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In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98-99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

BackgroundNeuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer.MethodsWe performed analytical validation of a Circulating Tumor Cell (CTC) multiplex RNA qPCR assay to identify the limit of quantification (LOQ) in cell lines, synthetic cDNA, and patient samples. We next profiled 116 longitudinal samples from a prospectively collected institutional cohort of 17 patients with metastatic prostate cancer (7 NEPC, 10 adenocarcinoma) as well as 265 samples from 139 patients enrolled in 3 adenocarcinoma phase II trials of androgen receptor signaling inhibitors (ARSIs). We assessed a NEPC liquid biomarker via the presence of neuroendocrine markers and the absence of androgen receptor (AR) target genes.ResultsUsing the analytical validation LOQ, liquid biomarker NEPC detection in the longitudinal cohort had a per-sample sensitivity of 51.35% and a specificity of 91.14%. However, when we incorporated the serial information from multiple liquid biopsies per patient, a unique aspect of this study, the per-patient predictions were 100% accurate, with a receiver-operating-curve (ROC) AUC of 1. In the adenocarcinoma ARSI trials, the presence of neuroendocrine markers, even while AR target gene expression was retained, was a strong negative prognostic factor.ConclusionOur analytically validated CTC biomarker can detect NEPC with high diagnostic accuracy when leveraging serial samples that are only feasible using liquid biopsies. Patients with expression of NE genes while retaining AR-target gene expression may indicate the transition to neuroendocrine differentiation, with clinical characteristics consistent with this phenotype.FundingNIH (DP2 OD030734, 1UH2CA260389, R01CA247479, and P30 CA014520), Department of Defense (PC190039 and PC200334), and Prostate Cancer Foundation (Movember Foundation - PCF Challenge Award).

DNA mutations in specific genes can confer preferential benefit from drugs targeting those genes. However, other molecular perturbations can "phenocopy" pathogenic mutations, but would not be identified using standard clinical sequencing, leading to missed opportunities for other patients to benefit from targeted treatments. We hypothesized that RNA phenocopy signatures of key cancer driver gene mutations could improve our ability to predict response to targeted therapies, despite not being directly trained on drug response. To test this, we built gene expression signatures in tissue samples for specific mutations and found that phenocopy signatures broadly increased accuracy of drug response predictions in-vitro compared to DNA mutation alone, and identified additional cancer cell lines that respond well with a positive/negative predictive value on par or better than DNA mutations. We further validated our results across four clinical cohorts. Our results suggest that routine RNA sequencing of tumors to identify phenocopies in addition to standard targeted DNA sequencing would improve our ability to accurately select patients for targeted therapies in the clinic., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Stem cells from human exfoliated deciduous teeth (SHEDs) can transform into odontoblasts in vitro and in vivo . The role of 1α, 25-dihydroxyvitamin D3 (1α,25 vitD3) has been reported in the mineralization of hard tissues and teeth, as well as osteoblastic differentiation. This study aimed to assess the effect of different concentrations of 1α,25 vitD3 on odontogenic differentiation of SHEDs., Materials and Methods: In this experimental study, second-passage SHEDs were exposed to odontogenic medium along with 0, 10, 50, 100, and 150 nmol concentrations of in 1α, 25 vitD3 to determine its optimal concentration for odontogenic differentiation. The methyl thiazolyl tetrazolium (MTT) assay was performed. Odontogenic differentiation was evaluated by QRT- polymerase chain reaction for dentin matrix protein (DMP1) and dentin sialophosphoprotein (DSPP) genes. Morphology of differentiated cells was studied by Scanning Electron Microscopy. Data were analyzed using the Kruskal-Wallis, Mann-Whitney, Friedman, and Chi-square test. P < 0.05 is considered statistically significant., Results: MTT test result showed the two groups of odontogenic medium + 10 nm 1α,25 vitD3 and odontogenic medium + 150 nm 1α,25 vitD3 provided the most suitable conditions for cell viability at 72 h. Expression of both genes significantly increased in the presence of 1α,25 vitD3 ( P < 0.001). Expression of both genes was significantly higher at 14 days compared with 7 days ( P < 0.01). At both time points, expression of both genes was significantly higher in the presence of 150 nm 1α,25 vitD3 compared with 10 nm ( P < 0.01). The accumulation of cells with odontoblastic morphology, cell interactions, and calcifications were evident., Conclusion: 1α,25 vitD3 upregulates DMP1 and DSPP and results in odontogenic differentiation of SHEDs in odontogenic medium. This upregulation increases with time and by an increase in concentration of 1α,25 vitD3., Competing Interests: The authors of this manuscript declare that they have no conflicts of interest, real or perceived, financial or non-financial in this article., (Copyright: © 2022 Dental Research Journal.)

