Although pain is a prevalent nonmotor symptom in Parkinson’s disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that...

Genetic polymorphisms in the region of the trimeric serine hydrolase high-temperature requirement 1 (HTRA1) are associated with increased risk of age-related macular degeneration (AMD) and disease progression, but the precise biological function of HtrA1 in the eye and its contribution to disease etiologies remain undefined. In this study, we have...

Background:

In 2015, Vyvanse (lisdexamfetamine) became the first Food and Drug Administration (FDA)-approved treatment for binge-eating disorder (BED), a condition first recognized by the DSM–V in 2013. Because pharmaceutical companies use continuing medical education (CME) to help sell drugs, we explored possible bias in CME modules on BED.

Methods:

We utilized a qualitative thematic analysis research approach to identify and classify patterns in CME activities focusing on BED.

Results:

We identified 27 online CME activities on BED in 2015. All were funded by Shire, which manufactures lisdexamfetamine. Seven of 16 presenters disclosed financial ties with Shire. Twenty-nine slides recurred in at least 2 CME modules, and 12 slides were repeated in 5 or more modules. Diagnosis-related themes included: BED is a real, treatable disease; BED is highly prevalent but often missed; BED can occur in anyone; BED results in poor quality of life; many patients with BED are obese; and BED makes losing weight difficult. Treatment-related themes included: lisdexamfetamine is highly effective; topiramate is limited by substantial adverse effects; and other therapeutic options for BED are inferior to lisdexamfetamine because they do not cause weight loss. Although amphetamines can cause addiction, myocardial infarction, stroke, and death, no module mentioned these serious adverse effects.

Conclusions:

It seems that CME is being used to promote lisdexamfetamine for weight loss (a contraindicated use) and to highlight benefits of lisdexamfetamine while underplaying the risks.

Imants G. Priede, Rhoderick W. Burgass, Manolis Mandalakis, Apostolos Spyros, Petros Gikas, Finlay Burns, and Jim Drewery

Whereas upper ocean pelagic sharks are negatively buoyant and must swim continuously to generate lift from their fins, deep-sea sharks float or swim slowly buoyed up by large volumes of low-density oils in their livers. Investigation of the Pressure, Volume, Temperature (PVT) relationships for liver oils of 10 species of deep-sea Chondrichthyes shows that the density difference between oil and seawater, remains almost constant with pressure down to full ocean depth (11 km, 1100 bar); theoretically providing buoyancy far beyond the maximum depth of occurrence (3700 m) of sharks. However, , does change significantly with temperature and we show that the combined effects of pressure and temperature can decrease buoyancy of oil by up to 10% between the surface and 3500 m depth across interfaces between warm southern and cold polar waters in the Rockall Trough in the NE Atlantic. This increases drag more than 10 fold compared with neutral buoyancy during horizontal slow swimming (0.1 m s^–1) but the effect becomes negligible at high speeds. Chondrichthyes generally experience positive buoyancy change during ascent and negative buoyancy change during descent but contrary effects can occur at interfaces between waters of different densities. During normal vertical migrations buoyancy changes are small, increasing slow-speed drag by no more than 2–3 fold. Equations and tables of density, pressure and temperature are provided for squalene and liver oils of Chimaeriformes (Harriotta raleighana, Chimaera monstrosa, Chimaera monstrosa), Squaliformes (Centrophorus squamosus, Deania calcea, Centroscymnus coelolepis, Centroscyllium fabricii, Etmopterus spinax) and Carcharhiniformes (Apristurus laurussonii, Galeus murinus).

Kelsey L. Jones, Rahmatollah Rajabzadeh, Guncha Ishangulyyeva, Nadir Erbilgin, and Maya L. Evenden

Flight polyphenisms naturally occur as discrete or continuous traits in insects. Discrete flight polyphenisms include winged and wingless morphs, whereas continuous flight polyphenisms can take the form of short- or long-distance fliers. The mountain pine beetle (Dendroctonus ponderosae) exhibits polyphenic variation in flight distance but the consequences of this flight variation on life history strategies of beetles is unknown. This study assessed the effect of flight on two particular aspects of beetle biology: (1) an energetic trade-off between flight distance and host colonisation capacity; and (2) the relationship between flight distance and pheromone production. A 23-h flight treatment was applied to a subset of beetles using computer. After flight treatment, both flown and unflown (control) beetles were given the opportunity to colonise bolts of host trees, and beetles that entered hosts were aerated to collect pheromone. A trade-off occurred between initiation of host colonisation and percent body weight lost during flight, which indicates energy-use during flight affects host acceptance in female mountain pine beetles. Furthermore, production of the aggregation pheromone trans-verbenol by female beetles was influenced by both percent weight lost during flight and flight distance. Male production of exo-brevicomin was affected by beetle condition following flight but not by the energy used during flight. These novel results give new insight into the polyphenic flight behaviour of mountain pine beetles. Flight variation is adaptive by acting to maintain population levels through safe and risky host colonisation strategies. These findings suggest mechanisms that facilitate the extremities of the continuous flight polyphenism spectrum. These opposing mechanisms appear to maintain the high variation in flight exhibited by this species.

