Cancer Treatment in the Genomic Era.

The complexity of human cancer underlies its devastating clinical consequences. Drugs designed to target the genetic alterations that drive cancer have improved the outcome for many patients, but not the majority of them. Here, we review the genomic landscape of cancer, how genomic data can provide much more than a sum of its parts, and the approaches developed to identify and validate genomic alterations with potential therapeutic value. We highlight notable successes and pitfalls in predicting the value of potential therapeutic targets and discuss the use of multi-omic data to better understand cancer dependencies and drug sensitivity. We discuss how integrated approaches to collecting, curating, and sharing these large data sets might improve the identification and prioritization of cancer vulnerabilities as well as patient stratification within clinical trials. Finally, we outline how future approaches might improve the efficiency and speed of translating genomic data into clinically effective therapies and how the use of unbiased genome-wide information can identify novel predictive biomarkers that can be either simple or complex.

Single particle cryo-EM analysis of Rickettsia conorii Sca2 reveals a formin-like core.

Spotted fever group Rickettsia undergo actin-based motility inside infected eukaryotic cells using Sca2 (surface cell antigen 2): an âˆ¼ 1800 amino-acid monomeric autotransporter protein that is surface-attached to the bacterium and responsible for the assembly of long unbranched actin tails. Sca2 is the only known functional mimic of eukaryotic formins, yet it shares no sequence similarities to the latter. Using structural and biochemical approaches we have previously shown that Sca2 uses a novel actin assembly mechanism. The first âˆ¼ 400 amino acids fold into helix-loop-helix repeats that form a crescent shape reminiscent of a formin FH2 monomer. Additionally, the N- and C- terminal halves of Sca2 display intramolecular interaction in an end-to-end manner and cooperate for actin assembly, mimicking a formin FH2 dimer. Towards a better structural understanding of this mechanism, we performed single-particle cryo-electron microscopy analysis of Sca2. While high-resolution structural details remain elusive, our model confirms the presence of a formin-like core: Sca2 indeed forms a doughnut shape, similar in diameter to a formin FH2 dimer and can accommodate two actin subunits. Extra electron density, thought to be contributed by the C-terminal repeat domain (CRD), covering one side is also observed. This structural analysis allows us to propose an updated model where nucleation proceeds by encircling two actin subunits, and elongation proceeds either by a formin-like mechanism that necessitates conformational changes in the observed Sca2 model, or via an insertional mechanism akin to that observed in the ParMRC system.

Anti-Balamuthia mandrillaris and anti-Naegleria fowleri effects of drugs conjugated with various nanostructures.

Balamuthia mandrillaris and Naegleria fowleri are protist pathogens that can cause fatal infections. Despite mortality rate of > 90%, there is no effective therapy. Treatment remains problematic involving repurposed drugs, e.g., azoles, amphotericin B and miltefosine but requires early diagnosis. In addition to drug discovery, modifying existing drugs using nanotechnology offers promise in the development of therapeutic interventions against these parasitic infections. Herein, various drugs conjugated with nanoparticles were developed and evaluated for their antiprotozoal activities. Characterizations of the drugs' formulations were accomplished utilizing Fourier-transform infrared spectroscopy, efficiency of drug entrapment, polydispersity index, zeta potential, size, and surface morphology. The nanoconjugates were tested against human cells to determine their toxicity in vitro. The majority of drug nanoconjugates exhibited amoebicidal effects against B. mandrillaris and N. fowleri. Amphotericin B-, Sulfamethoxazole-, Metronidazole-based nanoconjugates are of interest since they exhibited significant amoebicidal effects against both parasites (p < 0.05). Furthermore, Sulfamethoxazole and Naproxen significantly diminished host cell death caused by B. mandrillaris by up to 70% (p < 0.05), while Amphotericin B-, Sulfamethoxazole-, Metronidazole-based drug nanoconjugates showed the highest reduction in host cell death caused by N. fowleri by up to 80%. When tested alone, all of the drug nanoconjugates tested in this study showed limited toxic effects against human cells in vitro (less than 20%). Although these are promising findings, prospective work is warranted to comprehend the mechanistic details of nanoconjugates versus amoebae as well as their in vivo testing, to develop antimicrobials against the devastating infections caused by these parasites.

Gingival tissue samples from periodontitis patients demonstrate epithelial-mesenchymal transition phenotype.

