Clinical validation of a ctDNA-Based Assay for Multi-Cancer Detection: An Interim Report from a Vietnamese Longitudinal Prospective Cohort Study of 2795 Participants.

The SPOT-MAS assay "Screening for the Presence Of Tumor by Methylation And Size" detects the five most common cancers in Vietnam by evaluating circulating tumor DNA in the blood. Here, we validated its performance in a prospective multi-center clinical trial, K-DETEK. Our analysis of 2795 participants from 14 sites across Vietnam demonstrates its ability to detect cancers in asymptomatic individuals with a positive predictive value of 60%, with 83.3% accuracy in detecting tumor location. We present a case report to support further using SPOT-MAS as a complementary method to achieve early cancer detection and provide the opportunity for early treatment.

Fragment length profiles of cancer mutations enhance detection of circulating tumor DNA in patients with early-stage hepatocellular carcinoma.

BACKGROUND: Late detection of hepatocellular carcinoma (HCC) results in an overall 5-year survival rate of less than 16%. Liquid biopsy (LB) assays based on detecting circulating tumor DNA (ctDNA) might provide an opportunity to detect HCC early noninvasively. Increasing evidence indicates that ctDNA detection using mutation-based assays is significantly challenged by the abundance of white blood cell-derived mutations, non-tumor tissue-derived somatic mutations in plasma, and the mutational tumor heterogeneity. METHODS: Here, we employed concurrent analysis of cancer-related mutations, and their fragment length profiles to differentiate mutations from different sources. To distinguish persons with HCC (PwHCC) from healthy participants, we built a classification model using three fragmentomic features of ctDNA through deep sequencing of thirteen genes associated with HCC. RESULTS: Our model achieved an area under the curve (AUC) of 0.88, a sensitivity of 89%, and a specificity of 82% in the discovery cohort consisting of 55 PwHCC and 55 healthy participants. In an independent validation cohort of 54 PwHCC and 53 healthy participants, the established model achieved comparable classification performance with an AUC of 0.86 and yielded a sensitivity and specificity of 81%. CONCLUSIONS: Our study provides a rationale for subsequent clinical evaluation of our assay performance in a large-scale prospective study.

3D-ordered porous CdS/AgI/ZnO nanostructures for high-performance photoelectrochemical water splitting.

3D-ordered porous CdS/AgI/ZnO nanostructures were designed to perform as high-performance photoelectrodes for photoelectrochemical (PEC) water-splitting applications. They rely on the advantages of an extremely large active surface area, high absorption capacity in the visible-light region, fast carrier separation and transportation caused by the intrinsic ladder-like band arrangement. These nanostructures were fabricated by employing a three-stage experiment in a sequence of hard mold-assisted electrochemical deposition, wet chemical method and deposition-precipitation. First, 3D-ordered ZnO nanostructures were electrochemically deposited using a polystyrene film as the sacrificed template. AgI nanoparticles were then decorated on the interfacial ZnO nanostructures by deposition-precipitation. Finally, these binary AgI/ZnO nanoporous networks were thoroughly wet-chemically coated with a CdS film to form a so-called 'ternary interfacial CdS/AgI/ZnO nanostructures'. The PEC water-splitting properties of the fabricated 3D nanostructures were systematically studied and compared. As a result, the highest efficiency of the fabricated 3D-ordered porous CdS/AgI/ZnO measured under the irradiation of solar simulation is about 5.2%, which is relatively 1.5, 3.5 and 11.3 times greater than that of the corresponding CdS/ZnO (3,4%), AgI/ZnO (1.5%) and pristine porous ZnO (0.46%) photoelectrodes, respectively. The significant improvement in the PEC activity is attributed to the enhanced charge separation and transport of ternary photoelectrodes caused by an unconventional ladder-like band arrangement formed between interfacial CdS-AgI-ZnO. Our study provides a promising strategy for developing such ternary photoelectrode generation that possesses higher stability and efficiency towards water-splitting processes.

Exposure to Electronic Cigarette Advertisements and Use of Electronic Cigarettes: A Meta-analysis of Prospective Studies.

