Nanoparticle-aided glycovariant assays to bridge biomarker performance and ctDNA results

AbstractNumerous immunoassay based cancer biomarkers established in the 1970 and 1980'ies are widely used in clinical routine. Initial expectations of biomarkers such as CEA, CA125, CA19-9, AFP to provide decisive help in the diagnosis of early stage, pre-symptomatic cancers have not been realized. Thus, they are primarily used for monitoring disease progression and occasionally being useful as prognostic indicators. This limitation is due to the marker also being measurable in healthy individuals and frequently at elevated concentrations in common benign conditions. Most conventional tumor markers are glycosylated and interestingly specific alterations of the glycostructure part can often be seen early in the cancerous process. Conventional double monoclonal immunoassays are however blind to such changes as they are based on peptide epitope recognition. Wide selections of carbohydrate recognizing macromolecules, lectins, but also glycan structure recognizing antibodies are potentially useful for detecting such changes. Despite numerous attempts generating proof-of-principle evidence for this, such assays have generally not been successfully introduced into clinical routine. The affinity constants of lectin and glycan specific antibodies for their corresponding carbohydrate structures may be up to several orders too low to provide the detection limits and robustness expected from routine tumor markers. In this review, we describe an approach based on the use of highly fluorescent Eu3+--chelate dyed nanoparticles onto which lectins or glycan specific antibodies are coated to provide the necessary binding strength and signal amplification to provide low detection limits, while maintaining the original glycan-structure specificity. This concept applied to three markers, PSA, CA125 and CA15-3 provide glycoform assays of greatly enhanced cancer specificity using sample volumes similar or lower than corresponding traditional ELISAs. For ovarian cancer, we show that this new approach when applied to ovarian cyst fluid samples provide results similar to the performance obtained with ctDNA determinations of a set of 17 driver mutations and greatly superior compared to corresponding conventional immunoassays. Based on our results, we predict that the nanoparticle-lectin concept will enable a new generation of simple, low-cost biomarker assays of highly improved cancer specificity. Such tools should ideally be evaluated together with determination of ctDNA to establish early detection schemes for cancers e.g. ovarian, pancreas, lung where the detection rate of early stage disease is presently unacceptably low.</div

Predisposing factors for bacterial vaginosis, treatment efficacy and pregnancy outcome among term deliveries; results from a preterm delivery study

<p>Abstract</p> <p>Background</p> <p>Bacterial vaginosis (BV) during pregnancy is associated with an increased risk of preterm delivery but little is known about factors that could predict BV. We have analyzed if it is possible to identify a category of pregnant women that should be screened for BV, and if BV would alter the pregnancy outcome at term; we have also studied the treatment efficacy of clindamycin.</p> <p>Methods</p> <p>Prospective BV screening and treatment study of 9025 women in a geographically defined region in southeast Sweden. BV was defined as a modified Nugent score of 6 and above. Data was collected from the Swedish Medical Birth Register. Women allocated to treatment were supplied with vaginal clindamycin cream. The main outcome goals were to identify factors that could predict BV.</p> <p>Results</p> <p>Vaginal smears were consistent with BV criteria in 9.3%. Logistic regression indicates a significant correlation between smoking and BV (p < 0.001) and a greater prevalence of BV in the lower age groups (p < 0.001). We found no correlation between BV and history of preterm deliveries, previous miscarriages, extra-uterine pregnancies, infertility problems or reported history of urinary tract infections–factors that earlier have been associated with BV. Treatment with clindamycin cream showed a cure rate of 77%. Less than 1% of women with a normal vaginal smear in early pregnancy will develop BV during the pregnancy. There was no association between BV and the obstetric outcome among women who delivered at term. Women with BV, both treated patients and nontreated, had the same obstetric outcome at term as women with normal vaginal flora.</p> <p>Conclusion</p> <p>BV is more than twice as common among smokers, and there is a higher prevalence in the younger age group. However these two markers for BV do not suffice as a tool for screening, and considering the lack of other risk factors associated with BV, screening of all pregnant women might be a strategy to follow in a program intended to reduce the number of preterm births.</p

