Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl hydrocarbon receptor-tissue factor axis.

Patients with malignancy are at 4- to 7-fold higher risk of venous thromboembolism (VTE), a potentially fatal, yet preventable complication. Although general mechanisms of thrombosis are enhanced in these patients, malignancy-specific triggers and their therapeutic implication remain poorly understood. Here we examined a colon cancer-specific VTE model and probed a set of metabolites with prothrombotic propensity in the inferior vena cava (IVC) ligation model. Athymic mice injected with human colon adenocarcinoma cells exhibited significantly higher IVC clot weights, a biological readout of venous thrombogenicity, compared with the control mice. Targeted metabolomics analysis of plasma of mice revealed an increase in the blood levels of kynurenine and indoxyl sulfate (tryptophan metabolites) in xenograft-bearing mice, which correlated positively with the increase in the IVC clot size. These metabolites are ligands of aryl hydrocarbon receptor (AHR) signaling. Accordingly, plasma from the xenograft-bearing mice activated the AHR pathway and augmented tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) levels in venous endothelial cells in an AHR-dependent manner. Consistent with these findings, the endothelium from the IVC of xenograft-bearing animals revealed nuclear AHR and upregulated TF and PAI-1 expression, telltale signs of an activated AHR-TF/PAI-1 axis. Importantly, pharmacological inhibition of AHR activity suppressed TF and PAI-1 expression in endothelial cells of the IVC and reduced clot weights in both kynurenine-injected and xenograft-bearing mice. Together, these data show dysregulated tryptophan metabolites in a mouse cancer model, and they reveal a novel link between these metabolites and the control of the AHR-TF/PAI-1 axis and VTE in cancer.

Fifteen-year record of soil temperature at the Bear Brook Watershed in Maine.

This paper describes a record of air and soil temperature collected from 2001 to 2016 in temperate forests at the Bear Brook Watershed in Maine (BBWM). BBWM is a long-term research site established to study the response of forest ecosystem function to various environmental disturbances, including chronic acidic deposition. Replicate HOBO data loggers were deployed in BBWM's two forest types (coniferous and deciduous), to record temperatures at four positions: (1) air temperature, 100 cm above the forest floor; (2) surface organic soil, 2 cm below the forest floor surface; (3) mineral soil, 10 cm below the organic-mineral horizon interface; and (4) mineral soil, 25 cm below the organic-mineral horizon interface. Data were recorded every three hours, and these raw data were used to compute daily maximum, daily minimum, daily average, and monthly average values. This fifteen-year record represents one of the few readily-available soil temperature datasets in the region, and provides information on long-term changes in climatology, and seasonal and episodic weather patterns.

Detection of impaired homologous recombination repair in NSCLC cells and tissues.

INTRODUCTION: Homologous recombination repair (HRR) is a critical pathway for the repair of DNA damage caused by cisplatin or poly-ADP ribose polymerase (PARP) inhibitors. HRR may be impaired by multiple mechanisms in cancer, which complicates assessing the functional HRR status in cells. Here, we monitored the ability of non-small-cell lung cancer (NSCLC) cells to form subnuclear foci of DNA repair proteins as a surrogate of HRR proficiency. METHODS: We assessed clonogenic survival of 16 NSCLC cell lines in response to cisplatin, mitomycin C (MMC), and the PARP inhibitor olaparib. Thirteen tumor explants from patients with NSCLC were subjected to cisplatin ex vivo. Cells were assayed for foci of repair-associated proteins such as BRCA1, FANCD2, RAD51, and γ-H2AX. RESULTS: Four cell lines (25%) showed an impaired RAD51 foci-forming ability in response to cisplatin. Impaired foci formation correlated with cellular sensitivity to cisplatin, MMC and olaparib. Foci responses complemented or superseded genomic information suggesting alterations in the ATM/ATR and FA/BRCA pathways. Because baseline foci in untreated cells did not predict drug sensitivity, we adapted an ex vivo biomarker assay to monitor damage-induced RAD51 foci in NSCLC explants from patients. Ex vivo cisplatin treatment of explants identified two tumors (15%) exhibiting compromised RAD51 foci induction. CONCLUSIONS: A fraction of NSCLC harbors HRR defects that may sensitize the affected tumors to DNA-damaging agents including PARP inhibitors. We propose that foci-based functional biomarker assays represent a powerful tool for prospective determination of treatment sensitivity, but will require ex vivo techniques for induction of DNA damage to unmask the underlying HRR defect.

Functional outcomes and daily life activities of African-American elders after hospitalization.

OBJECTIVE: African-American elders were recruited from a transitional unit after hospitalization and tracked for 6 months in the community after discharge to (a) examine functional outcomes on the unit and in the community and (b) identify patterns of participation in daily life activities. The International Classification of Impairments, Disabilities, and Handicaps (ICIDH-2) framework provided the structure to examine the connections among body systems, functional outcomes, and social participation for this population that has been underrepresented in past research. METHOD: A mixed design combined qualitative and quantitative methods, including qualitative interviews to document personal adaptive experience, a standardized functional assessment to identify functional outcomes, and a structured format to record activity participation. RESULTS: Findings revealed that 11 of the 17 participants improved their functional outcomes after discharge. Three patterns of activity participation identified were self-care, self-care and household management, and mixed activities. Contextual influences were diverse family support arrangements. CONCLUSION: Complex relationships were identified among body systems, functional outcomes, and daily life activities that were influenced by individual values and support arrangements.