OBJECTIVE: To determine the expression of key epithelial-mesenchymal transition (EMT) markers in gingival tissue samples collected from patients with periodontitis. BACKGROUND: Epithelial-mesenchymal transition is a process responsible for shifting epithelial-phenotype to mesenchymal-phenotype leading to loss of epithelial-barrier function. Thus, EMT could be involved as a pathogenic mechanism in periodontitis as both conditions share common promoters and signalling pathways. MATERIALS AND METHODS: Gingival tissue samples were collected from patients with periodontitis (case) and healthy periodontium (control). Periodontal parameters including bleeding on probing, probing pocket depth (PPD), and clinical attachment loss were recorded. Paraffinized tissue samples were processed and immunohistochemically stained to determine the expression of key EMT markers which included E-cadherin, ß-catenin, Snail1 and vimentin. RESULTS: The majority of cases (n = 65, 72.2%) were diagnosed with periodontitis stage 3 or 4, grade b or c vs 25 (27.8%) subjects with intact healthy periodontium. Discontinuity of epithelium was detected in up to 80.9% of periodontitis cases associated with reduced number of epithelial layers as compared to controls. Immunohistochemical expression of epithelial markers (E-cadherin and ß-catenin) was significantly downregulated in periodontitis patients as compared with controls. Periodontitis cases exhibited significant upregulation of Snail1 expression. Furthermore, cytoplasmic vimentin (66.2%) and nuclear ß-catenin (27.7%) were solely expressed in periodontally diseased tissues compared with control. Epithelial markers, E-cadherin and ß-catenin, were significantly negatively correlated with increasing PPD, while vimentin showed positive correlation with this parameter. CONCLUSION: There were marked downregulation of epithelial molecules and upregulation of mesenchymal markers in gingival tissues derived from periodontitis patients, suggesting expression of the EMT phenotype in the pathological epithelial lining of periodontal pockets.

Assessing the state of LGBTQ+ diversity and inclusion in neurosurgery.

OBJECTIVE: The aim of this study was to assess the diversity of neurosurgeons in terms of lesbian, gay, bisexual, transgender, and/or queer (LGBTQ+) gender and sexual minority status using the Graduation Questionnaire (GQ) as the single nationalized source of LGBTQ+ identification. Additionally, inclusivity was assessed through interviews by residents and attendings in the field. METHODS: First, a PRISMA literature review was conducted and independently reviewed by two authors on studies involving LGBTQ+ representation in neurosurgery from PubMed, Web of Science, and Google Scholar. Then, aggregate responses of 16,901 participants' sexual and gender identities from the GQ administered between 2016 and 2022 were compiled. To statistically analyze the response frequencies, the authors performed a chi-square analysis. Finally, interviews were conducted with individuals who identify as LGBTQ+ and are currently neurosurgical residents or attendings. Direct invitations were extended to participate in interviews, and all participants gave informed consent prior to the interview. Interviews were conducted using standardized questions and were video recorded. RESULTS: Two studies were identified by literature review that referenced the LGBTQ+ community in neurosurgery. A GQ chi-square analysis comparing neurosurgical with nonneurosurgical LGBTQ+ identification proved statistically insignificant (p = 0.65). More broad analysis of majority sexual and gender identification (heterosexual and cisgendered) compared with the total gender and sexual minority group also proved statistically insignificant (p = 0.32) in response frequency. Five interviews, including 4 residents and 1 attending, provided several overarching themes including self-identification as an invisible minority, self-limiting behavior to ensure inclusion, and LGBTQ+ status as a direct departure from the stereotypical neurosurgeon. CONCLUSIONS: Results from the GQ analysis indicate that neurosurgery is achieving LGBTQ+ diversity of its incoming members comparable to that of other fields in medicine. However, qualitative data from the interviews and a lack of specific literature indicate that despite obtaining diversity, inclusion of LGBTQ+ neurosurgeons and trainees is lacking.

Metabolomic profiling of bacterial biofilm: trends, challenges, and an emerging antibiofilm target.