INTRODUCTION: Electronic cigarette (EC) advertisements remain unregulated and approach consumers in TV commercials, print ads, radio, and other forms of digital marketing. AIMS AND METHODS: This study aimed to assess whether exposure to EC advertisements is associated with the use of EC by using a meta-analysis of prospective studies. We searched PubMed, EMBASE, and Web of Science to locate eligible studies in November 2021. Pooled adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated using a random-effects meta-analysis. RESULTS: Out of 1635 articles searched from databases, we included seven prospective studies that met inclusion criteria in the final analysis. Four out of seven studies involved participants under 18 years of age. In the meta-analysis of all studies, exposure to EC advertisements was significantly associated with the increased use of ECs (aOR = 1.53, 95% CI 1.22 to 1.92; I2 = 60.1%). In the subgroup meta-analyses by source of advertisements, there was no significant association between exposure to EC advertisements on TV, radio, or billboards and the use of EC, while exposure to EC advertisements in retail stores and on Internet or social media significantly increased the use of EC. CONCLUSIONS: Exposure to EC advertisements was associated with the increased use of ECs, specifically in retail stores and on Internet or social media among adolescents and young adults. Because EC use could serve as a gateway to cigarette smoking in adolescents and young adults, more strict regulations and restrictions on EC advertisements are needed. IMPLICATIONS: Concurrent with the rise in electronic cigarette (EC) sales, advertising expenditures for ECs have been increased in the past decade, and there is controversy over the association between exposure to EC advertisements and the use of ECs. This meta-analysis of seven prospective studies showed that exposure to EC advertisements was significantly associated with the increased use of ECs, specifically in retail stores and on Internet or social media among adolescents and young adults. Because, EC use could serve as a gateway to cigarette smoking in adolescents and young adults, more strict regulations and restrictions on EC advertisements are needed.

Circulating DNA methylation profile improves the accuracy of serum biomarkers for the detection of nonmetastatic hepatocellular carcinoma.

Aim: This study exploited hepatocellular carcinoma (HCC)-specific circulating DNA methylation profiles to improve the accuracy of a current screening assay for HCC patients in high-risk populations. Methods: Differentially methylated regions in cell-free DNA between 58 nonmetastatic HCC and 121 high-risk patients with liver cirrhosis or chronic hepatitis were identified and used to train machine learning classifiers. Results: The model could distinguish HCC from high-risk non-HCC patients in a validation cohort, with an area under the curve of 0.84. Combining these markers with the three serum biomarkers (AFP, lectin-reactive AFP, des-γ-carboxy prothrombin) in a commercial test, µTASWako®, achieved an area under the curve of 0.87 and sensitivity of 68.8% at 95.8% specificity. Conclusion: HCC-specific circulating DNA methylation markers may be added to the available assay to improve the early detection of HCC.

The early detection of liver cancer in high-risk populations can help people with the disease have a higher chance of survival and better quality of life. However, this is still a healthcare challenge. Current commercial blood tests measuring protein signatures in the blood have low accuracy due to increased levels of these proteins being detected in both liver cancer patients and patients with chronic liver diseases. In this study, we identified a set of signatures in DNA released by cancer cells into the bloodstream and used them as biomarkers to distinguish liver cancer patients from high-risk patients. We also demonstrated that adding those signatures to a commercial blood test currently used in clinics could improve the accuracy in detecting liver cancer patients.

Emergence of Potential-Controlled Cu-Nanocuboids and Graphene-Covered Cu-Nanocuboids under Operando CO2 Electroreduction.

The electroreduction of CO2 (CO2RR) is a promising strategy toward sustainable fuels. Cu is the only Earth-abundant and pure metal capable of catalyzing CO2-to-hydrocarbons conversion with significant Faradaic efficiencies; yet, its dynamic structure under operando CO2RR conditions remains unknown. Here, we track the Cu structure operando by electrochemical scanning tunneling microscopy and Raman spectroscopy. Surprisingly, polycrystalline Cu surfaces reconstruct forming Cu nanocuboids whose size can be controlled by the polarization potential and the time employed in their in situ synthesis, without the assistance of organic surfactants and/or halide anions. If the Cu surface is covered by a graphene monolayer, smaller features with enhanced catalytic activity for CO2RR can be prepared. The graphene-protecting layer softens the 3D morphological changes that Cu-based catalysts suffer when exposed to aggressive electrochemical environments and allows us to track the kinetic roughening process. This novel strategy is promising for improving Cu long-term stability, and consequently, it could be used as a platform to ultimately control product selectivity.

Liquid Nickel Salts: Synthesis, Crystal Structure Determination, and Electrochemical Synthesis of Nickel Nanoparticles.

