Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer.

Chronic exposure to airborne carbon black ultrafine (nCB) particles generated from incomplete combustion of organic matter drives IL-17A-dependent emphysema. However, whether and how they alter the immune responses to lung cancer remains unknown. Here, we show that exposure to nCB particles increased PD-L1+ PD-L2+ CD206+ antigen-presenting cells (APCs), exhausted T cells, and Treg cells. Lung macrophages that harbored nCB particles showed selective mitochondrial structure damage and decreased oxidative respiration. Lung macrophages sustained the HIF1α axis that increased glycolysis and lactate production, culminating in an immunosuppressive microenvironment in multiple mouse models of non-small cell lung cancers. Adoptive transfer of lung APCs from nCB-exposed wild type to susceptible mice increased tumor incidence and caused early metastasis. Our findings show that nCB exposure metabolically rewires lung macrophages to promote immunosuppression and accelerates the development of lung cancer.

Podoplanin+ tumor lymphatics are rate limiting for breast cancer metastasis.

Metastatic dissemination employs both the blood and lymphatic vascular systems. Solid tumors dynamically remodel and generate both vessel types during cancer progression. Lymphatic vessel invasion and cancer cells in the tumor-draining lymph nodes (LNs) are prognostic markers for breast cancer metastasis and patient outcome, and tumor-induced lymphangiogenesis likely influences metastasis. Deregulated tumor tissue fluid homeostasis and immune trafficking associated with tumor lymphangiogenesis may contribute to metastatic spreading; however, the precise functional characterization of lymphatic endothelial cells (LECs) in tumors is challenged by the lack of specific reagents to decipher their rate-limiting role in metastasis. Therefore, we generated novel transgenic mice (PDPN promoter-driven Cre recombinase transgene [PDPN-Cre] and PDPN promoter-driven thymidine kinase transgene [PDPN-tk]) that allow for the identification and genetically controlled depletion of proliferating podoplanin (Pdpn)-expressing LECs. We demonstrate that suppression of lymphangiogenesis is successfully achieved in lymphangioma lesions induced in the PDPN-tk mice. In multiple metastatic breast cancer mouse models, we identified distinct roles for LECs in primary and metastatic tumors. Our findings support the functional contribution of primary tumor lymphangiogenesis in controlling metastasis to axillary LNs and lung parenchyma. Reduced lymphatic vessel density enhanced primary tumor lymphedema and increased the frequency of intratumoral macrophages but was not associated with a significant impact on primary tumor growth despite a marked reduction in metastatic dissemination. Our findings identify the rate-limiting contribution of the breast tumor lymphatic vessels for lung metastasis.

Geographical Information System Evaluation and Trends of Nonaccidental Trauma at a Level I Trauma Center, Pilot Study.

PREMISE: Although trauma may be considered a random act, geographical patterns of trauma potentially emerge. Our institution is unique in that it rests at an intersection of two of the highest areas of poverty and assault in New York City and has adequate data to analyze these patterns. METHODS: We review the incident reports logged by emergency medical services (EMS) technicians arriving with intentionally injured trauma patients from January 1 to December 31, 2013 at a single institution. After acquisition of this data, it was placed into a computer file using an individual identifying numbers for each incident along with latitude and longitude coordinates determined by global positioning software for each event. The data were separated into blunt and penetrating categories. Penetrating trauma was further separated into the type of instrument used: edged weapon or firearm. Kernel density estimate using the Crimestat program was then performed to determine the epicenters with the highest incidents of nonaccidental trauma. RESULTS: Two hundred eighty-three patients were evaluated for assault-related trauma. Two hundred fifty-four patients were included in the mapping of the data with almost equal blunt and penetrating trauma. Seventy-four percent of trauma occurred from 6 PM to 6 AM, and 41% occurring between midnight and 6 AM. Of patients, 32.7% were found to be assaulted at their home address. Regression analysis demonstrated that each type of trauma had unique epicenters of likelihood for occurrence. CONCLUSIONS: We can only speculate the reasons for many of these results at this time and further research into the sociological, psychological, and environmental factors is required. A high proportion of patients are assaulted at their home addresses. Further study is necessary to improve patient care with additional data provided by emergency medical services, police departments and surrounding hospitals.

Suppression of pancreatic cancer by sulfated non-anticoagulant low molecular weight heparin.

Sulfated non-anticoagulant heparins (S-NACHs) might be preferred for potential clinical use in cancer patients without affecting hemostasis as compared to low molecular weight heparins (LMWHs). We investigated anti-tumor effects, anti-angiogenesis effects, and mechanisms of S-NACH in a mouse model of pancreatic cancer as compared to the LMWH tinzaparin. S-NACH or tinzaparin with or without gemcitabine were administered, and tumor luminescent signal intensity, tumor weight, and histopathology were assessed at the termination of the study. S-NACH and LMWH efficiently inhibited tumor growth and metastasis, without any observed bleeding events with S-NACH as compared to tinzaparin. S-NACH distinctly increased tumor necrosis and enhanced gemcitabine response in the mouse pancreatic cancer models. These data suggest the potential implication of S-NACH as a neoadjuvant in pancreatic cancer.