The Ultraviolet-visible (UV-Vis) spectra indicate that anthracenyl chalcones (ACs) have high maximum wavelengths and good transparency windows for optical applications and are suitable for optoelectronic applications owing to their HOMO-LUMO energy gaps (2.93 and 2.76 eV). Different donor substituents on the AC affect their dipole moments and nonlinear optical (NLO) responses. The positive, negative, and neutral electrostatic potential regions of the molecules were identified using molecular electrostatic potential (MEP). The stability of the molecule on account of hyperconjugative interactions and accompanying charge delocalization was analyzed using natural bond orbital (NBO) analysis. Open and closed aperture Z-scans were performed using a continuous-wave frequency-doubled diode-pumped solid-state (DPSS) laser to measure the nonlinear absorption and nonlinear refractive index coefficients, respectively. The valley-to-peak profile of AC indicated a negative nonlinear refractive index coefficient. The obtained single crystals possess reverse saturation absorption due to excited-state absorption. The structural and nonlinear optical properties of the molecules have been discussed, along with the role of anthracene substitution for enhancing the nonlinear optical properties. The calculated third-order susceptibility value was 1.10 x10-4 esu at an intensity of 4.1 kW/cm2, higher than the reported values for related chalcone derivatives. The NLO response for both ACs offers excellent potential in optical switching and limiting applications., Competing Interests: The authors have declared that no competing interests exist.

We are now in an era of molecular medicine, where specific DNA alterations can be used to identify patients who will respond to specific drugs. However, there are only a handful of clinically used predictive biomarkers in oncology. Herein, we describe an approach utilizing in vitro DNA and RNA sequencing and drug response data to create TreAtment Response Generalized Elastic-neT Signatures (TARGETS). We trained TARGETS drug response models using Elastic-Net regression in the publicly available Genomics of Drug Sensitivity in Cancer (GDSC) database. Models were then validated on additional in-vitro data from the Cancer Cell Line Encyclopedia (CCLE), and on clinical samples from The Cancer Genome Atlas (TCGA) and Stand Up to Cancer/Prostate Cancer Foundation West Coast Prostate Cancer Dream Team (WCDT). First, we demonstrated that all TARGETS models successfully predicted treatment response in the separate in-vitro CCLE treatment response dataset. Next, we evaluated all FDA-approved biomarker-based cancer drug indications in TCGA and demonstrated that TARGETS predictions were concordant with established clinical indications. Finally, we performed independent clinical validation in the WCDT and found that the TARGETS AR signaling inhibitors (ARSI) signature successfully predicted clinical treatment response in metastatic castration-resistant prostate cancer with a statistically significant interaction between the TARGETS score and PSA response (p = 0.0252). TARGETS represents a pan-cancer, platform-independent approach to predict response to oncologic therapies and could be used as a tool to better select patients for existing therapies as well as identify new indications for testing in prospective clinical trials., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Two organometallic compounds known as (E)-1-ferrocenyl-(3-fluorophenyl)prop-2-en-1-one (Fc1) and (E)-1-ferrocenyl-(3-fluoro-4-methoxyphenyl)prop-2-en-1-one (Fc2) are designed and synthesized for application in dye-sensitized solar cell (DSSC) based on a donor-π-acceptor (D-π-A) architecture. By strategically introducing a methoxy group into the acceptor side of the compound, Fc2 which has adopted a D-π-A-AD structure are compared with the basic D-π-A structure of Fc1. Both compounds were characterized by utilizing the IR, NMR and UV-Vis methods. Target compounds were further investigated by X-ray analysis and studied computationally using Density Functional Theory (DFT) and Time-Dependent DFT (TD-DFT) approaches to explore their potential performances in DSSCs. An additional methoxy group has been proven in enhancing intramolecular charge transfer (ICT) by improving the planarity of Fc2 backbone. This good electronic communication leads to higher HOMO energy level, larger dipole moment and better short-circuit current density (Jsc) values. Eventually, the presence of methoxy group in Fc2 has improved the conversion efficiency as in comparison to Fc1 under the same conditions., Competing Interests: The authors have declared that no competing interests exist.

