Circulating Biomarkers in the Study and Early Detection of Ovarian Cancer

Ovarian cancer, the most lethal of all gynecological malignancies, represents a significant public health burden to women worldwide. The current challenges associated with ovarian cancer stem from a lack of effective screening strategies, an inability to detect the disease at a treatable stage, and the disappointing impact of treatment regimens over the entire disease course. A multi-faceted evaluation of circulating biomarkers of ovarian cancer was conducted in order to identify specific biomarkers and combinations which might serve as effective tools in the screening, triage, and therapeutic targeting of ovarian cancer patients. Ovarian epithelial carcinoma (OEC) represents a heterogeneous disease characterized by several histological subtypes displaying divergent etiology, pathology, and treatment responsiveness. Serum biomarkers were identified which displayed subtype-specific alterations in a comparison of OEC patients and benign controls. These results suggest that circulating biomarkers may assist in the selection of patients for targeted therapies. The efficient triage of women diagnosed with a pelvic mass based on risk of malignancy is known to result in a significant improvement in outcome for ovarian cancer patients and also a significant reduction in morbidity and anxiety for women with benign masses. Several multimarker panels, including the optimal combination of CA 125 and HE4, were capable of discriminating benign from malignant pelvic masses. Based on current and previous findings, this biomarker panel may represent a novel diagnostic tool in this clinical setting. Urine may offer several distinct advantages over serum as an analytical biofluid based on its low complexity, high stability, and lack of invasivity. An analysis of urine biomarkers revealed that several previously identified ovarian cancer biomarkers offer higher diagnostic performance in urine versus serum. Urine multimarker panels were effective in discriminating ovarian cancer cases from controls while a combination of urine and serum biomarkers resulted in the highest performance. The current study provides compelling evidence for the use of circulating biomarkers in several capacities within the setting of ovarian cancer. The collective impact of biomarker research on the clinical management of ovarian cancer has the potential to significantly improve overall public health

Prediagnostic serum biomarkers as early detection tools for pancreatic cancer in a large prospective cohort study

Background: The clinical management of pancreatic cancer is severely hampered by the absence of effective screening tools. Methods: Sixty-seven biomarkers were evaluated in prediagnostic sera obtained from cases of pancreatic cancer enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Results: The panel of CA 19-9, OPN, and OPG, identified in a prior retrospective study, was not effective. CA 19-9, CEA, NSE, bHCG, CEACAM1 and PRL were significantly altered in sera obtained from cases greater than 1 year prior to diagnosis. Levels of CA 19-9, CA 125, CEA, PRL, and IL-8 were negatively associated with time to diagnosis. A training/validation study using alternate halves of the PLCO set failed to identify a biomarker panel with significantly improved performance over CA 19-9 alone. When the entire PLCO set was used for training at a specificity (SP) of 95%, a panel of CA 19-9, CEA, and Cyfra 21-1 provided significantly elevated sensitivity (SN) levels of 32.4% and 29.7% in samples collected 1 year prior to diagnosis, respectively, compared to SN levels of 25.7% and 17.2% for CA 19-9 alone. Conclusions: Most biomarkers identified in previously conducted case/control studies are ineffective in prediagnostic samples, however several biomarkers were identified as significantly altered up to 35 months prior to diagnosis. Two newly derived biomarker combinations offered advantage over CA 19-9 alone in terms of SN, particularly in samples collected >1 year prior to diagnosis. However, the efficacy of biomarker-based tools remains limited at present. Several biomarkers demonstrated significant velocity related to time to diagnosis, an observation which may offer considerable potential for enhancements in early detection. © 2014 Nolen et al

A novel pH-sensitive liposome formulation containing oleyl alcohol

AbstractpH-sensitive liposomes are designed to undergo acid-triggered destabilization. First generation pH-sensitive liposomes, based on the cone-shaped lipid dioleoylphosphatidylethanolamine (DOPE), have been shown to lose fusogenicity in the presence of serum. Here, we report the design and evaluation of novel serum-resistant pH-sensitive liposome formulations that are based on the composition of egg phosphatidylcholine (PC), cholesteryl hemisuccinate (CHEMS), oleyl alcohol (OAlc), and Tween-80 (T-80). When loaded with the fluorescent probe calcein, these liposomes exhibited excellent stability at pH 7.4 and underwent rapid destabilization upon acidification as shown by calcein dequenching and particle size increase. Adjusting the mole percentages of T-80 and OAlc in the formulation could regulate the stability and pH-sensitive properties of these liposomes. Liposomes with a higher T-80 content exhibited greater stability but were less sensitive to acid-induced destabilization. Meanwhile, formulations with a higher OAlc content exhibited greater content release in response to low pH. The pH-triggered liposomal destabilization did not produce membrane fusion according to an octadecylrhodamine B chloride (R18) lipid-mixing assay. Compared to DOPE-based pH-sensitive liposomes, the above formulations showed much better retention of their pH-sensitive properties in the presence of 10% serum. These liposomes were then evaluated for intracellular delivery of entrapped cytosine-β-d-arabinofuranoside (araC) in KB human oral cancer cells, which have elevated folate receptor (FR) expression. The FR, which is amplified in many types of human tumors, has been shown to mediate the internalization of folate-derivatized liposomes into an acidic intracellular compartment. FR-targeted OAlc-based pH-sensitive liposomes, entrapping 200 mM araC, showed ∼17-times greater FR-dependent cytotoxicity in KB cells compared to araC delivered via FR-targeted non-pH-sensitive liposomes. These data indicated that pH-sensitive liposomes based on OAlc, combined with FR-mediated targeting, are promising delivery vehicles for membrane impermeable therapeutic agents

Circulating mediators of inflammation and immune activation in AIDS-related non-Hodgkin lymphoma

Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed beadbased immunoassays. Results: A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions: These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease. © 2014 Nolen et al

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with Vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet) METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (aHR 2.74, 95% confidence interval 1.76 - 4.26) and ischemic stroke (aHR 1.29, 95% confidence interval 1.04 - 1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleeds burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2-4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. This article is protected by copyright. All rights reserved

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Industry spotlight: Talent acquisition challenges in manufacturing

The manufacturing industry is facing a shortage of skilled workers, which is hindering its growth and competitiveness. To address this issue, companies are adopting various strategies to attract and recruit workers into the industry. These strategies include offering competitive wages and benefits, providing training and development opportunities, partnering with community organizations, and promoting the industry as a viable career option. Additionally, companies are leveraging technology and automation to make manufacturing jobs more attractive and less physically demanding. Despite these efforts, the industry still faces challenges in attracting younger generations and diversifying its workforce. Companies are realizing that it is crucial to continue to innovate and adapt their recruitment strategies to meet the changing needs and expectations of the workforce