Itsumi Nakamura, Rui Matsumoto, and Katsufumi Sato

It is generally assumed that the body temperature of large animals is less likely to change due to their large body size, resulting in a high thermal inertia and a smaller surface area to volume ratio. The goal of this study was to investigate the stability of body temperature in large fish using data from field experiments. We measured the muscle temperatures of free-ranging whale sharks (Rhincodon typus), the largest extant fish globally, and investigated their ectothermic physiology and the stability of their body temperatures. The measured muscle temperature of the whale sharks changed substantially more slowly than the water temperature fluctuations associated with vertical movements, and the whole-body heat-transfer coefficients (HTC) of whale sharks estimated using heat-budget models were lower than those of any other fish species measured to date. The heat-budget models also showed that internal heat production does not contribute to changes in muscle temperature. A comparative analysis showed that the HTC at cooling in various fish species including both ectothermic and endothermic species ranging from 10^–4 to 10³ kg was proportional to body mass^–0.63. This allometry was present regardless of whether the fish were ectothermic or endothermic, and was an extension of the relationship observed in previous studies on small fish. Thus, large fish have the advantage of body temperature stability while moving in environments with large temperature variations. Our results suggest that the large body size of whale sharks aids in preventing a decrease in body temperature during deep excursions to more than 1000 m depths without high metabolic costs of producing heat.

David E. Cade, J. Jacob Levenson, Robert Cooper, Rafael de la Parra, D. Harry Webb, and Alistair D. M. Dove

Whale sharks (Rhincodon typus Smith 1828) – the largest extant fish species – reside in tropical environments, making them an exception to the general rule that animal size increases with latitude. How this largest fish thrives in tropical environments that promote high metabolism but support less robust zooplankton communities has not been sufficiently explained. We used open-source inertial measurement units (IMU) to log 397 hours of whale shark behavior in Yucatan, Mexico, at a site of both active feeding and intense wildlife tourism. Here we show that the strategies employed by whale sharks to compensate for the increased drag of an open mouth are similar to ram-feeders five orders of magnitude smaller and one order of magnitude larger. Presumed feeding constituted 20% of the total time budget of four sharks, with individual feeding bouts lasting up to 11 consecutive hrs. Compared to normal, sub-surface swimming, three sharks increased their stroke rate and amplitude while surface feeding, while one shark that fed at depth did not demonstrate a greatly increased energetic cost. Additionally, based on time-depth budgets, we estimate that aerial surveys of shark populations should consider including a correction factor of 3 to account for the proportion of daylight hours that sharks are not visible at the surface. With foraging bouts generally lasting several hours, interruptions to foraging during critical feeding periods may represent substantial energetic costs to these endangered species, and this study presents baseline data from which management decisions affecting tourist interactions with whale sharks may be made.

Background

Nephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis.

Methods

We conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1β, IL-6, IL-18, and chitotriosidase enzyme activity.

Results

A multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications.

Conclusions

Chitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis.

Background

After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline.

Methods

We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30–90 ml/min per 1.73 m² and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD.

Results

Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m²), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly.

Conclusions

Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.

Paclitaxel has been considered to cause OATP1B-mediated drug-drug interactions at therapeutic doses; however, its clinical relevance has not been demonstrated. This study aimed to elucidate in vivo inhibition potency of paclitaxel against OATP1B1 and OATP1B3 using endogenous OATP1B biomarkers. Paclitaxel is an inhibitor of OATP1B1 and OATP1B3, with K_i of 0.579 ± 0.107 and 5.29 ± 3.87 μM, respectively. Preincubation potentiated its inhibitory effect on both OATP1B1 and OATP1B3, with K_i of 0.154 ± 0.031 and 0.624 ± 0.183 μM, respectively. Ten patients with non–small cell lung cancer who received 200 mg/m² of paclitaxel by a 3-hour infusion were recruited. Plasma concentrations of 10 endogenous OATP1B biomarkers—namely, coproporphyrin I, coproporphyrin III, glycochenodeoxycholate-3-sulfate, glycochenodeoxycholate-3-glucuronide, glycodeoxycholate-3-sulfate, glycodeoxycholate-3-glucuronide, lithocholate-3-sulfate, glycolithocholate-3-sulfate, taurolithocholate-3-sulfate, and chenodeoxycholate-24-glucuronide—were determined in the patients with non–small cell lung cancer on the day before paclitaxel administration and after the end of paclitaxel infusion for 7 hours. Paclitaxel increased the area under the plasma concentration-time curve (AUC) of the endogenous biomarkers 2- to 4-fold, although a few patients did not show any increment in the AUC ratios of lithocholate-3-sulfate, glycolithocholate-3-sulfate, and taurolithocholate-3-sulfate. Therapeutic doses of paclitaxel for the treatment of non–small cell lung cancer (200 mg/m²) will cause significant OATP1B1 inhibition during and at the end of the infusion. This is the first demonstration that endogenous OATP1B biomarkers could serve as surrogate biomarkers in patients.

