Neutrophil Biomarkers Can Predict Cardiotoxicity of Anthracyclines in Breast Cancer.

Doxorubicin (DOX), a commonly used anticancer agent, causes cardiotoxicity that begins with the first dose and may progress to heart failure years after treatment. An inflammatory response associated with neutrophil recruitment has been recognized as a mechanism of DOX-induced cardiotoxicity. This study aimed to validate mRNA expression of the previously identified biomarkers of DOX-induced cardiotoxicity, PGLYRP1, CAMP, MMP9, and CEACAM8, and to assay their protein expression in the peripheral blood of breast cancer patients. Blood samples from 40 breast cancer patients treated with DOX-based chemotherapy were collected before and after the first chemotherapy cycle and > 2 years after treatment. The protein and gene expression of PGLYRP1/Tag7, CAMP/LL37, MMP9/gelatinase B, and CEACAM8/CD66b were determined using ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of each candidate biomarker. Patients with cardiotoxicity (n = 20) had significantly elevated levels of PGLYRP1, CAMP, MMP9, and CEACAM8 at baseline, after the first dose of DOX-based chemotherapy, and at > 2 years after treatment relative to patients without cardiotoxicity (n = 20). The first dose of DOX induced significantly higher levels of all examined biomarkers in both groups of patients. At > 2 years post treatment, the levels of all but MMP9 dropped below the baseline. There was a good correlation between the expression of mRNA and the target proteins. We demonstrate that circulating levels of PGLYRP1, CAMP, MMP9, and CEACAM8 can predict the cardiotoxicity of DOX. This novel finding may be of value in the early identification of patients at risk for cardiotoxicity.

Racial Disparity in Adherence to Endocrine Therapy among Women with Early-Stage Hormone Receptor Positive Breast Cancer: An Analysis of Arkansas All-Payers Claims Database.

INTRODUCTION/BACKGROUND: To assess racial/ethnic disparities in endocrine therapy (ET) adherence among women with breast cancer. MATERIALS AND METHODS: A retrospective cohort study of Arkansas All-Payer Claims Database (APCD) linked to Arkansas Cancer Registry (ACR). Women with stages 0-3 HR+ breast cancer diagnosed in 2013-2017 were followed from cancer diagnosis for a year to determine ET initiation. Among women who initiated ETs within 1 year of diagnosis, we assessed first-year compliance (proportion of days covered ≥ 0.8) and followed them for 5 years, censoring at death, end of data availability (December 21, 2019), or disenrollment from insurance coverage, whichever occurred first, to determine time to discontinuation. Regression analysis was conducted to determine racial/ethnic disparities in ET use adjusting for patients demographic, clinical, tumor characteristics and county-level socioeconomic factors. RESULTS: Among women with continuous insurance coverage, 81% initiated ET within 1 year of diagnosis; 80% were compliant in the first year of ET use and 27.4% discontinued ET by year 5 among those who initiated ET in the first year. There were no racial/ethnic differences in ET initiation or first-year compliance adjusting for covariates. NHB women were significantly less likely to discontinue ET within 5 years after ET initiation compared to NHW women after (HR, 95% CI, 0.76, 0.58-0.98; P = .035). CONCLUSION: After adjusting for patients' and tumor characteristics, there were no racial/ethnic differences in ET initiation within 1 year of diagnosis and ET compliance within first year of ET use. However, NHB women were less likely to discontinue ET within 5 years of initiation.

Mid- and long-term risk of atrial fibrillation among breast cancer surgery survivors.

BACKGROUND: The risk of incident atrial fibrillation (AF) among breast cancer survivors, especially for younger women, and cancer treatment effects on the association remain unclear. This study aimed to investigate the risk of AF among breast cancer survivors and evaluate the association by age group, length of follow-up, and cancer treatment. METHODS: Using data from the Korean Health Insurance Service database (2010-2017), 113,232 women newly diagnosed with breast cancer (aged ≥ 18 years) without prior AF history who underwent breast cancer surgery were individually matched 1:5 by birth year to a sample female population without cancer (n = 566,160) (mean[SD] follow-up, 5.1[2.1] years). Sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) considering death as a competing risk were estimated, adjusting for sociodemographic factors and cardiovascular/non-cardiovascular comorbidities. RESULTS: BCS had a slightly increased AF risk compared to their cancer-free counterparts (sHR 1.06; 95% CI 1.00-1.13), but the association disappeared over time. Younger BCS (age < 40 years) had more than a 2-fold increase in AF risk (sHR 2.79; 95% CI 1.98-3.94), with the association remaining similar over 5 years of follow-up. The increased risk was not observed among older BCS, especially those aged > 65 years. Use of anthracyclines was associated with increased AF risk among BCS (sHR 1.57; 95% CI 1.28-1.92), which was more robust in younger BCS (sHR 1.94; 95% CI 1.40-2.69 in those aged ≤ 50 years). CONCLUSIONS: Our findings suggest that younger BCS had an elevated risk of incident AF, regardless of the length of follow-up. Use of anthracyclines may be associated with increased mid-to-long-term AF risk among BCS.

