Fragmentomic analysis of circulating tumor DNA-targeted cancer panels.

BACKGROUND: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner. PATIENTS AND METHODS: We used machine learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer and non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, n = 198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, n = 320). Each cohort was split 70%/30% into training and validation sets. RESULTS: In the UW cohort, training cross-validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross-validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer versus non-cancer area under the curve was 0.99. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Enzymatic modification of chitosan with quercetin and its application as antioxidant edible films.

Quercetin, rutin, naringin, hesperidin and chrysin were tested as substrates for chloroperoxidase to produce reactive quinones to graft onto chitosan. Quercetin and rutin quinones were successfully chemically attached to low molecular weight chitosan. The quercetin-modified chitosan showed an enhancement of plastic, antioxidant and antimicrobial properties as well as of thermal degradability. Finally, chitosan-quercetin films visibly decreased enzymatic oxidation when applied to Opuntia ficus indica cladodes.

PO-43 - Differential coagulation factor expression in neuroendocrine prostate cancer (PC), metastatic castrate-resistant PC, and localized prostatic adenocarcinoma.

INTRODUCTION: Neuroendocrine prostate cancer (NEPC) is an aggressive late-stage variant of PC that is often androgen-receptor negative. Most clinicians believe the VTE rate with NEPC is higher than with standard metastatic castration-resistant PC (mCRPC), but NEPC tends to present with bulkier visceral disease and include platinum chemotherapy unlike standard PC. In many solid tumors, a more aggressive phenotype correlates with increased VTE risk and elevated expression of coagulation factors. We previously reported on the differential expression of thrombin and tissue factor (TF) in NEPC versus localized PC and benign prostate tissue with a small NEPC cohort (N=7), which showed overexpression of prothrombin and reduced expression of TF in NEPC. AIM: To compare the expression of coagulation factors of NEPC vs mCRPC (and localized PC control) in an expanded datase. MATERIALS AND METHODS: Fresh frozen tissue biopsies were collected and separated into three cohorts based on pathology: localized PC (N=68), standard mCRPC (N=32), and NEPC (N=21). RNA was isolated and next generation paired-end mRNA sequencing was performed on Illumina Sequencers. F2 Prothrombin (F2), tissue factor (F3), carboxypeptidase (CPB2), fibrinogen (FGG, FGA), PAR-1 (F2R), and PAR-2 (F2RL1) were compared by Wilcoxon tests. RESULTS: Prothrombin had significantly higher expression in NEPC versus standard mCRPC (p <0.001). NEPC trended towards higher expression of CPB2 (p=0.1) and lower expression of F3 (p=0.23) and F2RL1 (p=0.14) compared to mCRPC. Compared to localized PC, both types of advanced disease (NEPC and mCRPC) overexpressed F2, FGA, FGB, and CPB2 (p<0.001) and had decreased expression of F3 and F2RL1 (p <0.001). CONCLUSIONS: Prothrombin is reliably overexpressed in NEPC vs mCRPC and localized PC. Advanced disease (regardless of subtype) is associated with significantly higher expression of prothrombin, fibrinogen, and carboxypeptidase and lower expression of TF and PAR-2. It is possible that there may be PC-specific differences with aggressive disease associated with the thrombin axis vs the more common TF/PAR2 axis commonly seen in other advanced solid tumors. Further research is required to understand these differences in biology and resulting thrombotic and hemostatic outcomes.

Inflammatory and bone regulators expression in murine macrophages under exposure of commercial and experimental mineral trioxide aggregate.

BACKGROUND: Mineral trioxide aggregate (MTA) has been used in a variety of surgical and non-surgical endodontic applications. The aim of this study was to evaluate the gene expression and protein production of TNF-α, IL-1ß and IL-6, as well as the gene expression of RANKL and OPG using both commercial and experimental MTA in macrophage cell cultures. METHODS: Peritoneal macrophage cell culture was performed. Viability, gene expression of cytokines, RANKL and OPG, and protein levels in experimental- and commercial-grey MTA co-cultured with peritoneal macrophages was determined by tryptan blue, real time PCR and ELISA. RESULTS: The expression of TNF-α for both commercial and experimental MTA was higher, while the expression of IL-1ß and IL-6 was similar when compared to the negative control. At protein expression level, no differences were observed between the negative control and cements. RANKL did not show a significant improvement in gene expression when compared with the negative control, but OPG expression in cement samples was higher when compared to the negative control. CONCLUSIONS: This study suggests that commercial and experimental MTA promotes anti-inflammatory processes, as well as bone healing capacity.