New nickel-containing ionic liquids were synthesized, characterized and their electrochemistry was investigated. In addition, a mechanism for the electrochemical synthesis of nanoparticles from these compounds is proposed. In these so-called liquid metal salts, the nickel(II) cation is octahedrally coordinated by six N-alkylimidazole ligands. The different counter anions that were used are bis(trifluoromethanesulfonyl)imide (Tf2 N(-) ), trifluoromethanesulfonate (OTf(-) ) and methanesulfonate (OMs(-) ). Several different N-alkylimidazoles were considered, with the alkyl sidechain ranging in length from methyl to dodecyl. The newly synthesized liquid metal salts were characterized by CHN analysis, FTIR, DSC, TGA and viscosity measurements. An odd-even effect was observed for the melting temperatures and viscosities of the ionic liquids, with the complexes with an even number of carbon atoms in the alkyl chain of the imidazole having a higher melting temperature and a lower viscosity than the complexes with an odd number of carbons. The crystal structures of several of the nickel(II) complexes that are not liquid at room temperature were determined. The electrochemistry of the compounds with the lowest viscosities was investigated. The nickel(II) cation could be reduced but surprisingly no nickel deposits were obtained on the electrode. Instead, nickel nanoparticles were formed at 100 % selectivity, as confirmed by TEM. The magnetic properties of these nanoparticles were investigated by SQUID measurements.

Redox-activity and self-organization of iron-porphyrin monolayers at a copper/electrolyte interface.

The electrochemical behaviour and molecular structure of a layer of water-soluble 5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)-porphyrin-Fe(III) pentatosylate, abbreviated as FeTMPyP, on a chloride modified Cu(100) electrode surface were investigated by means of cyclic voltammetry (CV) and in-situ electrochemical scanning tunneling microscopy. Voltammetric results of HOPG in an electrolyte containing FeTMPyP molecules indicate three distinguishable redox steps involving both the central iron metal and the π-conjugated ring system. However, only the first two reduction steps are observable within the narrow potential window of CVs of Cu(100) measured in the same electrolyte. In the potential range below the first reduction peak, at which the [Fe(III)TMPyP](5+) molecules are reduced to the corresponding [Fe(II)TMPyP](4+) species, in-situ scanning tunneling microscopy (STM) images revealed, for the first time, a highly ordered adlayer of this reduced porphyrin species on the chloride terminated Cu(100) surface. The ordered adlayer exhibits a (quasi)square unit cell with the lattice vectors |a→2|=|b→2|=1.53±0.1 nm and an angle of 93° ± 2° between them. A model is proposed based on the STM observation illustrating the arrangement of the [Fe(II)TMPyP](4+) molecules at the electrolyte/copper interface.

Molecular ordering at electrified interfaces: Template and potential effects.

A combination of cyclic voltammetry and in situ scanning tunneling microscopy was employed to examine the adsorption and phase transition of 1,1'-dibenzyl-4,4'-bipyridinium molecules (abbreviated as DBV(2+)) on a chloride-modified Cu(111) electrode surface. The cyclic voltammogram (CV) of the Cu(111) electrode exposed to a mixture of 10 mM HCl and 0.1 mM DBVCl2 shows three distinguishable pairs of current waves P1/P'1, P2/P'2, and P3/P'3 which are assigned to two reversible electron transfer steps, representing the reduction of the dicationic DBV(2+) to the corresponding radical monocationic DBV(+•) (P1/P'1) and then to the uncharged DBV(0) (P3/P'3) species, respectively, as well as the chloride desorption/readsorption processes (P2/P'2). At positive potentials (i.e., above P1) the DBV(2+) molecules spontaneously adsorb and form a highly ordered phase on the c(p × âˆš3)-precovered Cl/Cu(111) electrode surface. A key element of this DBV(2+) adlayer is an assembly of two individual DBV(2+) species which, lined up, forms a so-called "herring-bone" structure. Upon lowering the electrode potential the first electron transfer step (at P1) causes a phase transition from the DBV(2+)-related herring-bone phase to the so-called "alternating stripe" pattern built up by the DBV(+•) species following a nucleation and growth mechanism. Comparison of both observed structures with those found earlier at different electrode potentials on a c(2 × 2)Cl-precovered Cu(100) electrode surface enables a clear assessment of the relative importance of adsorbate-substrate and adsorbate-adsorbate interactions, i.e., template vs self-assembly effects, in the structure formation process of DBV cations on these modified Cu electrode surfaces.

A consultation and work-up diagnosis protocol for a multicancer early detection test: a case series study.