Comparative analysis on efficiency and accuracy of parallel confocal microscopy and three-dimensional in motion video with triangulation technology-based intraoral scanner under influence of moisture and mouth opening - A crossover clinical trial.

Aim: The intraoral scanners are digital devices used to digitise the oral tissues. The accuracy of the intraoral scanners has been studied under different environmental conditions, but there might be differences that occur in the actual oral environment, which is still in question. The aim of the study was to evaluate the accuracy and efficiency of Parallel Confocal Microscopy and 3D in motion video with triangulation technology-based intraoral scanners under the influence of moisture and mouth opening. Settings and Design: This was an Cross over clinical controlled study. Materials and Methods: The controlled in vivo study included healthy subjects who were in need of CBCT for the purpose of locating the position of unerupted third molars before going abroad for a job. The subjects were exposed to scans in the upper and lower jaws with two intraoral scanners based on 3D motion video technology with triangulation (Medit) and parallel confocal microscopy (Trios) under the influence of two oral conditions, which were moisture (presence and absence of moisture) and mouth opening (30 mm and 50 mm, respectively). A total of 96 scans were obtained and superimposed individually over the reference CBCT scans to find the deviations in the Geomagic Rapidform (version 2020, USA) software. The efficiency of the scanners was calculated by recording the time taken and the number of images obtained after each scan. Statistical Analysis Used: The significance was calculated by using the independent and paired sample t test in SPSS software (IBM, version 23). Results: Based on the surface analysis, the trueness of the intra-oral scanners had statistically significant differences when compared between 3D in motion video technology with Triangulation and Parallel Confocal Microscopy (P < 0.05) whereas no statistical significance was observed in precision. There was a significant difference observed in the efficiency of the intra-oral scanners (P < 0.05). Conclusion: There is a significant difference in the accuracy and efficiency of the intraoral scanners under the influence of oral conditions, such as different moisture levels and mouth opening conditions. 3D in motion video technology with Triangulation showed better results with the least deviation than Parallel Confocal Microscopy.

QSAR study of tetrahydropteridin derivatives as polo-like kinase 1(PLK1) Inhibitors with molecular docking and dynamics study.

PLK1 is the key target for dealing with different cancer because it plays an important role in cell proliferation. According to the regulation of OECD, a QSAR model was developed from a dataset of 68 tetrahydropteridin derivatives. Three descriptors (maxHaaCH, ATSC7i, AATS7m) were considered for the development of the QSAR model. The reliability and predictability of the developed QSAR model were evaluated by various statistical parameters (r2 = 0.8213, r2ext = 0.8771 and CCCext = 0.9364). The maxHaaCH descriptor is positively correlated to pIC50 whereas, the ATSC7i and AATS7m are negatively correlated with pIC50. The QSAR model explains all the structural features and shows a good correlation with the activity. Based on molecular modelling techniques, five compounds (D1-D5) were designed. Molecular docking and dynamics studies of the most active compound were performed with PDB ID: 2RKU. The results of the present investigation may be employed to identify and develop effective inhibitors for the treatment of PLK1-related pathophysiological disorders.

Consistency Between State's Cancer Registry and All-Payer Claims Database in Documented Radiation Therapy Among Patients Who Received Breast Conservative Surgery.

PURPOSE: Arkansas is one of only four known states that have linked All-Payer Claims Database (APCD) to state's cancer registry (Arkansas Cancer Registry [ACR]). We evaluated the reporting consistency of radiation therapy (RT) between the two sources. METHODS: Women age ≥ 18 years diagnosed in 2013-2017 with early-stage hormone receptor-positive breast cancer who received breast-conserving surgery were identified. Patients must have continuous insurance coverage (any private plans, Medicaid, and Medicare) in the 13 months (month of diagnosis and 12 months after). Receipt of RT was identified independently from ACR and APCD. We calculated sensitivity, specificity, positive predictive value, and negative predictive value for receipt of RT coded by the registry compared with APCD billing claims as the gold standard. We assessed the degree of concordance between the data sources by Cohen's kappa statistics. RESULTS: The final sample included 2,695 patients who were in both databases and satisfied our inclusion/exclusion criteria. Using APCD as the gold standard, there were high sensitivity (88.1%) and positive predictive value (87.7%) and moderate specificity (71.1%) and negative predictive value (71.8%). The overall agreement between the two sources was 83.0%, with a kappa statistic of 0.59 (95% CI, 0.56 to 0.63). Consistency measures varied by age, stage, and insurance type with Medicare fee-for-service coverage only having the best and private insurance only the worse consistency. CONCLUSION: In patients with early-stage hormone receptor-positive breast cancer who received breast-conserving surgery, recording of RT receipt was moderately consistent between Arkansas APCD and ACR. Future studies are needed to identify factors affecting reporting consistency to better use this unique resource in addressing population health problems.