Prospective memory, emotional valence, and multiple sclerosis.

Cognitive impairments in multiple sclerosis (MS) extend to tasks demanding prospective memory (PM): remembering to perform an intended act during ongoing activity. This study investigated whether emotional content influenced the effects of MS on PM, following evidence that emotional valence can influence other aspects of memory. Thirty participants with MS were compared to 30 controls on a PM task, Virtual Week, in which emotion was manipulated. People with MS showed a consistent deficit in PM performance across manipulations of task and valence. Results indicated that emotionally positive tasks improved the PM performance of MS participants, with implications for rehabilitation.

Inhibitory effect of non-anticoagulant heparin (S-NACH) on pancreatic cancer cell adhesion and metastasis in human umbilical cord vessel segment and in mouse model.

Metastasis is the most devastating aspect of cancer and it is the main cause of morbidity and mortality in cancer patients. Tumor cell adhesion to the vascular endothelial cell lining is an important step in metastatic progression and is prompted by platelets. Mucin 1 is over-expressed and aberrantly glycosylated in more than 60% of pancreatic ductal adeno-carcinomas, which mediate adhesion of pancreatic cancer cells to platelets via P-selectin. The anticoagulant low molecular weight heparins (LMWHs), which are commonly used in venous Thromboprophylaxis and treatment, appear to have an effect on cancer survival. The aim of this study is to investigate the effect of platelets on human pancreatic cancer MPanc96 cell adhesion to the endothelial cell vessel wall, and to examine the effect of heparin derivatives on MPanc96 adhesion using a novel, in vitro model of human umbilical cord vein. The modified heparin S-NACH (sulfated non-anticoagulant heparin), which is devoid of antithrombin (AT) binding and devoid of inhibition of systemic AT-dependent coagulation factors such as factor Xa and IIa, and the LMWH tinzaparin both potently reduced adhesion and invasion of fluorescence-labeled MPanc96 cancer cells to the endothelial layer of umbilical cord vein in a dose-dependent manner. S-NACH effectively inhibited P-selectin mediated MPanc96 cell adhesion, and inhibited cell adhesion and invasion similar to tinzaparin, indicating that systemic anticoagulation is not a necessary component for heparin attenuation of cancer cell adhesion, invasion, and metastasis. Also, S-NACH and tinzaparin versus unfractionated heparin, heparin derivatives enoxaparin, deltaparin, fraxiparin, and fondaparinux were evaluated for their effect on platelet-cancer cell adhesion. An in vivo anti-metastatic S-NACH-treated nude mouse model of MPanc96 pancreatic cancer cell metastasis demonstrated potent anti-metastasis efficacy as evidenced by IVIS imaging and histological staining.

Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin.

BACKGROUND: Recent prospective clinical trials of low molecular weight heparins (LMWHs) have demonstrated that these agents may provide significant advantages in terms of progression-free and overall survival in certain subgroups of cancer patients. The mechanisms of improved survival associated with LMWHs are not known, and may involve direct and/or indirect effects on tumor growth. The purpose of this study was to investigate the effects of LMWH and a sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake and chemoresponse. MATERIALS AND METHODS: LMWH and S-NACH were tested for their ability to reduce tumor growth and tumor-associated angiogenesis using three different in vivo models. Biodistribution studies were undertaken to determine the effect of these agents on uptake of paclitaxel (PACL) and doxorubicin (Dox) by breast cancer tumor xenografts. RESULTS: LMWH and S-NACH (10 mg/kg s.c. daily) effectively limited tumor growth of human A549 lung adenocarcinoma xenografts in the nude mouse. In an MDA453/LCC6 breast tumor xenograft model, PACL plus S-NACH showed significant (p < 0.01) tumor growth suppression and improved survival when compared to PACL alone. LMWH increased [(124-)I]-PACL uptake into MDA453/LCC6 tumors, with tumor:muscle ratios several fold greater than that of [(124-)I]-PACL alone 24 h post-injection. Similarly, LMWH and S-NACH significantly (p < 0.01) increased the uptake of Dox by 1.5-2 fold in MCF7 Dox-resistant tumor xenografts. CONCLUSION: Protocols utilizing adjuvant or neo-adjuvant therapy with LMWH or S-NACH could lead to increased tumor chemo responsiveness, potentially overcoming tumor chemoresistance.

Health-related quality of life in patients undergoing anterior cervical discectomy fusion.

