, the stability research for the topical herbal gel composition was completed, and Freund's Complete Adjuvant (FCA) induced arthritis technique was used to assess the anti-arthritic efficacy. Additional procedures included measuring the body weight, paw volume, biochemical and hematological variables, histological analysis, and in vitro serum biomarker detection. The prepared gels followed the instructions and were uniform and stable. F5 performed better than the other compositions in terms of release kinetics (97.20%). The gel proved safe and non-toxic since no erythema or edema was seen during the skin irritation test. Comparing the herbal gel F5 comprising carbopol 940 to rats with arthritis, the topical treatment showed considerable (p < .001) anti-arthritic effect. The anti-arthritic action of the gel formulations was confirmed by decreased paw volume, absence of agglutination in reacting protein and rheumatic factor, a decline in TNFα level, restoration to baseline biochemical and hematological characteristics, decrease in thymus and spleen weight, and histopathological study.

Blockchain technology: A potential tool for the management of pharma supply chain.

BACKGROUND: The pharma supply chain comprises various parties including distributors, manufacturers, raw material suppliers, regulators, pharmacies, hospitals, and patients. Due to the product's complexity and transaction flows, an efficient traceability system is needed in the pharma supply chain to identify the current and all previous product owners. Digitizing the track and trace process significantly improves regulatory oversight and guarantees product quality. A distributed platform for shared data that is immutable, trustworthy, accountable, and transparent in the pharmaceutical supply chain could be built using blockchain-based drug traceability. OBJECTIVE: This review aims to shed light on blockchain technology's significance and necessity for pharmaceutical supply chain management systems. METHOD: A comprehensive literature review was performed between January 2017 and September 2023. The search was conducted to elaborate on blockchain technology. Blockchain is a software-based technology that logs and records transactions using a block structure arranged chronologically. Cryptography technology links and secures these blocks on a peer-to-peer network. Blockchain is anticipated to transform the pharmaceutical supply chain by giving all participants access to a single, straightforward system that provides transparency, security, and oversight of the end-to-end delivery of goods. RESULT: In all, various literature data were included in this review. Using a supply chain powered by blockchain has many benefits. To begin with, it gives a thorough account of the entire procedure from start to finish. A single piece of software can manage the entire supply chain. Additionally, it increases communication between parties with permission. The enhanced security and traceability that blockchain offers is another important benefit. A blockchain system can track, trace, and recall products. CONCLUSION: Blockchain-based pharmaceutical supply chain management enables the tracking of medicinal drug transactions from raw materials suppliers to end consumers. The pharma blockchain has the potential to enhance the security, integrity, data provenance, and functionality of the supply chain due to its transparency, immutability, and auditability.

Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.

PURPOSE: Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD- and TKD-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML. METHODS: Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m2) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m2 or idarubicin 12 mg/m2, once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m2 twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant. RESULTS: Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD, and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3-mutant clones were detected at relapse in patients completing consolidation. CONCLUSION: Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.

Stem cells in regenerative dentistry: Current understanding and future directions.

BACKGROUND: Regenerative dentistry aims to enhance the structure and function of oral tissues and organs. Modern tissue engineering harnesses cell and gene-based therapies to advance traditional treatment approaches. Studies have demonstrated the potential of mesenchymal stem cells (MSCs) in regenerative dentistry, with some progressing to clinical trials. This review comprehensively examines animal studies that have utilized MSCs for various therapeutic applications. Additionally, it seeks to bridge the gap between related findings and the practical implementation of MSC therapies, offering insights into the challenges and translational aspects involved in transitioning from preclinical research to clinical applications. HIGHLIGHTS: To achieve this objective, we have focused on the protocols and achievements related to pulp-dentin, alveolar bone, and periodontal regeneration using dental-derived MSCs in both animal and clinical studies. Various types of MSCs, including dental-derived cells, bone-marrow stem cells, and umbilical cord stem cells, have been employed in root canals, periodontal defects, socket preservation, and sinus lift procedures. Results of such include significant hard tissue reconstruction, functional pulp regeneration, root elongation, periodontal ligament formation, and cementum deposition. However, cell-based treatments for tooth and periodontium regeneration are still in early stages. The increasing demand for stem cell therapies in personalized medicine underscores the need for scientists and responsible organizations to develop standardized treatment protocols that adhere to good manufacturing practices, ensuring high reproducibility, safety, and cost-efficiency. CONCLUSION: Cell therapy in regenerative dentistry represents a growing industry with substantial benefits and unique challenges as it strives to establish sustainable, long-term, and effective oral tissue regeneration solutions.