Biofilm-related infections substantially contribute to bacterial illnesses, with estimates indicating that at least 80% of such diseases are linked to biofilms. Biofilms exhibit unique metabolic patterns that set them apart from their planktonic counterparts, resulting in significant metabolic reprogramming during biofilm formation. Differential glycolytic enzymes suggest that central metabolic processes are markedly different in biofilms and planktonic cells. The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is highly expressed in Staphylococcus aureus biofilm progenitors, indicating that changes in glycolysis activity play a role in biofilm development. Notably, an important consideration is a correlation between elevated cyclic di-guanylate monophosphate (c-di-GMP) activity and biofilm formation in various bacteria. C-di-GMP plays a critical role in maintaining the persistence of Pseudomonas aeruginosa biofilms by regulating alginate production, a significant biofilm matrix component. Furthermore, it has been demonstrated that S. aureus biofilm development is initiated by several tricarboxylic acid (TCA) intermediates in a FnbA-dependent manner. Finally, Glucose 6-phosphatase (G6P) boosts the phosphorylation of histidine-containing protein (HPr) by increasing the activity of HPr kinase, enhancing its interaction with CcpA, and resulting in biofilm development through polysaccharide intercellular adhesion (PIA) accumulation and icaADBC transcription. Therefore, studying the metabolic changes associated with biofilm development is crucial for understanding the complex mechanisms involved in biofilm formation and identifying potential targets for intervention. Accordingly, this review aims to provide a comprehensive overview of recent advances in metabolomic profiling of biofilms, including emerging trends, prevailing challenges, and the identification of potential targets for anti-biofilm strategies.

Weighty Matters: The Obesity-Thyroid Nodule Connection Unveiling the Impact of Obesity on Thyroid Cancer Risk.

Background and Objectives: The effect of obesity on the development/progression of thyroid nodules with uncertain cytology is unknown. Therefore, our objective was to assess the role of body mass index (BMI) in predicting malignancy in patients with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) nodules. Materials and Methods: We retrospectively analyzed 113 patients with available BMI data and final histopathology of benign or differentiated thyroid cancer. Patients were classified into four groups based on BMI: <18.5 (underweight), 18.5-24.9 (normal weight), 25-29.9 (overweight), and ≥30 (obesity) kg/m2. The association between risk of malignancy and BMI was examined for all data and subgroups based on nodule size, sex, and age. Results: Overall, 44.2% were obese, 36.3% were ≥45 years, and 75.4% were women. Final pathological results showed malignant nodules in 52 patients (46%) and benign nodules in 61 patients (54%) (mean age: 41 ± 11.6 vs. 39.9 ± 11.7 years; p = 0.62). Men had more malignant nodules than benign nodules (32.7% vs. 16.4%, p < 0.05). Overall, no significant correlation was identified between the risk of thyroid cancer and BMI, and the risk of malignancy was not significantly different between obese men and women (p = 0.4). However, in individuals with BMI < 30 kg/m2 (non-obese group), malignant nodules were more frequent in men than in women (71% vs. 41%, p = 0.04). No significant difference was observed in mean nodule size between the benign and malignant groups. Furthermore, BMI was not related to increased risk of malignancy in multiple logistic regression models using all data, even after controlling for confounding variables (odds ratio, 0.99, 95% confidence interval: 0.93-1.06, p = 0.87) or when stratifying by sex. Conclusions: Our study showed no correlation between obesity and thyroid cancer in patients with AUS/FLUS. Moreover, men had more malignant nodules than benign nodules. Further well-designed prospective studies are required to confirm our findings.

Androgen receptor function and targeted therapeutics across breast cancer subtypes.

Despite significant progress in breast cancer (BC) therapy, it is globally the most commonly diagnosed cancer and leads to the death of over 650,000 women annually. Androgen receptor (AR) is emerging as a potential new therapeutic target in BC. While the role of AR is well established in prostate cancer (PCa), its function in BC remains incompletely understood. Emerging data show that AR's role in BC is dependent on several factors including, but not limited to, disease subtype, tumour microenvironment, and levels of circulating oestrogens and androgens. While targeting AR in PCa is becoming increasingly effective, these advances have yet to make any significant impact on the care of BC patients. However, this approach is increasingly being evaluated in BC and it is clear that improvements in our understanding of AR's role in BC will increase the likelihood of success for AR-targeted therapies. This review summarizes our current understanding of the function of AR across BC subtypes. We highlight limitations in our current knowledge and demonstrate the importance of categorizing BC subtypes effectively, in relation to determining AR activity. Further, we describe the current state of the art regarding AR-targeted approaches for BC as monotherapy or in combination with radiotherapy.

Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer.

Unlike many cancers, the pattern of tumor evolution in papillary thyroid cancer (PTC) and its potential role in relapse have not been elucidated. In this study, multi-region whole-exome sequencing (WES) was performed on early-stage PTC tumors (n = 257 tumor regions) from 79 individuals, including 17 who had developed relapse, to understand the temporal and spatial framework within which subclonal mutations catalyze tumor evolution and its potential clinical relevance. Paired primary-relapse tumor tissues were also available for a subset of individuals. The resulting catalog of variants was analyzed to explore evolutionary histories, define clonal and subclonal events, and assess the relationship between intra-tumor heterogeneity and relapse-free survival. The multi-region WES approach was key in correctly classifying subclonal mutations, 40% of which would have otherwise been erroneously considered clonal. We observed both linear and branching evolution patterns in our PTC cohort. A higher burden of subclonal mutations was significantly associated with increased risk of relapse. We conclude that relapse in PTC, while generally rare, does not follow a predictable evolutionary path and that subclonal mutation burden may serve as a prognostic factor. Larger studies utilizing multi-region sequencing in relapsed PTC case subjects with matching primary tissues are needed to confirm these observations.

An Effective Feature Selection Model Using Hybrid Metaheuristic Algorithms for IoT Intrusion Detection.

The increasing use of Internet of Things (IoT) applications in various aspects of our lives has created a huge amount of data. IoT applications often require the presence of many technologies such as cloud computing and fog computing, which have led to serious challenges to security. As a result of the use of these technologies, cyberattacks are also on the rise because current security methods are ineffective. Several artificial intelligence (AI)-based security solutions have been presented in recent years, including intrusion detection systems (IDS). Feature selection (FS) approaches are required for the development of intelligent analytic tools that need data pretreatment and machine-learning algorithm-performance enhancement. By reducing the number of selected features, FS aims to improve classification accuracy. This article presents a new FS method through boosting the performance of Gorilla Troops Optimizer (GTO) based on the algorithm for bird swarms (BSA). This BSA is used to boost performance exploitation of GTO in the newly developed GTO-BSA because it has a strong ability to find feasible regions with optimal solutions. As a result, the quality of the final output will increase, improving convergence. GTO-BSA's performance was evaluated using a variety of performance measures on four IoT-IDS datasets: NSL-KDD, CICIDS-2017, UNSW-NB15 and BoT-IoT. The results were compared to those of the original GTO, BSA, and several state-of-the-art techniques in the literature. According to the findings of the experiments, GTO-BSA had a better convergence rate and higher-quality solutions.

Functional Mimicry of Eukaryotic Actin Assembly by Pathogen Effector Proteins.

The actin cytoskeleton lies at the heart of many essential cellular processes. There are hundreds of proteins that cells use to control the size and shape of actin cytoskeletal networks. As such, various pathogens utilize different strategies to hijack the infected eukaryotic host actin dynamics for their benefit. These include the control of upstream signaling pathways that lead to actin assembly, control of eukaryotic actin assembly factors, encoding toxins that distort regular actin dynamics, or by encoding effectors that directly interact with and assemble actin filaments. The latter class of effectors is unique in that, quite often, they assemble actin in a straightforward manner using novel sequences, folds, and molecular mechanisms. The study of these mechanisms promises to provide major insights into the fundamental determinants of actin assembly, as well as a deeper understanding of host-pathogen interactions in general, and contribute to therapeutic development efforts targeting their respective pathogens. This review discusses mechanisms and highlights shared and unique features of actin assembly by pathogen effectors that directly bind and assemble actin, focusing on eukaryotic actin nucleator functional mimics Rickettsia Sca2 (formin mimic), Burkholderia BimA (Ena/VASP mimic), and Vibrio VopL (tandem WH2-motif mimic).

CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells.