Identifications of good and bad structural fragments of hydrazone/2,5-disubstituted-1,3,4-oxadiazole hybrids with correlation intensity index and consensus modelling using Monte Carlo based QSAR studies, their molecular docking and ADME analysis.

The application of QSAR along with other in silico tools like molecular docking, and molecular dynamics provide a lot of promise for finding new treatments for life-threatening diseases like Type 2 diabetes mellitus (T2DM). The present study is an attempt to develop Monte Carlo algorithm-based QSAR models using freely available CORAL software. The experimental data on the α-amylase inhibition by a series of benzothiazole-linked hydrazone/2,5-disubstituted-1,3,4-oxadiazole hybrids were selected as endpoint for the model generation. Initially, a total of eight QSAR models were built using correlation intensity index (CII) as a criterion of predictive potential. The model developed from split 6 using CII was the most reliable because of the highest numerical value of the determination coefficient of the validation set (r2VAL = 0.8739). The important structural fragments responsible for altering the endpoint were also extracted from the best-built model. With the goal of improved prediction quality and lower prediction errors, the validated models were used to build consensus models. Molecular docking was used to know the binding mode and pose of the selected derivatives. Further, to get insight into their metabolism by living beings, ADME studies were investigated using internet freeware, SwissADME.

Effects of conventional and herbal irrigants on microhardness and flexural strength of root canal dentin: An in vitro study.

AIM: The aim of this in vitro study was to compare the effects of herbal irrigants with conventional irrigants on microhardness and flexural strength of root dentin. MATERIALS AND METHODS: Sixty extracted permanent maxillary canines were selected. Decoronated roots were sectioned longitudinally into buccal and lingual segments to get 120 specimens. These were embedded in auto polymerizing acrylic resin and further grounded with fine emery papers under distilled water. Of these, 100 root segments without any defects were selected, further divided into four test groups and a control group according to the irrigants used (n = 20). Group 1: 2.5% Sodium hypochlorite, Group 2: Miswak stick extract, Group 3: Cashew leaves extract. Group 4: Mango leaves extract and Group 5: Normal saline (control). All specimens were treated with 5 ml of each irrigant for 10 minutes and rinsed immediately. Dentin microhardness was measured with a Vickers indenter, and the flexural strength test was done using a universal testing machine. The data were analyzed using one-way ANOVA and the intergroup comparison by student t-test. RESULTS: The experimental groups showed a significant reduction in microhardness values when compared with the control group. Intragroup comparison among experimental groups, herbal irrigants showed the least reduction in microhardness values at cervical, middle, and apical thirds. When compared to the control group, the flexural strength values decreased significantly with experimental groups. CONCLUSION: Within the limitation of this study, it was concluded that herbal irrigants were least detrimental to root dentin microhardness when compared with conventional irrigant. But the flexural strength was equally reduced by both conventional and herbal irrigants.

Dynamics of a fractional epidemiological model with disease infection in both the populations.

In order to depict a situation of possible spread of infection from prey to predator, a fractional-order model is developed and its dynamics is surveyed in terms of boundedness, uniqueness, and existence of the solutions. We introduce several threshold parameters to analyze various points of equilibrium of the projected model, and in terms of these threshold parameters, we have derived some conditions for the stability of these equilibrium points. Global stability of axial, predator-extinct, and disease-free equilibrium points are investigated. Novelty of this model is that fractional derivative is incorporated in a system where susceptible predators get the infection from preys while predating as well as from infected predators and both infected preys and predators do not reproduce. The occurrences of transcritical bifurcation for the proposed model are investigated. By finding the basic reproduction number, we have investigated whether the disease will become prevalent in the environment. We have shown that the predation of more number of diseased preys allows us to eliminate the disease from the environment, otherwise the disease would have remained endemic within the prey population. We notice that the fractional-order derivative has a balancing impact and it assists in administering the co-existence among susceptible prey, infected prey, susceptible predator, and infected predator populations. Numerical computations are conducted to strengthen the theoretical findings.

NCDB Analysis of Melanoma 2004-2015: Epidemiology and Outcomes by Subtype, Sociodemographic Factors Impacting Clinical Presentation, and Real-World Survival Benefit of Immunotherapy Approval.