Integrative Metatranscriptomic Analysis Reveals Disease-specific Microbiome-host Interactions in Oral Squamous Cell Carcinoma.

Studies on the microbiome of oral squamous cell carcinoma (OSCC) have been limited to 16S rRNA gene sequencing. Here, laser microdissection coupled with brute-force, deep metatranscriptome sequencing was employed to simultaneously characterize the microbiome and host transcriptomes and predict their interaction in OSCC. The analysis involved 20 HPV16/18-negative OSCC tumor/adjacent normal tissue pairs (TT and ANT) along with deep tongue scrapings from 20 matched healthy controls (HC). Standard bioinformatic tools coupled with in-house algorithms were used to map, analyze, and integrate microbial and host data. Host transcriptome analysis identified enrichment of known cancer-related gene sets, not only in TT versus ANT and HC, but also in the ANT versus HC contrast, consistent with field cancerization. Microbial analysis identified a low abundance yet transcriptionally active, unique multi-kingdom microbiome in OSCC tissues predominated by bacteria and bacteriophages. HC showed a different taxonomic profile yet shared major microbial enzyme classes and pathways with TT/ANT, consistent with functional redundancy. Key taxa enriched in TT/ANT compared with HC were Cutibacterium acnes, Malassezia restricta, Human Herpes Virus 6B, and bacteriophage Yuavirus. Functionally, hyaluronate lyase was overexpressed by C. acnes in TT/ANT. Microbiome-host data integration revealed that OSCC-enriched taxa were associated with upregulation of proliferation-related pathways. In a preliminary in vitro validation experiment, infection of SCC25 oral cancer cells with C. acnes resulted in upregulation of MYC expression. The study provides a new insight into potential mechanisms by which the microbiome can contribute to oral carcinogenesis, which can be validated in future experimental studies. Significance: Studies have shown that a distinct microbiome is associated with OSCC, but how the microbiome functions within the tumor interacts with the host cells remains unclear. By simultaneously characterizing the microbial and host transcriptomes in OSCC and control tissues, the study provides novel insights into microbiome-host interactions in OSCC which can be validated in future mechanistic studies.

Non-linear dose response of DNA double strand breaks in response to chronic low dose radiation in individuals from high level natural radiation areas of Kerala coast.