Chromodomain-helicase-DNA-binding protein 4 (CHD4), a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex is highly expressed in several cancers. However, its role in the pathogenesis and progression of papillary thyroid carcinoma (PTC) has not been investigated. We investigated the prognostic significance of CHD4 in a large cohort of Middle Eastern PTC patients and explored the functional role of CHD4 in regulating cancer stemness and EMT in PTC cells. CHD4 overexpression was observed in 45.3% (650/1436) of PTCs, and was associated with aggressive clinico-pathological parameters and worse outcome. Functional analysis using PTC cell lines showed that forced expression of CHD4 promoted cell proliferation, spheroid growth, migration, invasion and progression of epithelial to mesenchymal transition (EMT) in PTC cells whereas its knockdown reversed the effect. Methylation of E-cadherin was associated with loss of expression in CHD4 expressing cells, while CHD4 depletion reactivated E-cadherin expression. Most importantly, knockdown of mesenchymal transcriptional factors, Snail1 or Zeb1, attenuated the spheroid growth in CHD4 expressing PTC cells, showing a potential link between EMT activation and stemness maintenance in PTC. These findings suggest that CHD4 might be a promising therapeutic target in the treatment of patients with an aggressive subtype of PTC.

Loss of ZNF677 Expression Is an Independent Predictor for Distant Metastasis in Middle Eastern Papillary Thyroid Carcinoma Patients.

Thyroid cancer incidence has increased in recent decades. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Approximately 30% of PTC patients develop recurrence or distant metastasis and tend to have poor prognosis. Therefore, the identification of targetable biomarkers in this subset of patients is of great importance. Accumulating evidence indicates that zinc finger protein 677 (ZNF677), which belongs to the zinc finger protein family, is an important effector during the progression of multiple malignancies. However, its role in Middle Eastern PTC patients has not been fully illustrated. Here, we uncovered the molecular mechanism and the clinical impact of ZNF677 expression in a large cohort of more than 1200 Middle Eastern PTC and 15 metastatic tissues. We demonstrated that ZNF677 is frequently downregulated in primary PTC (13.6%, 168/1235) and showed that complete loss of expression of ZNF677 is significantly associated with aggressive clinico-pathological markers such as extrathyroidal extension (p = 0.0008) and distant metastases (p < 0.0001). We also found a significantly higher incidence of ZNF677 loss in primary tumors with distant metastases (33.3%; p < 0.0001) as well as in distant metastatic tissues (46.7%; p = 0.0002) compared to the overall cohort (13.6%). More importantly, PTC with loss of ZNF677 expression showed significantly lower metastasis-free survival (p = 0.0090). Interestingly, on multivariate logistic regression analysis, ZNF677 loss was an independent predictor of distant metastasis in PTC (Odds ratio = 2.60, 95% Confidence interval = 1.20-5.62, p = 0.0155). In addition, we found a significant association between ZNF677 loss and phospho-AKT expression (p < 0.0001). Our functional molecular results suggest that ZNF677 acts as a tumor suppressor, mediating its effect by inhibiting AKT phosphorylation. Taken together, our results highlight the pivotal role played by ZNF677 during carcinogenesis and metastasis formation in Middle Eastern PTC patients.

Prognostic Significance of COX-2 Overexpression in BRAF-Mutated Middle Eastern Papillary Thyroid Carcinoma.

The cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) pathway has been implicated in carcinogenesis, with BRAF mutation shown to promote PGE2 synthesis. This study was conducted to evaluate COX-2 expression in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC), and further evaluate the prognostic significance of COX-2 expression in strata of BRAF mutation status. BRAF mutation analysis was performed using Sanger sequencing, and COX-2 expression was evaluated immunohistochemically using tissue microarray (TMA). COX-2 overexpression, noted in 43.2% (567/1314) of cases, was significantly associated with poor prognostic markers such as extra-thyroidal extension, lymph-node metastasis, and higher tumor stage. COX-2 was also an independent predictor of poor disease-free survival (DFS). Most notably, the association of COX-2 expression with DFS differed by BRAF mutation status. COX-2 overexpression was associated with poor DFS in BRAF-mutant but not BRAF wild-type PTCs, with a multivariate-adjusted hazard ratio of 2.10 (95% CI = 1.52-2.92; p < 0.0001) for COX-2 overexpressed tumors in BRAF-mutant PTC. In conclusion, the current study shows that COX-2 plays a key role in prognosis of PTC patients, especially in BRAF-mutated tumors. Our data suggest the potential therapeutic role of COX-2 inhibition in patients with BRAF-mutated PTC.

Rickettsia Sca2 Recruits Two Actin Subunits for Nucleation but Lacks WH2 Domains.