SIGNIFICANCE STATEMENT

Endogenous biomarkers can address practical and ethical issues in elucidating transporter-mediated drug-drug interaction (DDI) risks of anticancer drugs clinically. We could elucidate a significant increment of the plasma concentrations of endogenous OATP1B biomarkers after a 3-hour infusion (200 mg/m²) of paclitaxel, a time-dependent inhibitor of OATP1B, in patients with non–small cell lung cancer. The endogenous OATP1B biomarkers are useful to assess the possibility of OATP1B-mediated DDIs in patients and help in appropriately designing a dosing schedule to avoid the DDIs.

The ₂ receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-¹⁸F-fluoroethoxy)-5-methylbenzamide (¹⁸F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of ¹⁸F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether ¹⁸F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression. Methods: Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT 02284919) between March 2015 and January 2017. Each received an injection of 278–527 MBq of ¹⁸F-ISO-1 and then underwent PET/CT imaging of the breasts 50–55 min later. In vivo uptake of ¹⁸F-ISO-1 was quantitated by SUV_max and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67. Results: Tumor SUV_max (median, 2.0 g/mL; range, 1.3–3.3 g/mL), partial-volume–corrected SUV_max, and SUV ratios were tested against Ki-67. Tumors stratified into the high–Ki-67 (≥20%) group had SUV_max greater than the low–Ki-67 (<20%) group (P = 0.02). SUV_max exhibited a positive correlation with Ki-67 across all breast cancer subtypes ( = 0.46, P = 0.01, n = 29). Partial-volume–corrected SUV_max was positively correlated with Ki-67 for invasive ductal carcinoma ( = 0.51, P = 0.02, n = 21). Tumor–to–normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 (P > 0.05). Conclusion: ¹⁸F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.

Chitotriosidase (CHIT1) is a highly conserved and regulated chitinase secreted by activated macrophages; it is a member of the 18-glycosylase family (GH18). CHIT1 is the most prominent chitinase in humans, can cleave chitin and participates in the body's immune response and is associated with inflammation, infection, tissue damage and remodelling processes. Recently, CHIT1 has been reported to be involved in the molecular pathogenesis of pulmonary fibrosis, bronchial asthma, COPD and pulmonary infections, shedding new light on the role of these proteins in lung pathophysiology. The potential roles of CHIT1 in lung diseases are reviewed in this article.

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55 ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 μmol/L and mean left ventricular septal wall thickness, 10 mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (n=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (P<0.008, hazard ratio [HR] 3.180, confidence interval [CI]: 1.349-7.495) and cardiac involvement on magnetic resonance imaging (P=0.026, HR=5.360, CI: 1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.

Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically "favorable adiposity" phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.

The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population.We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro–B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, β-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A_1c [Hb A_1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016–2017; age 71–94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors.In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44–3.22]; no diabetes: OR, 2.31 [95%CI, 1.76–3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08–1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22–1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A_1c (OR, 1.76 [95% CI, 1.22–2.54]), fructosamine (OR, 1.71 [95% CI, 1.19–2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03–2.03]) with PN were significant only among participants with diabetes.Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Peripheral neuropathy (PN) is a condition affecting up to 20% of the general population. The symptoms range from mild to disabling, depending on the types of nerve fiber affected and the type and severity of damage.

Purpose:

Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC.

Experimental Design:

Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial (n = 46).

Results:

Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase—correlating with a worse outcome than those with decreased/stable TKa (n = 33; mPFS 3.0 vs 9.0 months; P = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; P = 0.05).

Conclusions:

TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.

Purpose:

Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMMs) as surrogate markers of response to radium-223 in mCRPC.

Patients and Methods:

A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination.