BACKGROUND: The human population living in high level natural radiation areas (HLNRAs) of Kerala coast provide unique opportunities to study the biological effects of low dose and low dose rate ionizing radiation below 100 mGy. The level of radiation in this area varies from < 1.0 to 45 mGy/year. The areas with ≤ 1.50 mGy/year are considered as normal level natural radiation areas (NLNRA) and > 1.50 mGy/year, as high level natural radiation areas (HLNRA). The present study evaluated dose response relationship between DNA double strand breaks (DSBs) and background radiation dose in individuals residing in Kerala coast. Venous blood samples were collected from 200 individuals belonging to NLNRA (n = 50) and four dose groups of HLNRA; 1.51-5.0 mGy/year (n = 50), 5.01-10.0 mGy/year (n = 30), 10.01-15.0 mGy/year (n = 33), > 15.0 mGy/year (n = 37) with written informed consent. The mean dose of NLNRA and four HLNRA dose groups studied are 1.21 ± 0.21 (range: 0.57-1.49), 3.02 ± 0.95 (range: 1.57-4.93), 7.43 ± 1.48 (range: 5.01-9.75), 12.22 ± 1.47 (range: 10.21-14.99), 21.64 ± 6.28 (range: 15.26-39.88) mGy/year, respectively. DNA DSBs were quantified using γH2AX as a marker, where foci were counted per cell using fluorescence microscopy. RESULTS: Our results revealed that the frequency of γH2AX foci per cell was 0.090 ± 0.051 and 0.096 ± 0.051, respectively in NLNRA and HLNRA individuals, which were not significantly different (t198 = 0.33; P = 0.739). The frequency of γH2AX foci was observed to be 0.090 ± 0.051, 0.096 ± 0.051, 0.076 ± 0.036, 0.087 ± 0.042, 0.108 ± 0.046 per cell, respectively in different dose groups of ≤ 1.50, 1.51-5.0, 5.01-10.0, 10.01-15.0, > 15.0mGy/year (ANOVA, F4,195 = 2.18, P = 0.072) and suggested non-linearity in dose response. The frequency of γH2AX foci was observed to be 0.098 ± 0.042, 0.078 ± 0.037, 0.084 ± 0.042, 0.099 ± 0.058, 0.097 ± 0.06 and 0.114 ± 0.033 per cell in the age groups of ≤ 29, 30-34, 35-39, 40-44, 45-49 and ≥ 50 years, respectively (ANOVA, F5,194 = 2.17, P = 0.059), which suggested marginal influence of age on the baseline of DSBs. Personal habits such as smoking (No v/s Yes: 0.092 ± 0.047 v/s 0.093 ± 0.048, t198 = 0.13; P = 0.895) and drinking alcohol (No v/s Yes: 0.096 ± 0.052 v/s 0.091 ± 0.045, t198 = 0.62; P = 0.538) did not show any influence on DSBs in the population. CONCLUSION: The present study did not show any increase in DSBs in different dose groups of HLNRA compared to NLNRA, however, it suggested a non-linear dose response between DNA DSBs and chronic low dose radiation.

Addressing the genetic/nongenetic duality in cancer with systems biology.

The dogma that cancer is a genetic disease is being questioned. Recent findings suggest that genetic/nongenetic duality is necessary for cancer progression. A think tank organized by the Shraman Foundation's Institute for Theoretical Biology compiled key challenges and opportunities that theoreticians, experimentalists, and clinicians can explore from a systems biology perspective to provide a better understanding of the disease as well as help discover new treatment options and therapeutic strategies.

Determination of bioavailable arsenic threshold and validation of modeled permissible total arsenic in paddy soil using machine learning.

Minimizing arsenic intake from food consumption is a key aspect of the public health response in arsenic (As)-contaminated regions. In many of these regions, rice is the predominant staple food. Here, we present a validated maximum allowable concentration of total As in paddy soil and provide the first derivation of a maximum allowable soil concentration for bioavailable As. We have previously used meta-analysis to predict the maximum allowable total As in soil based on decision tree (DT) and logistic regression (LR) models. The models were defined using the maximum tolerable concentration (MTC) of As in rice grains as per the codex recommendation. In the present study, we validated these models using three test data sets derived from purposely collected field data. The DT model performed better than the LR in terms of accuracy and Matthews correlation coefficient (MCC). Therefore, the DT estimated maximum allowable total As in paddy soil of 14 mg kg-1 could confidently be used as an appropriate guideline value. We further used the purposely collected field data to predict the concentration of bioavailable As in the paddy soil with the help of random forest (RF), gradient boosting machine (GBM), and LR models. The category of grain As (MTC) was considered as the dependent variable; bioavailable As (BAs), total As (TAs), pH, organic carbon (OC), available phosphorus (AvP), and available iron (AvFe) were the predictor variables. LR performed better than RF and GBM in terms of accuracy, sensitivity, specificity, kappa, precision, log loss, F1score, and MCC. From the better-performing LR model, bioavailable As (BAs), TAs, AvFe, and OC were significant variables for grain As. From the partial dependence plots (PDP) and individual conditional expectation (ICE) of the LR model, 5.70 mg kg-1 was estimated to be the limit for BAs in soil.

A Deep Ranking Weighted Multihashing Recommender System for Item Recommendation.