The Rickettsia ∼1800-amino-acid autotransporter protein surface cell antigen 2 (Sca2) promotes actin polymerization on the surface of the bacterium to drive its movement using an actin comet-tail mechanism. Sca2 mimics eukaryotic formins in that it promotes both actin filament nucleation and elongation and competes with capping protein to generate filaments that are long and unbranched. However, despite these functional similarities, Sca2 is structurally unrelated to eukaryotic formins and achieves these functions through an entirely different mechanism. Thus, while formins are dimeric, Sca2 functions as a monomer. However, Sca2 displays intramolecular interactions and functional cooperativity between its N- and C-terminal domains that are crucial for actin nucleation and elongation. Here, we map the interaction of N- and C- terminal fragments of Sca2 and their contribution to actin binding and nucleation. We find that both the N- and C-terminal regions of Sca2 interact with actin monomers but only weakly, whereas the full-length protein binds two actin monomers with high affinity. Moreover, deletions at both ends of the N- and C-terminal regions disrupt their ability to interact with each other, suggesting that they form a contiguous ring-like structure that wraps around two actin subunits, analogous to the formin homology-2 domain. The discovery of Sca2 as an actin nucleator followed the identification of what appeared to be a repeat of three Wiskott-Aldrich syndrome homology 2 (WH2) domains in the middle of the molecule, consistent with the presence of WH2 domains in most actin nucleators. However, we show here that contrary to previous assumptions, Sca2 does not contain WH2 domains. Instead, our analysis indicates that the region containing the putative WH2 domains is folded as a globular domain that cooperates with other parts of the Sca2 molecule for actin binding and nucleation.

Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis.

Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene-panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p < 0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.

A bibliometric study of the top 100 most-cited randomized controlled trials, systematic reviews and meta-analyses published in endodontic journals.

AIM: To identify and analyse the main features of the top 100 most-cited randomized controlled trials, systematic reviews and meta-analyses published in endodontic journals from 1961 to 2018. METHODOLOGY: The Clarivate Analytics' Web of Science 'All Databases' was used to search and analyse the 100 most frequently cited randomized controlled trials, systematic reviews and meta-analyses having 'randomized', 'randomised', 'randomized controlled', 'randomised controlled', 'randomized controlled trial', 'randomized controlled trials', 'clinical trial', 'systematic', 'systematic review', 'meta-analysis', and 'meta-analyses' in the title section. The 'International Endodontic Journal', 'Journal of Endodontics', 'Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology', 'Australian Endodontic Journal', 'Endodontics & Dental Traumatology', 'Endo-Endodontic Practice Today' and 'European Endodontic Journal' were included in the publication name section. After ranking the articles in a descending order based on their citation counts, each article was cross-matched with the citation counts in Elsevier's Scopus and Google Scholar. The articles were analysed, and information on citation counts, citation density, year of publication, contributing authors, institutions and countries, journal of publication, study design, topic of the article and keywords was extracted. RESULTS: The citation counts of the 100 most-cited articles varied from 235 to 20 (Web of Science), 276 to 17 (Scopus) and 696 to 1 (Google Scholar). The year in which the top 100 articles were published was 2010 (n = 13). Among 373 authors, the greatest number of articles was associated with three individuals namely Reader A (n = 5), Beck M (n = 5) and Kvist T (n = 5). Most of the articles originated from the United States (n = 24) with the greatest contribution from Ohio State University (USA) (n = 5). Randomized controlled trials were the most frequent study design (n = 45) followed by systematic reviews (n = 30) with outcome studies of root canal treatment being the major topic (n = 35). The Journal of Endodontics published the largest number of included articles (n = 70) followed by the International Endodontic Journal (n = 27). Among 259 unique keywords, meta-analysis (n = 23) and systematic review (n = 23) were the most frequently used. CONCLUSION: This study has revealed that year of publication had no obvious impact on citation count. The bibliometric analysis highlighted the quantity and quality of research, and the evolution of scientific advancements made in the field of Endodontology over time. Articles before 1996, that is prior to the CONSORT statement that encouraged authors to include specific terms in the title and keywords, may not have been included in this electronic search.

Design, Development, and Characterization of Imiquimod-Loaded Chitosan Films for Topical Delivery.