Outcomes are an integral part of surgical decision making among patients, families, physicians, and nurses. The purpose of this descriptive, longitudinal study was to investigate and compare health-related quality of life as an outcome measure in patients undergoing anterior cervical discectomy and fusion (ACDF). Data were collected preoperatively, and at 6 weeks and 3 and 6 months postoperatively. Potential participants were identified by staff members at two neurosurgical practices in central New Jersey. Findings revealed improved health over time with significant change in 6 of the 9 subscales of health-related quality of life. Cervical disk disease and ACDF impact health-related quality of life. A holistic approach to the education and support of patients undergoing ACDF surgery is recommended throughout the preoperative and postoperative periods.

Nitric oxide modulates caveolin-1 and matrix metalloproteinase-9 expression and distribution at the endothelial cell/tumor cell interface.

We used a two-compartment coculture model comprising human endothelial cells (EC) and non-small cell lung carcinoma (CA) cells to study capillary formation. Elevated NO concentrations, contributed in part by CA cells, lead to inhibited capillary formation (Phillips PG, Birnby LM, Narendran A, and Milonovich WL. Am J Physiol Lung Cell Mol Physiol 281: L278-L290, 2001). Here we demonstrate using gelatin substrate zymography that high NO concentrations, whether produced endogenously or by NO donor spermine-NONOate or peroxynitrite-generating compound SIN-1, significantly inhibit MMP-9 expression and activation. Furthermore, high NO concentrations decrease Cav-1 abundance and alter its cellular distribution in EC. Cav-1 is essential for capillary formation in this model because Cav-1 antisense treatments targeted to EC significantly inhibit capillary formation. Laser confocal microscopy demonstrated extensive colocalization of MMP-9 with Cav-1 in sprouting EC, primarily at the basolateral surfaces of EC in focal structures associated with directed migration. This codistribution was NO concentration dependent, and elevated NO concentrations lead to marked dissociation of these two proteins. We propose that compartmentalization of MMP-9 within caveolar structures does occur, and that this could facilitate directed proteolysis essential for early migratory and invasive processes. Our data suggest elevated NO concentrations could impact on capillary formation via a combination of direct effects on MMP activation and by altering the distribution or abundance of Cav-1. Consequences of Cav-1 alterations may include impaired activation of proteolytic enzymes that utilize caveolar structure for stabilization and/or compartmentalization of MMP-9 as well as other putative members of an ECM proteolytic cascade.

Isolation of murine aortic endothelial cells in culture and the effects of sex steroids on their growth.

The lack of commercially available primary murine endothelial cells prompted us to isolate and cultivate this cell type. We report here the effect of sex steroids on the in vitro growth of murine aortic endothelial cells. Murine aortic endothelial cells were isolated by a combination of explant outgrowth from aortic rings and enzymatic digestion. The endothelial nature of the cells was verified by uptake of acylated low-density lipoprotein and positive staining for CD-31. Murine aortic endothelial cell growth is stimulated by physiological concentrations of estrogen. Progesterone, when given simultaneously with estrogen, inhibited the stimulatory growth effect of estrogen. Murine aortic endothelial cells grown in vitro continue to express messenger ribonucleic acid for proteins related to endothelial growth. These include vascular endothelial growth factor, its receptors Flt-1 and Flk-1, and the angiogenesis-associated transcription factor, Ets-1.

Estrogen-induced Ets-1 promotes capillary formation in an in vitro tumor angiogenesis model.

We employed an in vitro angiogenesis model that simulates the in vivo milieu for tumor capillary formation to study the direct effects of estrogen. 17beta-estradiol (E2) treatment significantly stimulated capillary sprouting within 8 h in co-cultures of rat aortic endothelial cells (RAECs) and mouse mammary tumor cells. Co-cultures treated with either progesterone (P4) or E2+P4 showed minimal endothelial cell (EC) sprouting when compared to E2 treated cultures. Treatment with the E2 agonist ICI 182,780 dramatically inhibited capillary formation, demonstrating E2-specificity. Within hours, of E2 treatment ECs isolated from tumor cell/EC co-cultures demonstrated a statistically significant increase in both mRNA and protein levels of the transcription factor Ets-1. We observed increased matrix metalloproteinase (MMP) and decreased tissue inhibitor of metalloproteinase (TIMP) mRNA levels in these ECs following E2 treatment. Ets-1 upregulates expression of the vascular endothelial growth factor (VEGF) receptor, Flt-1 and we detected increased Flt-1 mRNA levels in ECs co-cultured with tumor cells following E2 treatment. Expression of Ets-1 contributes to destabilization of a quiescent EC phenotype in favor of an invasive angiogenic one, in part, by increasing expression of MMPs and integrin molecules that favor migration and invasion. Transfection of ECs with Ets-1 antisense prior to co-culture with E2 resulted in a 95% inhibition in capillary formation. We demonstrate here, for the first time that nanomolar concentrations of E2 directly and rapidly induced new capillary formation in a mammary tumor/EC co-culture system and suggest that this response may be mediated, in part, by an E2-induced increase in Ets-1 expression.