Collaborative filtering (CF) techniques are used in recommender systems to provide users with specialised recommendations on social websites and in e-commerce. But they suffer from sparsity and cold start problems (CSP) and fail to interpret why they recommend a new item. A novel deep ranking weighted multihash recommender (DRWMR) system is designed to suppress sparsity and CSP. The proposed DRWMR system contains two stages: the neighbours' formation and recommendation phases. Initially, the data is fed to the deep convolutional neural network (CNN). The significant features are extracted from CNN. The CNN contains an additional layer; the hash code is generated by minimising pairwise ranking loss and classification loss. Therefore, a weight is assigned to different hash tables and hash bits for a recommendation. Then, the similarity between users is obtained based on the weighted hammering distance; the similarity between users helps to form the neighbourhood for the active user. Finally, the rating for unknown items can be obtained by taking the weighted average rating of the neighbourhood, and a list of the top n items can be produced. The effectiveness and accuracy of the proposed DRWMR system are tested on the MovieLens 100 K dataset and compared with the existing methods. Based on the evaluation results, the proposed DRWMR system gives precision (0.16), the root mean squared error (RMSE) of 0.73 and the recall (0.08), the mean absolute error (MAE) of 0.57, and the F - 1 measure (0.101).

Evaluation of natural chronic low dose radiation exposure on telomere length and transcriptional response of shelterin complex in individuals residing in Kerala coast, India.

The high level natural radiation areas (HLNRA) of Kerala coast provide unique opportunity to study the biological effect of chronic low dose ionizing radiation (LDIR) on human population below 100 mSv. The radiation level in this area varies from < 1.0-45 mGy /year due to patchy distribution of monazite in the sand, which contains 232Th (8-10%), 238U (0.3%), and their decay products. Telomere length attrition has been correlated to DNA damage due to genotoxic agents. The objective of the present study is to evaluate the effect of natural chronic LDIR exposure on telomere length and transcriptional response of telomere specific and DNA damage repair genes in peripheral blood mononuclear cells (PBMCs) of individuals from normal level natural radiation areas (NLNRA) and HLNRA of Kerala coast, southwest India. Blood samples were collected from 71 random male donors (24-80 years) from NLNRA (≤1.50 mGy/year; N = 19) and two HLNRA dose groups [1.51-10 mGy/year (N = 17); > 10 mGy/year, (N = 35)]. Genomic DNA was isolated from PBMCs and relative telomere length (RTL) was determined using real time q-PCR. Radio-adaptive response (RAR) study was carried out in PBMCs of 40 random males from NLNRA (N = 20) and HLNRA (>10 mGy/year; N = 20), where PBMCs were given a challenged dose of 2.0 Gy gamma radiation at 4 h. Transcriptional profile of telomere specific (TRF1, TRF2, POT1, TIN2, TPP1, RAP1), DNA damage response (RAD17, ATM, CHEK1) and base excision repair pathway (BER) (OGG1, XRCC1, NTH1, NEIL1, MUTYH, MBD4) genes were analysed at basal level and after a challenge dose of 2.0 Gy at 4 h. Our results did not show any significant effect of chronic LDR on RTL among the individuals from NLNRA and two HLNRA groups (p = 0.195). However, influence of age on RTL was clearly evident among NLNRA and HLNRA individuals. At basal level, TRF1, TRF2, TIN2, MBD4, NEIL1 and RAD17 showed significant up-regulation, whereas XRCC1 was significantly down regulated in HLNRA individuals. After a challenge dose of 2.0 Gy, significant transcriptional up-regulation was observed at telomere specific (TRF2, POT1) and BER (MBD4, NEIL1) genes in HLNRA individuals as compared to NLNRA suggesting their role in RAR. In conclusion, elevated level of natural chronic LDR exposure did not have any adverse effect on telomere length in Kerala coast. Significant transcriptional response at TRF2, MBD4 and NEIL1 at basal level and with a challenge dose of 2.0 Gy suggested their active involvement in efficient repair and telomere maintenance in individuals from HLNRA of Kerala coast.

Bond strength of lithium disilicate to polyetheretherketone.