Background: A successful endodontic treatment depends on efficient cleaning and shaping and effective irrigation of root canals. The irrigating solution may not be effective in some areas in the canal. The manufacturer of XP-Endo finisher claims that it can effectively clean the root canals with complex morphology. This study aimed to assess the effect of XP-Endo finisher on the amount of residual debris and smear layer on the root canal walls of mandibular second premolars., Materials and Methods: In this In vitro study Fifty extracted mandibular second premolars with a root curvature <20° were collected. Root canals were prepared using BioRaCe rotary system. The root canals were in contact with the file and different irrigating solutions for 1 min. The teeth were then randomly divided into four experimental ( n = 10) and one positive control group as follows: (1) XPF + saline, (2) XPF + ethylenediaminetetraacetic acid (EDTA), (3) XPF + sodium hypochlorite (NaOCl), (4) XPF + EDTA + NaOCl and (control) EDTA + NaOCl. The teeth were longitudinally sectioned into two halves and the amount of debris and smear layer remaining in the coronal, middle, and apical thirds of the roots was quantified and scored under an electron microscope. The Kruskal-Wallis test was used to compare the groups, and P < 0.05 was considered statistically significant., Results: The highest mean amount of residual debris (2.9 ± 1.13) was noted in XPF + saline group ( P < 0.05). XPF + saline and XPF + NaOCl (3.8 ± 0.60) had the lowest efficacy for smear layer removal ( P < 0.05) with no significant within-group difference. No significant difference was noted between Groups 2, 3, and 4 with the positive control group regarding debris removal. Groups 2 and 4 had no significant difference with the positive control group regarding smear layer removal., Conclusion: Use of XP-Endo finisher has no superiority to the standard protocol for the use of irrigating solutions (EDTA + NaOCl) for debris and smear layer removal, but in some cases, such as second appointment of regeneration treatment we cannot use NaOCl because of its destructive effects on stem cells; thus, we can benefit from the synergistic effects of XPF and EDTA for better smear layer removal., Competing Interests: The authors of this manuscript declare that they have no conflicts of interest, real or perceived, financial or nonfinancial in this article.

Infection of the dental pulp will result in inflammation and eventually tissue necrosis which is treated conventionally by pulpectomy and root canal treatment. Advances in regenerative medicine and tissue engineering along with the introduction of new sources of stem cells have led to the possibility of pulp tissue regeneration. This systematic review analyzes animal studies published since 2010 to determine the ability of stem cell therapy to regenerate the dentine-pulp complex (DPC) and the success of clinical protocols. In vitro and human clinical studies are excluded and only the experimental studies on animal models were included. Dental pulp stem cells constitute the most commonly used cell type. The majority of stem cells are incorporated into various types of scaffold and implanted into root canals. Some of the studies combine growth factors with stem cells in an attempt to improve the outcome. Studies of ectopic transplantation using small animal models are simple and non-systematic evaluation techniques. Stem cell concentrations have not been so far reported; therefore, the translational value of such animal studies remains questionable. Though all types of stem cells appear capable of regenerating a dentine-pulp complex, still several factors have been considered in selecting the cell type. Co-administrative factors are essential for inducing the systemic migration of stem cells, and their vascularization and differentiation into odontoblast-like cells. Scaffolds provide a biodegradable structure able to control the release of growth factors. To identify problems and reduce costs, novel strategies should be initially tested in subcutaneous or renal capsule implantation followed by root canal models to confirm results.