Results:

Thirty-nine men were randomized to RE (n = 27) or enzalutamide (n = 12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% confidence interval, 0.51–0.81; P = 0.00048) favored RE versus enzalutamide. Overall, BMMs decreased with the RE therapy compared with enzalutamide. Improved PSA response rate in RE versus enzalutamide (P = 0.024), correlated with decline in BMMs.

Conclusions:

BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radium-223 in real-time.

Plasma DNA fragmentomics is an emerging area of research covering plasma DNA sizes, end points, and nucleosome footprints. In the present study, we found a significant increase in the diversity of plasma DNA end motifs in patients with hepatocellular carcinoma (HCC). Compared with patients without HCC, patients with HCC showed a preferential pattern of 4-mer end motifs. In particular, the abundance of plasma DNA motif CCCA was much lower in patients with HCC than in subjects without HCC. The aberrant end motifs were also observed in patients with other cancer types, including colorectal cancer, lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. We further observed that the profile of plasma DNA end motifs originating from the same organ, such as the liver, placenta, and hematopoietic cells, generally clustered together. The profile of end motifs may therefore serve as a class of biomarkers for liquid biopsy in oncology, noninvasive prenatal testing, and transplantation monitoring.

Significance:

Plasma DNA molecules originating from the liver, HCC and other cancers, placenta, and hematopoietic cells each harbor a set of characteristic plasma DNA end motifs. Such markers carry tissue-of-origin information and represent a new class of biomarkers in the nascent field of fragmentomics.

This article is highlighted in the In This Issue feature, p. 627

Background:

Pancreatic cancer is the third leading cause of cancer death in the United States, and 80% of patients present with advanced, incurable disease. Risk markers for pancreatic cancer have been characterized, but combined models are not used clinically to identify individuals at high risk for the disease.

Methods:

Within a nested case–control study of 500 pancreatic cancer cases diagnosed after blood collection and 1,091 matched controls enrolled in four U.S. prospective cohorts, we characterized absolute risk models that included clinical factors (e.g., body mass index, history of diabetes), germline genetic polymorphisms, and circulating biomarkers.

Results:

Model discrimination showed an area under ROC curve of 0.62 via cross-validation. Our final integrated model identified 3.7% of men and 2.6% of women who had at least 3 times greater than average risk in the ensuing 10 years. Individuals within the top risk percentile had a 4% risk of developing pancreatic cancer by age 80 years and 2% 10-year risk at age 70 years.

Conclusions:

Risk models that include established clinical, genetic, and circulating factors improved disease discrimination over models using clinical factors alone.

Impact:

Absolute risk models for pancreatic cancer may help identify individuals in the general population appropriate for disease interception.

Background:

Early diagnosis can significantly reduce colorectal cancer deaths. We sought to identify serum PIWI-interacting RNAs (piRNAs) that could serve as sensitive and specific noninvasive biomarkers for early colorectal cancer detection.

Methods:

We screened the piRNA expression profile in sera from 7 patients with colorectal cancer and 7 normal controls using small RNA sequencing. Differentially expressed piRNAs were measured in a training cohort of 140 patients with colorectal cancer and 140 normal controls using reverse transcription quantitative PCR. The identified piRNAs were evaluated in two independent validation cohorts of 180 patients with colorectal cancer and 180 normal controls. Finally, the diagnostic value of the identified piRNAs for colorectal adenoma (CRA) was assessed, and their expression was measured in 50 patients with lung cancer, 50 with breast cancer, and 50 with gastric cancer.

Results:

The piRNAs piR-020619 and piR-020450 were consistently elevated in sera of patients with colorectal cancer as compared with controls. A predicative panel based on the two piRNAs was established that displayed high diagnostic accuracy for colorectal cancer detection. The two-piRNA panel could detect small-size and early-stage colorectal cancer with an area under the ROC curve of 0.863 and 0.839, respectively. Combined use of the two piRNAs could effectively distinguish CRA from controls. Aberrant elevation of the two piRNAs was not observed in sera of patients with lung, breast, and gastric cancer.

Conclusions:

Serum piR-020619 and piR-020450 show a strong potential as colorectal cancer-specific early detection biomarkers.

Impact:

The field of circulating piRNAs could allow for novel tumor biomarker development.

Background:

Energy balance–related factors, such as body mass index (BMI), diet, and physical activity, may influence colorectal cancer etiology through interconnected metabolic pathways, but their combined influence is less clear.

Methods:

We used reduced rank regression to derive three energy balance scores that associate lifestyle factors with combinations of prediagnostic, circulating levels of high-sensitivity C-reactive protein (hsCRP), C-peptide, and hemoglobin A_1c (HbA_1c) among 2,498 participants in the Cancer Prevention Study-II Nutrition Cohort. Among 114,989 participants, we verified 2,228 colorectal cancer cases. We assessed associations of each score with colorectal cancer incidence and by tumor molecular phenotypes using Cox proportional hazards regression.