The Effect of Treating Bacterial Vaginosis on Preterm Labor

Objective: Multiple studies suggest that bacterial vaginosis (BV) causes preterm labor; yet its routine treatment remains controversial. In order to help to elucidate this controversy, we performed a thorough review of studies with levels of evidence ranging from I to II–II. Methods: We searched for all of the studies from the years 1994 to 2001 via Medline’s database, including MD Consult and Ovid Mednet. Results: Several trials discovered a decrease in the incidence of preterm labor when BV was treated, but most of those trials were performed on women with a history of preterm labor. However, the majority of trials reviewed advise against treatment of a general low-risk obstetric population, as there was no significant decrease in preterm labor. Conclusions: Therefore, based on the above studies and the current guidelines of the Centers for Disease Control and Prevention (CDC), treating pregnant women in high-risk populations who are diagnosed with BV provides the clinician with an opportunity to possibly prevent preterm labor in this population. In nulliparous women without a history of preterm birth, treatment is recommended if other risk factors are present (e.g. gonorrhea or chlamydia). However, in the general low-risk populations, routine screening is not indicated

Veterans Affairs Health System and Mental Health Treatment Retention among Patients with Serious Mental Illness: Evaluating Accessibility and Availability Barriers

We examine the impact of two dimensions of access—geographic accessibility and availability—on VA health system and mental health treatment retention among patients with serious mental illness (SMI). Methods . Among 156,631 patients in the Veterans Affairs (VA) health care system with schizophrenia or bipolar disorder in fiscal year 1998 (FY98), we used Cox proportional hazards regression to model time to first 12-month gap in health system utilization, and in mental health services utilization, by the end of FY02. Geographic accessibility was operationalized as straight-line distance to nearest VA service site or VA psychiatric service site, respectively. Service availability was assessed using county-level VA hospital beds and non-VA beds per 1,000 county residents. Patients who died without a prior gap in care were censored. Results . There were 32, 943 patients (21 percent) with a 12-month gap in health system utilization; 65,386 (42 percent) had a 12-month gap in mental health services utilization. Gaps in VA health system utilization were more likely if patients were younger, nonwhite, unmarried, homeless, nonservice-connected, if they had bipolar disorder, less medical morbidity, an inpatient stay in FY98, or if they lived farther from care or in a county with fewer VA inpatient beds. Similar relationships were observed for mental health, however being older, female, and having greater morbidity were associated with increased risks of gaps, and number of VA beds was not significant. Conclusions . Geographic accessibility and resource availability measures were associated with long-term continuity of care among patients with SMI. Increased distance from providers was associated with greater risks of 12-month gaps in health system and mental health services utilization. Lower VA inpatient bed availability was associated with increased risks of gaps in health system utilization. Study findings may inform efforts to improve treatment retention.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73433/1/j.1475-6773.2006.00642.x.pd

Extensions of known geographic distribution of aphyllophoroid fungi (Basidiomycota) in Finland

This article contributes the knowledge of Finnish aphyllophoroid funga with nationally or regionally new species, and records of rare species. Ceriporia bresadolae, Clavaria tenuipes and Renatobasidium notabile are presented as new aphyllophoroid species to Finland. Ceriporia bresadolae and R. notabile are globally rare species. The records of Ceriporia aurantiocarnescens, Crustomyces subabruptus, Sistotrema autumnale, Trechispora elongata, and Trechispora silvaeryae are the second in Finland. New records (or localities) are provided for 33 species with no more than 10 records in Finland. In addition, 76 records of aphyllophoroid species are reported as new to some subzones of the boreal vegetation zone in Finland. Notes on substrata and habitats of each record are given, and the ecology and distribution of some species are discussed.peerReviewe