Introduction: Maintaining the original central canal path is an important parameter in efficient root canal preparation. Instruments causing minimal changes in original canal path are preferred for this purpose. This study sought to compare canal transportation and centering ability of ProTaper and SafeSider instruments in curved mesiobuccal root canals of mandibular first molars using cone beam computed tomography (CBCT)., Methods and Materials: In this experimental study, 30 mesiobuccal root canals of extracted human mandibular first molars with 20° to 40° curvature were randomly divided into two groups ( n =15). After mounting in putty, preoperative CBCT scans were obtained of teeth. Root canals in group A were shaped using S1, S2, F1 and F2 of ProTaper system. Root canals in group B were instrumented to size 25 using SafeSider system according to the manufacturers' instructions. Postoperative CBCT scans were then obtained. The distance between the external root surface and internal canal wall was measured at the mesial and distal at 1, 3 and 7 mm from the apex. The values measured on primary and secondary CBCT scans were compared to assess possible changes in original central canal path and canal transportation. Data were compared using the t -test and repeated measure ANOVA., Results: ProTaper and SafeSider were significantly different in terms of canal transportation and centering ability, and ProTaper was significantly superior to SafeSider in this respect ( P <0.001)., Conclusion: ProTaper (in contrast to SafeSider) is well capable of maintaining the original central canal path with the least amount of transportation., Competing Interests: ‘None declared’.

The aim of this study was to perform a literature review of published in-vitro and ex-vivo studies, which evaluated microbial leakage in endodontics in the past 10 years. A comprehensive electronic literature search was carried out in PubMed database for English articles published from 2005 to 2016 using the keywords "endodontics," " in vitro ," " ex vivo ," "microbial leakage," "microbial penetration," "saliva," " Enterococcus faecalis ," " E. faecalis ," "endodontic sealers," "temporary filling material," "apical plug," "mineral trioxide aggregate," and "MTA." The keywords were combined using Boolean operators AND/OR. Based on our search strategy, 33 relevant articles were included in the study. There are three main methods for assessment of bacterial microleakage, namely, (A) the dual-chamber leakage model, (B) detection of bacteria using a scanning electron microscope (SEM), and (C) polymerase chain reaction. All bacterial leakage models have some limitations and may yield different results compared to other microleakage evaluation techniques (i.e., dye penetration, fluid filtration, or electrochemical tests). The results of SEM correlated with those of microbial leakage test in most studies. Microbial leakage test using saliva better simulates the clinical setting for assessment of the leakage of single or mixed bacterial species., Competing Interests: There are no conflicts of interest.

Aim: To compare the apical seal of lateral condensation technique, thermafil and one-step by using this model., Materials and Methods: A two-chamber bacterial microleakage model using E. faecalis as microbial marker was used for evaluation of the leakage. Bacterial penetration was monitored over a 60-day period. Leakage was recorded when turbidity was observed in the lower chamber., Results: After comparing the bacterial penetration values, total penetration was observed 45% in lateral condensation technique, 80% in thermafil and 75% in one-step. There was no significant difference between groups after 60 days; however, the microleakage in lateral condensation group was seen later than one-step and thermafil., Conclusion: Thermafil and one-step obturator can be advocated as effective obturation techniques for achieving predictable success in endodontic therapy., Clinical Significance: Thermafil and one-step obturator are suitable devices for obturation.