STATEMENT OF PROBLEM: Polyetheretherketone (PEEK) is a high-performance polymer that is increasingly used in dentistry, for example, as a framework for implant-supported fixed complete dentures. One protocol calls for individual lithium disilicate crowns to be cemented on preparation-shaped retentive elements on the framework. However, the flexibility and strength of the bonded system is unclear. PURPOSE: The purpose of this in vitro study was to compare the flexibility and strength of bonded lithium disilicate to PEEK with the bond between lithium disilicate and zirconia. MATERIAL AND METHODS: Fifteen PEEK (JUVORA Dental Disc), 15 zirconia (ArgenZ HT+), and 30 lithium disilicate (IPS e.max CAD) beam-shaped specimens (12.5×2×2 mm) were prepared. The ends of the PEEK beams were conditioned with 50-µm aluminum oxide airborne-particle abrasion, followed by primer (visio.link) and light-activated polymerization. Zirconia specimens were prepared with airborne-particle abrasion and primer (Monobond Plus). Lithium disilicate specimens were etched with 4.5% hydrofluoric acid (IPS Ceramic Etching Gel) and primed (Monobond Plus). The lithium disilicate specimens were cemented (Multilink Automix) to the PEEK and zirconia specimens. Light- and chemical-activated polymerization were used. Monolithic specimens of PEEK and zirconia (25×2×2 mm) were also prepared. All specimens were stored overnight in distilled water and submitted to a 4-point bend test in a universal testing machine at 0.5 mm/min crosshead speed until fracture, and the flexural modulus and strength were calculated. Differences among groups were statistically tested by using 1-way analysis of variance followed by the Student-Newman-Keuls post hoc test (α=.05). RESULTS: All bonded specimens fractured at their adhesive interface. Zirconia bonded to lithium disilicate specimens (29.7 ±8.8 MPa) were approximately 3 times stronger than PEEK bonded to lithium disilicate specimens (10.4 ±2.7 MPa) and approximately 12 times more rigid (78.5 ±6.7 GPa and 6.5 ±1.8 GPa, respectively). The flexure of monolithic PEEK was such that it did not fracture when loaded at 0.5 mm/min, while zirconia fractured at 413.9 ±38.5 MPa. Monolithic PEEK was approximately 37 times more flexible than monolithic zirconia (4.3 ±0.3 GPa and 157.2 ±7.2 GPa, respectively). All values were statistically significantly different except between the flexural moduli of monolithic PEEK and PEEK bonded to lithium disilicate. CONCLUSIONS: The bond strength between PEEK and lithium disilicate was significantly weaker than between zirconia and lithium disilicate. Monolithic zirconia was significantly stiffer than monolithic PEEK.

Adenosine: a partially discovered medicinal agent.

BACKGROUND: A plethora of chemicals exists in human body which can alter physiology in one way or other. Scientists have always been astounded by such abilities of chemicals but as the technology advances, even the chemical which was once expected to be well known changes its status to not really well known. Adenosine is one of the chemicals which is in consonance with the aforementioned statements, although previous articles have covered vast information on role of adenosine in cardiovascular physiology, bacterial pathophysiology and inflammatory diseases. In this review we have discussed adenosine and its congeners as potential promising agents in the treatment of Huntington's disease, post-traumatic stress disorder, erectile dysfunction, viral infections (SARS-CoV) and anxiety. MAIN TEXT: Adenosine is a unique metabolite of ATP; which serves in signalling as well. It is made up of adenine (a nitrogenous base) and ribo-furanose (pentose) sugar linked by ß-N9-glycosidic bond. Adenosine on two successive phosphorylation forms ATP (Adenosine Triphosphate) which is involved in several active processes of cell. It is also one of the building blocks (nucleotides) involved in DNA (Deoxy-ribonucleic Acid) and RNA (Ribonucleic Acid) synthesis. It is also a component of an enzyme called S-adenosyl-L-methionine (SAM) and cyano-cobalamin (vitamin B-12). Adenosine acts by binding to G protein-coupled receptor (GPCR: A1, A2A, A2B and A3) carries out various responses some of which are anti-platelet function, hyperaemic response, bone remodelling, involvement in penile erection and suppression of inflammation. On the other hand, certain microorganisms belonging to genus Candida, Staphylococcus and Bacillus utilize adenosine in order to escape host immune response (phagocytic clearance). These microbes evade host immune response by synthesizing and releasing adenosine (with the help of an enzyme: adenosine synthase-A), at the site of infection. CONCLUSION: With the recent advancement in attribution of adenosine in physiology and pathological states, adenosine and its congeners are being looked forward to bringing a revolution in treatment of inflammation, viral infections, psychiatric and neurodegenerative disorders.