The emergence of multicancer early detection (MCED) tests holds promise for improving early cancer detection and public health outcomes. However, positive MCED test results require confirmation through recommended cancer diagnostic imaging modalities. To address these challenges, we have developed a consultation and work-up protocol for definitive diagnostic results post MCED testing, named SPOT-MAS. Developed through circulating tumor DNA (ctDNA) analysis and in line with professional guidelines and advisory board consensus, this protocol standardizes information to aid general practitioners in accessing, interpreting and managing SPOT-MAS results. Clinical effectiveness is demonstrated through a series of identified cancer cases. Our research indicates that the protocol could empower healthcare professionals to confidently interpret circulating tumor DNA test results for 5 common types of cancer, thereby facilitating the clinical integration of MCED tests.

New tests can now screen for multiple types of cancer early, offering hope for better health outcomes. If one of these tests shows a positive result, doctors need to confirm it with imaging tests. We have developed a guide to help doctors understand and confirm these results. This guide could help healthcare professionals interpret results for five common types of cancer, making it easier to use these tests in regular medical practice.

Lymphangioma of the vagina.

BACKGROUND: Vaginal lymphangioma is an extremely rare lesion. Lymphangioma in other areas is usually asymptomatic, and bleeding is a common complication and presentation. CASE: We describe the identification of a vaginal lymphangioma in a 47-year-old woman and discuss the histopathology, diagnosis, and management, based on colposcopy and histology results. CONCLUSION: Vaginal lymphangioma should be identified by histopathology to exclude other malignant tumours in the vagina and to plan appropriate therapy.

Contexte : Le lymphangiome vaginal est une lésion extrêmement rare. Lorsqu'il affecte d'autres parties du corps, le lymphangiome est habituellement asymptomatique; les saignements en constituent une complication et une présentation courantes. Cas : Nous décrivons l'identification d'un lymphangiome vaginal chez une femme de 47 ans et nous discutons de son histopathologie, de son diagnostic et de sa prise en charge, en fonction des résultats de la colposcopie et de l'histologie. Conclusion : Le lymphangiome vaginal devrait être identifié par histopathologie afin d'écarter la présence possible d'autres tumeurs malignes dans le vagin et de planifier un traitement adéquat.

Molecular self-assembly at metal-electrolyte interfaces.

The self-assembly of molecular layers has become an important strategy in modern design of functional materials. However, in particular, large organic molecules may no longer be sufficiently volatile to be deposited by vapor deposition. In this case, deposition from solution may be a promising route; in ionic form, these molecules may even be soluble in water. In this contribution, we present and discuss results on the electrochemical deposition of viologen- and porphyrin molecules as well as their co-adsorption on chloride modified Cu(100) and Cu(111) single crystal electrode surfaces from aqueous acidic solutions. Using in situ techniques like cyclic voltametry and high resolution scanning tunneling microscopy, as well as ex-situ photoelectron spectroscopy data the highly ordered self-assembled organic layers are characterized with respect to their electrochemical behavior, lateral order and inner conformation as well as phase transitions thereof as a function of their redox-state and the symmetry of the substrate. As a result, detailed structure models are derived and are discussed in terms of the prevailing interactions.

On the role of functional groups in the formation of diazonium based covalent attachments: dendritic vs. layer-by-layer growth.

Multilayered growth is often observed upon electrografting aryl diazonium derivatives on graphitic substrates due to the reactive nature of aryl radicals. The mechanism of the multilayer formation has been investigated either by measuring the thickness of the grafted layer, the charge transfer, or via simulations. Spectroscopy and in particular microscopy approaches are underrepresented. Herein, we demonstrate a comparative characterization of the multilayer growth of two diazonium derivatives on highly oriented pyrolytic graphite using a combination of cyclic voltammetry, atomic force microscopy, and scanning tunneling microscopy. While dendritic growth is observed for 4-nitro phenyl diazonium (4-NBD), 4-carboxy phenyl diazonium (4-CBD) shows layer-by-layer growth upon increasing the molecular concentration, revealing the impact of the functional groups on the growth mechanism.

Multimodal analysis of genome-wide methylation, copy number aberrations, and end motif signatures enhances detection of early-stage breast cancer.