Aldara™ (5% w/w imiquimod) topical cream is approved by the US FDA for the treatment of superficial basal cell carcinoma. However, the cream formulation suffers from dose variability, low drug availability due to the incomplete release, and poor patient compliance. To achieve sustained and complete release of imiquimod, chitosan films were prepared by casting using propylene glycol as a plasticizer. Chitosan films had appropriate physicochemical characteristics for wound dressing and excellent content uniformity and maintained the original physical form of imiquimod. Films were capable of releasing a defined dose of imiquimod over a period of 7 days. The bioactivity of imiquimod was not affected by its entrapment in chitosan matrix as indicated by the results of in vitro growth inhibition assay. In addition, the film formulation showed significantly (p Ë‚ 0.05) higher drug accumulation in the skin when compared to commercial cream formulation.

Telomerase reverse transcriptase mutations are independent predictor of disease-free survival in Middle Eastern papillary thyroid cancer.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Tumor recurrence occurs in ∼20% of PTCs and some reach advanced stages. Promoter mutation in the telomerase reverse transcriptase (TERT) gene is identified to be a prognostic marker in PTC. However, the contribution of TERT promoter mutation to cancer progression in PTC patients is still not fully understood. In this study, we investigated the incidence of TERT promoter mutations and TERT protein expression and their association with clinicopathological outcomes in a large cohort of PTC samples using direct sequencing technology and immunohistochemistry. Furthermore, two PTC cell lines were utilized to investigate role of TERT mutations in mediating metastasis. Two promoter hotspot mutations C228T and C250T were identified in 18.0% (167/927) of our cohort and were significantly associated with poor 5 years disease-free survival and distant metastasis of PTC. TERT protein overexpression was noted in 20.1% of our PTC cohort and was significantly associated with poor prognostic markers such as older age, extrathyroidal extension and Stage IV tumors. A significant association was also found between TERT overexpression and epithelial-mesenchymal transition (EMT) markers. Functional analysis showed that TERT inhibition reduced cell growth, invasion, migration and angiogenesis in PTC via suppression of EMT in PTC cells. Our results suggest that TERT promoter mutation is an independent predictor of disease-free survival and might drive the metastasis, and downregulation of TERT could potentiate antitumor and antimetastatic activities in PTC.

Assessment of Personal Health Care Management and Chronic Disease Prevalence: Comparative Analysis of Demographic, Socioeconomic, and Health-Related Variables.

BACKGROUND: The use of personal health care management (PHM) is increasing rapidly within the United States because of implementation of health technology across the health care continuum and increased regulatory requirements for health care providers and organizations promoting the use of PHM, particularly the use of text messaging (short message service), Web-based scheduling, and Web-based requests for prescription renewals. Limited research has been conducted comparing PHM use across groups based on chronic conditions. OBJECTIVE: This study aimed to describe the overall utilization of PHM and compare individual characteristics associated with PHM in groups with no reported chronic conditions, with 1 chronic condition, and with 2 or more such conditions. METHODS: Datasets drawn from the National Health Interview Survey were analyzed using multiple logistic regression to determine the level of PHM use in relation to demographic, socioeconomic, or health-related factors. Data from 47,814 individuals were analyzed using logistic regression. RESULTS: Approximately 12.19% (5737/47,814) of respondents reported using PHM, but higher rates of use were reported by individuals with higher levels of education and income. The overall rate of PHM remained stable between 2009 and 2014, despite increased focus on the promotion of patient engagement initiatives. Demographic factors predictive of PHM use included people who were younger, non-Hispanic, and who lived in the western region of the United States. There were also differences in PHM use based on socioeconomic factors. Respondents with college-level education were over 2.5 times more likely to use PHM than respondents without college-level education. Health-related factors were also predictive of PHM use. Individuals with health insurance and a usual place for health care were more likely to use PHM than individuals with no health insurance and no usual place for health care. Individuals reporting a single chronic condition or multiple chronic conditions reported slightly higher levels of PHM use than individuals reporting no chronic conditions. Individuals with no chronic conditions who did not experience barriers to accessing health care were more likely to use PHM than individuals with 1 or more chronic conditions. CONCLUSIONS: The findings of this study illustrated the disparities in PHM use based on the number of chronic conditions and that multiple factors influence the use of PHM, including economics and education. These findings provide evidence of the challenge associated with engaging patients using electronic health information as the health care industry continues to evolve.