Phase I study using crenolanib to target PDGFR kinase in children and young adults with newly diagnosed DIPG or recurrent high-grade glioma, including DIPG.

BACKGROUND: Platelet-derived growth factor receptor (PDGFR) signaling has been directly implicated in pediatric high-grade gliomagenesis. This study evaluated the safety and tolerability of crenolanib, a potent, selective inhibitor of PDGFR-mediated phosphorylation, in pediatric patients with high-grade glioma (HGG). METHODS: We used a rolling-6 design to study the maximum tolerated dose (MTD) of once-daily crenolanib administered during and after focal radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (stratum A) or with recurrent/progressive HGG (stratum B). Pharmacokinetics were studied during the first cycle at the first dose and at steady state (day 28). Alterations in PDGFRA were assessed by Sanger or exome sequencing and interphase fluorescence in situ hybridization or single nucleotide polymorphism arrays. RESULTS: Fifty evaluable patients were enrolled in the 2 strata, and an MTD of 170 mg/m2 was established for both. Dose-limiting toxicities were primarily liver enzyme elevations and hematologic count suppression in both strata. Crenolanib AUC0-48h and C MAX did not differ significantly for crushed versus whole-tablet administration. Overall, PDGFRA alterations were observed in 25% and 30% of patients in stratum A and B, respectively. Neither crenolanib therapy duration nor survival outcomes differed significantly by PDGFRA status, and overall survival of stratum A was similar to that of historical controls. CONCLUSIONS: Children tolerate crenolanib well at doses slightly higher than the established MTD in adults, with a toxicity spectrum generally similar to that in adults. Studies evaluating intratumoral PDGFR pathway inhibition in biomarker-enriched patients are needed to evaluate further the clinical utility of crenolanib in this population.

Screening of Health-Associated Oral Bacteria for Anticancer Properties in vitro.

While extensive literature exists about the role of oral bacterial pathogens like Porphyromonas gingivalis and Fusobacterium nucleatum in oral squamous cell carcinoma (OSCC), the role of health-associated species has been largely unexplored. In this study, we assessed the effect of Streptococcus mitis, Rothia mucilaginosa, Neisseria flavescens, Haemophilus parainfluenzae, Lautropia mirabilis, and Veillonella parvula on proliferation and expression of marker genes (IL-6, TNF-α, MMP3, CD36, CCD1, and NANOG) in OSCC cell lines CAL27, SCC25, and SCC4. Porphyromonas gingivalis was included as a pathogenic control. Both bacterial lysates (3 concentrations) and live cells (3 MOIs) were tested. S. mitis, H. parainfluenzae, and N. flavescens resulted in substantial, dose-dependent reduction of proliferation, which was found to be mediated by H2O2 for the former and intracellular infection in the latter two species. However, only H. parainfluenzae showed differential antiproliferative effect against the cancer cell lines vs. the normal control (TIGKs). In the gene expression assays, the health-associated species mostly downregulated CD36, a gene that plays an important role in tumor growth and metastasis, while P. gingivalis upregulated it. IL6 and TNF expression, on the other hand, was upregulated by almost all species, particularly the Gram-negatives including P. gingivalis. The effect on other genes was less evident and varied significantly by cell line. This exploratory study is the first insight into how health-associated bacteria may interact with OSCC. Further studies to explore whether the observed effects may have implications for the prevention or treatment of oral cancer are warranted.

Diffuse Sarcoidosis Masquerading as Widespread Malignant Disease: A Rare Case Report and Literature Review.

Sarcoidosis is a multisystem granulomatous disease commonly involving the lungs and mediastinal lymph nodes with the exact etiology being unclear. The simultaneous presence of malignant disease such as breast cancer and sarcoidosis has been reported. Sarcoidosis preceding a diagnosis of malignancy and that occurring years after treatment of malignant disease has been noted in the past. The presence of sarcoidosis in the setting of malignant disease carries a high risk of misdiagnosis. In this article, we report the case of a 45-year-old female with stage IA invasive ductal carcinoma of left breast that was in remission for 2 years; however, radiological imaging including magnetic resonance imaging of thoracic spine and positron emission tomography-computed tomography scanning were highly suspicious for malignant disease metastasis versus lymphoma with the widespread lymphadenopathy. Multiple tissue biopsies with histopathological evaluation allowed us to definitively exclude malignant disease metastasis and to correctly diagnose her atypical presentation of sarcoidosis.

