Hepatic lipids promote liver metastasis

Obesity predisposes to cancer and a virtual universality of nonalcoholic fatty liver disease (NAFLD). However, the impact of hepatic steatosis on liver metastasis is enigmatic. We find that while control mice were relatively resistant to hepatic metastasis, those which were lipodystrophic or obese, with NAFLD, had a dramatic increase in breast cancer and melanoma liver metastases. NAFLD promotes liver metastasis by reciprocal activation initiated by tumor-induced triglyceride lipolysis in juxtaposed hepatocytes. The lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, where they are metabolized by mitochondrial oxidation to promote tumor growth. The histology of human liver metastasis indicated the same occurs in humans. Furthermore, comparison of isolates of normal and fatty liver established that steatotic lipids had enhanced tumor-stimulating capacity. Normalization of glucose metabolism by metformin did not reduce steatosis-induced metastasis, establishing the process is not mediated by the metabolic syndrome. Alternatively, eradication of NAFLD in lipodystrophic mice by adipose tissue transplantation reduced breast cancer metastasis to that of control mice, indicating the steatosis-induced predisposition is reversible

A vacuum ultraviolet ion source (VUV-IS) for iodide-chemical ionization mass spectrometry: a substitute for radioactive ion sources

A&nbsp;new ion source (IS) utilizing vacuum ultraviolet (VUV) light is developed and characterized for use with iodide&ndash;chemical ionization mass spectrometers (I&minus;-CIMS). The VUV-IS utilizes a&nbsp;compact krypton lamp that emits light at two wavelengths corresponding to energies of &sim;10.030 and 10.641&thinsp;eV. The VUV light photoionizes either methyl iodide (ionization potential, IP&thinsp;=&thinsp;9.54&thinsp;&plusmn;&thinsp;0.02&thinsp;eV) or benzene (IP&thinsp;=&thinsp;9.24378&thinsp;&plusmn;&thinsp;0.00007&thinsp;eV) to form cations and photoelectrons. The electrons react with methyl iodide to form I&minus;, which serves as the reagent ion for the CIMS. The VUV-IS is characterized by measuring the sensitivity of a&nbsp;quadrupole CIMS (Q-CIMS) to formic acid, molecular chlorine, and nitryl chloride under a&nbsp;variety of flow and pressure conditions. The sensitivity of the Q-CIMS, with the VUV-IS, reached up to &sim;700&thinsp;Hz&thinsp;pptv&minus;1, with detection limits of less than 1&thinsp;pptv for a&nbsp;1&thinsp;min integration period. The reliability of the Q-CIMS with a&nbsp;VUV-IS is demonstrated with data from a&nbsp;month-long ground-based field campaign. The VUV-IS is further tested by operation on a&nbsp;high-resolution time-of-flight CIMS (TOF-CIMS). Sensitivities greater than 25&thinsp;Hz&thinsp;pptv&minus;1 were obtained for formic acid and molecular chlorine, which were similar to that obtained with a&nbsp;radioactive source. In addition, the mass spectra from sampling ambient air was cleaner with the VUV-IS on the TOF-CIMS compared to measurements using a&nbsp;radioactive source. These results demonstrate that the VUV lamp is a&nbsp;viable substitute for radioactive ion sources on I&minus;-CIMS systems for most applications. In addition, initial tests demonstrate that the VUV-IS can be extended to other reagent ions by the use of VUV absorbers with low IPs to serve as a&nbsp;source of photoelectrons for high IP electron attachers, such as SF&minus;6</p

Exploratory spatial data analysis for the identification of risk factors to birth defects

BACKGROUND: Birth defects, which are the major cause of infant mortality and a leading cause of disability, refer to "Any anomaly, functional or structural, that presents in infancy or later in life and is caused by events preceding birth, whether inherited, or acquired (ICBDMS)". However, the risk factors associated with heredity and/or environment are very difficult to filter out accurately. This study selected an area with the highest ratio of neural-tube birth defect (NTBD) occurrences worldwide to identify the scale of environmental risk factors for birth defects using exploratory spatial data analysis methods. METHODS: By birth defect registers based on hospital records and investigation in villages, the number of birth defects cases within a four-year period was acquired and classified by organ system. The neural-tube birth defect ratio was calculated according to the number of births planned for each village in the study area, as the family planning policy is strictly adhered to in China. The Bayesian modeling method was used to estimate the ratio in order to remove the dependence of variance caused by different populations in each village. A recently developed statistical spatial method for detecting hotspots, Getis's [Image: see text] [7], was used to detect the high-risk regions for neural-tube birth defects in the study area. RESULTS: After the Bayesian modeling method was used to calculate the ratio of neural-tube birth defects occurrences, Getis's [Image: see text] statistics method was used in different distance scales. Two typical clustering phenomena were present in the study area. One was related to socioeconomic activities, and the other was related to soil type distributions. CONCLUSION: The fact that there were two typical hotspot clustering phenomena provides evidence that the risk for neural-tube birth defect exists on two different scales (a socioeconomic scale at 6.84 km and a soil type scale at 22.8 km) for the area studied. Although our study has limited spatial exploratory data for the analysis of the neural-tube birth defect occurrence ratio and for finding clues to risk factors, this result provides effective clues for further physical, chemical and even more molecular laboratory testing according to these two spatial scales

Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes.