Cáncer glótico temprano: influencia del tratamiento primario en la funcionalidad de la voz / Early glottic cancer: influence of primary treatment on the performance voice

Objetivo: Describir en pacientes con cáncer glótico temprano tratado con cirugía y radioterapia, la calidad y funcionalidad de la voz. Diseño: Estudio de serie de casos. Materiales y métodos: Los parámetros objetivos de la voz fueron evaluados con análisis acústico. La funcionalidad de la voz fue evaluada con el índice de incapacidad vocal (VHI). El análisis estadístico fue realizado con SPSS 11.5 y SuperSMITHWeibull. Resultados: 12 sujetos que recibieron tratamiento para cáncer glótico temprano fueron incluidos en la muestra. El seguimiento clínico fue de 53.1 meses en promedio. El control de la enfermedad se observó en 100% de los casos, sin recaídas. El análisis acústico evaluó lafrecuencia fundamental de la voz, que fue normal en 63,6% de los casos; adicionalmente las medidas del Jitter y Shimmer fueron anormales en todos los pacientes. El valor del índice de incapacidad mostró una disfuncionalidad leve en 58,4% de los casos y normal en 41,6% de los casos. Conclusionese importancia clínica: El manejo del cáncer glótico temprano con cirugía y radioterapia resultó en una alteración de los parámetros objetivos de la voz en todos los sujetos; sin embargo, en nuestra muestra los pacientes refieren poca o ninguna disfuncionalidad en la vida diaria.

Objective: To describe on an adult population with early glottic cancer, treated with surgery and radiotherapy, the voice quality and functional outcome. Design: Case series study. Materials andMethods: Voice parameters were assessed using acoustic analysis. Voice functional outcome was evaluated with the voice handicap index (VHI). Statistical analysis was performed using the statistical software SPSS 11.5 and SuperSMITHWeibull. Results: 12 subjects that received treatment for early glottic cancer were included in the sample. The subjects were followed up during an average of 53.1 months. Effective control of disease without relapse was observed in 100% of the cases. The acoustic analysis assessed the fundamental frequency which was normal in 63,63% of the cases. Moreover, the mean of the Jitter and Shimmer was abnormal in the whole sample. The voice handicap index revealed a mild impairment in 58,4% of subjects, and was normal in 41,6% of cases. Conclusion and clinical significance: The management of early glottic cancer with surgery and radiotherapy resulted in alterations of objective voice parameters in the whole sample, however the patients report mild or none voice dysfunction on their daily life.

Time-asymmetric fluctuations of light and the breakdown of detailed balance.

Temporal fluctuations of the light radiated by a photoemissive source are studied through the cross correlation of output fields. Whereas microscopic reversibility guarantees time-symmetric fluctuations in thermal equilibrium--where detailed balance holds--away from equilibrium time asymmetry is permitted. Examples of time asymmetry in cavity QED are reported.

Quantum state reduction and conditional time evolution of wave-particle correlations in cavity QED.

We report measurements in cavity QED of a wave-particle correlation function which records the conditional time evolution of the field of a fraction of a photon. Detection of a photon prepares a state of well-defined phase that evolves back to equilibrium via a damped vacuum Rabi oscillation. We record the regression of the field amplitude. The recorded correlation function is nonclassical and provides an efficiency independent path to the spectrum of squeezing. Nonclassicality is observed even when the intensity fluctuations are classical.

La obesidad exógena: una causa de pubertad temprana en las niñas / The obesity: a causality of puberty precocius in the girls

Estudio prospectivo observacional de 115 niñas para evaluar la relación entre la obesidad exógena y la pubertad temprana. En conclusión, el sobrepeso enlas niñas podría ser una causa del desarrollo puberal temprano, probablemente a través de la leptina