Results:

The derived scores comprised BMI, physical activity, screen time, and 14 food groups, and explained 5.1% to 10.5% of the variation in biomarkers. The HR and 95% confidence interval (CI) for quartile 4 versus 1 of the HbA_1c+C peptide–based score and colorectal cancer was 1.30 (1.15–1.47), the hsCRP-based score was 1.35 (1.19–1.53), and the hsCRP, C-peptide, and HbA_1c-based score was 1.35 (1.19–1.52). The latter score was associated with non-CIMP tumors (HR_Q4vsQ1: 1.59; 95% CI: 1.17–2.16), but not CIMP-positive tumors (P_{heterogeneity} = 0.04).

Conclusions:

These results further support hypotheses that systemic biomarkers of metabolic health—inflammation and abnormal glucose homeostasis—mediate part of the relationship between several energy balance–related modifiable factors and colorectal cancer risk.

Impact:

Results support cancer prevention guidelines for maintaining a healthful body weight, consuming a healthful diet, and being physically active. More research is needed on these clusters of exposures with molecular phenotypes of tumors.

Background:

Visceral adipose tissue (VAT) may play a greater role than subcutaneous fat in increasing cancer risk but is poorly estimated in epidemiologic studies.

Methods:

We developed a VAT prediction score by regression equations averaged across 100 least absolute shrinkage and selection operator models in a cross-sectional study of 1,801 older adults in the Multiethnic Cohort (MEC). The score was then used as proxy for VAT in case–control studies of postmenopausal breast (950 case–control pairs) and colorectal (831 case–control pairs) cancer in an independent sample in MEC. Abdominal MRI–derived VAT; circulating biomarkers of metabolic, hormonal, and inflammation dysfunctions; and ORs for incident cancer adjusted for BMI and other risk factors were assessed.

Results:

The final score, composed of nine biomarkers, BMI, and height, explained 11% and 15% more of the variance in VAT than BMI alone in men and women, respectively. The area under the receiver operator curve for VAT >150 cm² was 0.90 in men and 0.86 in women. The VAT score was associated with risk of breast cancer [OR (95% confidence interval [CI]) by increasing tertiles: 1.00, 1.09 (0.86–1.39), 1.48 (1.16–1.89); P_trend = 0.002] but not with colorectal cancer (P = 0.84), although an association [1.00, 0.98 (0.68–1.39), 1.24 (0.88–1.76); P_trend = 0.08] was suggested for this cancer after excluding cases that occurred within 7 years of blood draw (P_{heterogeneity} = 0.06).

Conclusions:

The VAT score predicted risks of postmenopausal breast cancer and can be used for risk assessment in diverse populations.

Impact:

These findings provide specific evidence for a role of VAT in breast cancer.

Background:

Asian Americans are at higher risk for noncardia gastric cancers (NCGC) relative to non-Hispanic Whites (NHW). Asian Americans are genetically, linguistically, and culturally heterogeneous, yet have mostly been treated as a single population in prior studies. This aggregation may obscure important subgroup-specific cancer patterns.

Methods:

We utilized data from 13 regional United States cancer registries from 1990 to 2014 to determine secular trends in incidence and survivorship from NCGC. Data were analyzed for NHWs and the six largest Asian American subgroups: Chinese, Japanese, Filipino, Korean, Vietnamese, and South Asian (Indian/Pakistani).

Results:

There exists substantial heterogeneity in NCGC incidence between Asian subgroups, with Koreans (48.6 per 100,000 person-years) having seven-fold higher age-adjusted incidence than South Asians (7.4 per 100,000 person-years). Asians had generally earlier stages of diagnosis and higher rates of surgical resection compared with NHWs. All Asian subgroups also demonstrated higher 5-year observed survival compared with NHWs, with Koreans (41.3%) and South Asians (42.8%) having survival double that of NHWs (20.1%, P < 0.001). In multivariable regression, differences in stage of diagnosis and rates of resection partially explained the difference in survivorship between Asian subgroups.

Conclusions:

We find substantial differences in incidence, staging, histology, treatment, and survivorship from NCGC between Asian subgroups, data which challenge our traditional perceptions about gastric cancer in Asians. Both biological heterogeneity and cultural/environmental differences may underlie these findings.

Impact:

These data are relevant to the national discourse regarding the appropriate role of gastric cancer screening, and identifies high-risk racial/ethnic subgroups who many benefit from customized risk attenuation programs.

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.

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