Background: The aim of this study was to compare the antibacterial efficacy of endemic Satureja Khuzistanica Jamzad (SKJ) essential oil as root canal irrigation versus 2.5% sodium hypochlorite and 2% chlorhexidine gluconate., Methods: In current in vitro experimental study, fifty four single-rooted teeth were randomly divided into 6 groups of 9 samples: 2.5% sodium hypochlorite (NaOCl), 2% chlorhexidine gluconate (CHX), 0.31 mg/ml SKJ, 0.62 mg/ml SKJ, positive and negative controls. Each tooth was instrumented, sealed and autoclaved. Then, test groups were inoculated with E. faecalis, treated with irrigation solution and viable bacterial counts in intracanal dentin chips were determined. Utilizing SPSS 18 software, collected data were analyzed by Kruskal-Wallis one way analysis of variance (P = 0.05)., Results: 99.94 % and 99.50% reduction in bacteria load after 5 min treatment with NaOCl and CHX were detected, respectively. Similarly, 99.97% and 99.96% reduction in bacterial counts were observed after 5 min application of 0.62 mg/ml and 0.31 mg/ml SKJ essential. No significant differences were detected among the four irrigation solutions (P = 0.755)., Conclusion: SKJ essential oil with the minimum inhibitory concentration (MIC) of 0.31 mg/ml could be an effective antibacterial irrigation solution.

Introduction: Mineral trioxide aggregate (MTA) is an endodontic material with different clinical applications e.g. root-end filling, pulp capping and perforation repair. It has been reported to possess antimicrobial and antifungal activities. The aim of this study was to examine the effect of White MTA on formalin-induced hyperalgesia in a rat with inflammatory pain., Materials and Methods: Inflammatory pain was induced by subcutaneous (SC) injection of formalin (40 µL, 2.5%) into the rat upper lip. The nociceptive behavioral responses i.e. shaking of the lower jaw and face rubbing were quantified. 40 µL of eugenol (50 mg/kg), WMTA (20 mg/0.2 mL) or ketoprofen were injected solely or in combination with formalin 2.5% and the behavioral responses were compared with those observed after formalin treatment alone. One-way ANOVA, Tukey were used for analysis of data., Results: Formalin 2.5% provoked a biphasic nociceptive response, with an early and short lasting first tonic phase followed by a second phase. Solely SC injection of either WMTA or ketoprofen (a non steroidal anti-inflammatory drug) did not stimulate any significant nociceptive behaviour. However, injection of eugenol (a pain relieving agent) induced the early phase not the tonic phase of nociceptive response. WMTA, eugenol or ketoprofen injection 20 min before formalin injection attenuated the first phase but somehow prevented the induction of the second phase of nociceptive responses which were produced by formalin. Behavioural nociceptive responses including shaking of the lower jaw and face rubbing were significantly reduced when the subject was pretreated with either WMTA or ketoprofen (P<0.001)., Conclusion: In this study, WMTA induced pain reduction by suppression of the formalininduced nociceptive response.

We examined the macronutrient intake of residents in Padang area, West Sumatra, Indonesia. The daily energy intake (1130±420 kcal) of elderly people in a rural traditional group was significantly lower than that in an urbanised "modernised" group (1700±460 kcal) (p<0.01). Even in young urbanised people (younger than 60 years old), 44.2% were below 2000 kcal per day. In the case of elderly people, in rural and urbanised groups 90%, and 33% of the respondents were below 1500 kcal per day, respectively. As for individual nutrients, the daily protein intake of elderly people in both the urbanised and rural groups was rather low. However, daily fat intake and carbohydrate intake of the younger people in the urbanised group were adequate, but those in the elderly group were not. In the case of the rural elderly group, macronutrient and energy intake were extremely low. To improve dietary habits and nutrient intakes of people in the Padang area, rural elderly people need a greater energy intake and an increased intake of all macronutrients.