Introduction: Breast cancer causes the most cancer-related death in women and is the costliest cancer in the US regarding medical service and prescription drug expenses. Breast cancer screening is recommended by health authorities in the US, but current screening efforts are often compromised by high false positive rates. Liquid biopsy based on circulating tumor DNA (ctDNA) has emerged as a potential approach to screen for cancer. However, the detection of breast cancer, particularly in early stages, is challenging due to the low amount of ctDNA and heterogeneity of molecular subtypes. Methods: Here, we employed a multimodal approach, namely Screen for the Presence of Tumor by DNA Methylation and Size (SPOT-MAS), to simultaneously analyze multiple signatures of cell free DNA (cfDNA) in plasma samples of 239 nonmetastatic breast cancer patients and 278 healthy subjects. Results: We identified distinct profiles of genome-wide methylation changes (GWM), copy number alterations (CNA), and 4-nucleotide oligomer (4-mer) end motifs (EM) in cfDNA of breast cancer patients. We further used all three signatures to construct a multi-featured machine learning model and showed that the combination model outperformed base models built from individual features, achieving an AUC of 0.91 (95% CI: 0.87-0.95), a sensitivity of 65% at 96% specificity. Discussion: Our findings showed that a multimodal liquid biopsy assay based on analysis of cfDNA methylation, CNA and EM could enhance the accuracy for the detection of early- stage breast cancer.

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization.

Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published assays to date demanded a very high-depth sequencing, resulting in an elevated price of test. Herein, we developed a multimodal assay called SPOT-MAS (screening for the presence of tumor by methylation and size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (~0.55×) of cell-free DNA. We applied SPOT-MAS to 738 non-metastatic patients with breast, colorectal, gastric, lung, and liver cancer, and 1550 healthy controls. We then employed machine learning to extract multiple cancer and tissue-specific signatures for detecting and locating cancer. SPOT-MAS successfully detected the five cancer types with a sensitivity of 72.4% at 97.0% specificity. The sensitivities for detecting early-stage cancers were 73.9% and 62.3% for stages I and II, respectively, increasing to 88.3% for non-metastatic stage IIIA. For tumor-of-origin, our assay achieved an accuracy of 0.7. Our study demonstrates comparable performance to other ctDNA-based assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening.

Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort.

BACKGROUND: Hereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown. METHODS: 1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing. RESULTS: A total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing. CONCLUSION: This is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies.

Graphite and Graphene Fairy Circles: A Bottom-Up Approach for the Formation of Nanocorrals.

A convenient covalent functionalization approach and nanopatterning method of graphite and graphene is developed. In contrast to expectations, electrochemically activated dediazotization of a mixture of two aryl diazonium compounds in aqueous media leads to a spatially inhomogeneous functionalization of graphitic surfaces, creating covalently modified surfaces with quasi-uniform spaced islands of pristine graphite or graphene, coined nanocorrals. Cyclic voltammetry and chronoamperometry approaches are compared. The average diameter (45-130 nm) and surface density (20-125 corrals/µm2) of these nanocorrals are tunable. These chemically modified nanostructured graphitic (CMNG) surfaces are characterized by atomic force microscopy, scanning tunneling microscopy, Raman spectroscopy and microscopy, and X-ray photoelectron spectroscopy. Mechanisms leading to the formation of these CMNG surfaces are discussed. The potential of these surfaces to investigate supramolecular self-assembly and on-surface reactions under nanoconfinement conditions is demonstrated.

Antenatal ultrasonography findings and magnetic resonance imaging in a case of Pena-Shokeir phenotype.

Pena-Shokeir phenotype is a lethal anomaly characterized by neurogenic arthrogryposis, craniofacial anomalies, and pulmonary hypoplasia. This syndrome should be distinguished from trisomy 18 and arthrogryposis multiplex congenita for better counseling and establishing fetal prognosis. We present the case of a pregnant woman diagnosed with a Pena-Shokeir phenotype affected fetus at 24 weeks of gestation. Prenatal ultrasonography and fetal magnetic resonance imaging detected persistent hyperextension of the lumbar spine, micrognathia, absent septum pellucidum, and all characteristic features of Pena-Shokeir phenotype. Karyotyping was performed to exclude fetal chromosomal anomalies. Antenatal ultrasonography is an essential tool in the diagnosis of Pena-Shokeir phenotype while fetal magnetic resonance imaging is necessary to identify any associated anomalies of central nervous system.

Nanoconfined self-assembly on a grafted graphitic surface under electrochemical control.

Highly oriented pyrolytic graphite (HOPG) can be covalently grafted with aryl radicals generated via the electrochemical reduction of 3,5-bis-tert-butyl-diazonium cations (3,5-TBD). The structure of the grafted layer and its stability under electrochemical conditions were assessed with electrochemical scanning tunneling microscopy (EC-STM) and cyclic voltammetry (CV). Stable within a wide (>2.5 V) electrochemical window, the grafted species can be locally removed using EC-STM-tip nanolithography. Using dibenzyl viologen as an example, we show that the generated nanocorrals of bare graphitic surface can be used to study nucleation and growth of self-assembled structures under conditions of nanoconfinement and electrochemical potential control.