Background: The incidence of invasive melanoma is rising, and approval for the first immune checkpoint inhibitor (ICI) to treat metastatic melanoma occurred in 2011. We aim to describe the epidemiology and outcomes in recent years, sociodemographic factors associated with the presence of metastasis at diagnosis, and the real-world impact of ICI approval on survival based on melanoma subtype and race. Methods: This is a retrospective analysis of the National Cancer Database (NCDB) from the years 2004-2015. The primary outcome was the overall survival of metastatic melanoma by subtype. Secondary outcomes included sociodemographic factors associated with the presence of metastasis at diagnosis and the impact of treatment facility type and ICI approval on the survival of metastatic melanoma. Results: Of the 419,773 invasive melanoma cases, 93.80% were cutaneous, and 4.92% were metastatic at presentation. The odds of presenting with metastatic disease were higher in African Americans (AA) compared to Caucasians (OR 2.37; 95% CI 2.11-2.66, p < 0.001). Treatment of metastatic melanoma at an academic/research facility was associated with lower mortality versus community cancer programs (OR 0.75, 95 % CI 0.69-0.81, p-value < 0.001). Improvement in survival of metastatic melanoma was noted for Caucasians after the introduction of ICI (adjusted HR 0.80, 95% CI 0.78-0.83, p < 0.001); however, this was not statistically significant for AA (adjusted HR 0.80, 95% CI 0.62-1.02, p-value = 0.073) or ocular cases (HR 1.03, 95% CI 0.81-1.31, p-value = 0.797). Conclusion: Real-world data suggest a 20% improvement in survival of metastatic melanoma since the introduction of ICI. The disproportionately high odds of metastatic disease at presentation in AA patients with melanoma suggest the need for a better understanding of the disease and improvement in care delivery.

In silico design of diacylglycerol acyltransferase-1 (DGAT1) inhibitors based on SMILES descriptors using Monte-Carlo method.

Diabetes, obesity and other diseases related to metabolism are worldwide health problems. These syndromes can be well treated when a particular enzyme-based therapy is developed. Diacylglycerol acyltransferase (DGAT; EC 2.3.1.20) is a microsomal enzyme which is responsible for the synthesis of triglycerides from 1,2-diacylglycerol by catalyzing the acyl-CoA-dependent acylation. The obesity and type-II diabetes can be checked by the inhibition of DGAT1 enzyme. Quantitative structure-activity relationship (QSAR) modelling is an essential technique in drug design and development. To study the aspect of DGAT1 inhibitors, Monte-Carlo method-based QSAR was developed for 197 DGAT1 inhibitors. QSAR models were derived by using the optimal descriptor based on SMILES notation. Different statistical parameters including the novel index of ideality of correlation were applied to validate the generated QSAR models. Four random splits were prepared from the data set. The statistical criteria r2 = 0.8129, CCC = 0.8979 and Q2 = 0.7962 of the validation set of split 1 were the best; therefore, the developed QSAR model of split 1 was decided to be the leading model. The molecular fragments, which were promoter of endpoint increase or decrease were also determined. Thirteen new DGAT1 inhibitors were designed from the lead compound DGAT011.

Design and development of novel focal adhesion kinase (FAK) inhibitors using Monte Carlo method with index of ideality of correlation to validate QSAR.

Quantitative structure-activity relationship (QSAR) modelling of 55 focal adhesion kinase (FAK) (EC 2.7.10.2) inhibitors of triazinic nature was performed using the Monte Carlo method. The QSAR models were designed by CORAL software, and optimal descriptors were calculated with the simplified molecular input line entry system (SMILES). Four splits were made from the triazinic derivative data by random division into training, invisible training, calibration and validation sets. The QSAR results from these four random splits were robust, very simple, predictive and reliable. The best statistical parameters of the validation set (r2 = 0.8398 and Q2 = 0.7722) for the QSAR equation for split 3 with IIC = 0.9127 were obtained. The predictive potential of QSAR models of FAK inhibitors was explored by applying the index of ideality of correlation (IIC), which is a new criterion for the prediction of the potential for quantitative structure-property activity relationships (QSPRs/QSARs). The present method follows OECD principles.

Re-colorization of museum specimens: a modification of Romhanyi's technique based on pyridine/nicotine hemochromogen reactions.

Romhanyi's technique for preservation and restoration of color in museum specimens is almost unknown outside Hungary. The technique was based on the use of pyridine, nicotine and sodium dithionite (sodium hydrosulphite) for restoring the natural red color of formalin-fixed gross specimens. We developed a modification of the original technique using a mounting medium containing citrate-phosphate-dextrose (CPD) buffer and glycerin to control pH and osmolality. Specimens re-colorized with the modified and improved Romhanyi technique remained stable with a natural red color, and no histological deterioration, for more than 18 years. The technique demonstrates the formation of red colored complexes between nicotine and pyridine and ferro-hemochromes such as hemoglobin, myoglobin and other cytochromes in tissues, giving specimens a natural color. The modified technique enables further improvement for the old process of re-colorization of museum specimens. In addition, it opens up new methods for demonstration of nicotine, pyridine and their analogues in biological tissues.