Constrictive Pericarditis: A Commonly Missed Cause of Treatable Diastolic Heart Failure.

Constrictive pericarditis arises as a result of the fibrous thickening of the pericardium due to chronic inflammatory changes from various injuries. Increased pulmonary and systemic venous pressures manifest clinical features of left and right heart failure. Idiopathic or post-viral pericarditis is the most common cause followed by postpericardiotomy, radiation-induced causes. Right-sided heart failure symptoms predominate over left-sided heart failure symptoms due to the equalization of pressures. No single diagnostic test can provide a definitive diagnosis or evidence of constrictive pericarditis. Medical management is difficult for constrictive pericarditis. The treatment of choice for constrictive pericarditis is pericardiectomy.

Artificial Intelligence in Modern Medicine - The Evolving Necessity of the Present and Role in Transforming the Future of Medical Care.

The dexterity of computer systems to resemble and mimic human intelligence is artificial intelligence. Artificial intelligence has reformed the diagnostic and therapeutic precision and competence in various fields of medicine. Artificial intelligence appears to play a bright role in medical diagnosis. Computer systems using artificial intelligence help in the assessment of medical images and enormous data. This research aims to identify how artificial intelligence-based technology is reforming the art of medicine. Artificial intelligence empowers providers in improving efficiency and overall healthcare. Newer machine learning techniques lead the automatic diagnostic systems. Areas of medicine such as medical imaging, automated clinical decision-making support have made significant advances with respect to artificial intelligence technology. With improved diagnosis and prognosis, artificial intelligence possesses the capability to revolutionize various fields of medicine. Artificial intelligence has its own limitations and cannot replace a bedside clinician. In the evolving modern medical digital world, physicians need to support artificial intelligence rather than fear it replacing trained physicians for improved healthcare.

Renal Artery Stenosis As Etiology of Recurrent Flash Pulmonary Edema and Role of Imaging in Timely Diagnosis and Management.

Renal hypoperfusion from renal artery stenosis (RAS) activates the renin-angiotensin system, which in turn causes volume overload and hypertension. Atherosclerosis and fibromuscular dysplasia are the most common causes of renal artery stenosis. Recurrent flash pulmonary edema, also known as Pickering syndrome, is commonly associated with bilateral renal artery stenosis. There should be a high index of clinical suspicion for renal artery stenosis in the setting of recurrent flash pulmonary edema and severe hypertension in patients with atherosclerotic disease. Duplex ultrasonography is commonly recommended as the best initial test for the detection of renal artery stenosis. Computed tomography (CT) angiography (CTA) or magnetic resonance (MR) angiography (MRA) are useful diagnostic imaging studies for the detection of renal artery stenosis in patients where duplex ultrasonography is difficult. If duplex ultrasound, CTA, and MRA are indeterminate or pose a risk of significant renal impairment, renal angiography is useful for a definitive diagnosis of RAS. The focus of medical management for RAS relies on controlling renovascular hypertension and aggressive lifestyle modification with control of atherosclerotic disease risk factors. The restoration of renal artery patency by revascularization in the setting of RAS due to atherosclerosis may help in the management of hypertension and minimize renal dysfunction.

Modified Technique for CAD/CAM Guided Implant Planning in the Presence of Existing Hopeless Teeth.

Immediate placement of dental implants presents many challenges, especially when partial or complete fixed restorations are the intended prosthetic outcome. With modern advancements in CAD/CAM technology, the ease and predictability of such complex cases is vastly improved. However, certain clinical situations remain that preclude the traditional implementation of this controlled approach to implant planning/placement and the current solutions to these problems each impose some level of compromise. This article describes a technique permitting both prosthetically-driven implant planning and increased surgical guide accuracy in situations where existing hopeless teeth would otherwise impede optimal treatment.