Eradication of Mycobacterium tuberculosis (MTB) infection requires daily administration of combinations of rifampin (RIF), isoniazid [isonicotinylhydrazine (INH)], pyrazinamide, and ethambutol, among other drug therapies. To facilitate and optimize MTB therapeutic selections, a mononuclear phagocyte (MP; monocyte, macrophage, and dendritic cell)-targeted drug delivery strategy was developed. Long-acting nanoformulations of RIF and an INH derivative, pentenyl-INH (INHP), were prepared, and their physicochemical properties were evaluated. This included the evaluation of MP particle uptake and retention, cell viability, and antimicrobial efficacy. Drug levels reached 6 μg/10(6) cells in human monocyte-derived macrophages (MDMs) for nanoparticle treatments compared with 0.1 μg/10(6) cells for native drugs. High RIF and INHP levels were retained in MDM for \u3e15 d following nanoparticle loading. Rapid loss of native drugs was observed in cells and culture fluids within 24 h. Antimicrobial activities were determined against Mycobacterium smegmatis (M. smegmatis). Coadministration of nanoformulated RIF and INHP provided a 6-fold increase in therapeutic efficacy compared with equivalent concentrations of native drugs. Notably, nanoformulated RIF and INHP were found to be localized in recycling and late MDM endosomal compartments. These were the same compartments that contained the pathogen. Our results demonstrate the potential of antimicrobial nanomedicines to simplify MTB drug regimens

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFβ signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ∼12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site

Evaluation of three commercial metal artifact reduction methods for CT simulations in radiation therapy

Purpose: To evaluate the success of three commercial metal artifact reduction methods (MAR) in the context of radiation therapy treatment planning.Methods: Three MAR strategies were evaluated: Philips O-MAR, monochromatic imaging using Gemstone Spectral Imaging (GSI) dual energy CT, and monochromatic imaging with metal artifact reduction software (GSI-MARs). The Gammex RMI 467 tissue characterization phantom with several metal rods and two anthropomorphic phantoms (pelvic phantom with hip prosthesis and head phantom with dental fillings), were scanned with and without metals (baseline). Each MAR method was evaluated based on CT number accuracy, metal size accuracy, and reduction in the severity of streak artifacts. CT number difference maps between the baseline and metal scan images were calculated, and the severity of streak artifacts was quantified using the percentage of pixels with &gt; 40 HU error (“bad pixels”).Results: Philips O-MAR generally reduced HU errors in the RMI phantom. However, increased errors and induced artifacts were observed for lung materials. GSI monochromatic 70keV images generally showed similar HU errors as conventional 120kVp imaging, while 140keV images reduced HU errors. All the imaging techniques represented the diameter of a stainless steel rod to within ±1.6mm (2 pixels). For the hip prosthesis, O-MAR reduced the average % bad pixels from 47% to 32%. For GSI 140keV imaging, the % bad pixels was reduced from 37% to 29% compared to 120kVp imaging, and GSI-MARs further reduced it to 12%. For the head phantom, none of the MAR methods was particularly successful.Conclusion: O-MAR resulted in consistent artifact reduction but exhibited induced artifacts for metals located near lung tissue. GSI imaging at 140keV gave consistent reduction in HU errors and severity of artifacts. GSI-MARs at 140keV was the most successful MAR method for the hip prosthesis but exhibited induced artifacts at the edges of metals in some cases.---------------------------------Cite this article as: Huang JY, Kerns JR, Nute JL, Liu X, Stingo FC, Followill DS, Mirkovic D, Howell RM, Kry SF. Evaluation of three commercial metal artifact reduction methods for CT simulations in radiation therapy. Int J Cancer Ther Oncol 2014; 2(2):020224. DOI: 10.14319/ijcto.0202.2

Breast cancer derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment

Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (Arg-1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular L-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor derived GM-CSF as the primary regulator of myeloid cell Arg-1 expression and local immune suppression through a gene knockout screen of breast tumor cell-produced factors. The induction of myeloid cell Arg-1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3, p38 MAPK, and acid signaling through cAMP were required to activate myeloid cell Arg-1 expression in a STAT6 independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host anti-tumor immunity, driving a significant accumulation of Arg-1 expressing myeloid cells compared to lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T-cell therapy and immune checkpoint blockade. Taken together, breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell Arg-1 expression and can be targeted to enhance breast cancer immunotherapy

Prior Sexual Trauma Exposure Impacts Posttraumatic Dysfunction and Neural Circuitry Following a Recent Traumatic Event in the AURORA Study

Background: Prior sexual trauma (ST) is associated with greater risk for posttraumatic stress disorder after a subsequent traumatic event; however, the underlying neurobiological mechanisms remain opaque. We investigated longitudinal posttraumatic dysfunction and amygdala functional dynamics following admission to an emergency department for new primarily nonsexual trauma in participants with and without previous ST. Methods: Participants (N = 2178) were recruited following acute trauma exposure (primarily motor vehicle collision). A subset (n = 242) completed magnetic resonance imaging that included a fearful faces task and a resting-state scan 2 weeks after the trauma. We investigated associations between prior ST and several dimensions of posttraumatic symptoms over 6 months. We further assessed amygdala activation and connectivity differences between groups with or without prior ST. Results: Prior ST was associated with greater posttraumatic depression (F1,1120 = 28.35, p = 1.22 × 10−7, ηp2 = 0.06), anxiety (F1,1113 = 17.43, p = 3.21 × 10−5, ηp2 = 0.05), and posttraumatic stress disorder (F1,1027 = 11.34, p = 7.85 × 10−4, ηp2 = 0.04) severity and more maladaptive beliefs about pain (F1,1113 = 8.51, p = .004, ηp2 = 0.02) but was not related to amygdala reactivity to fearful versus neutral faces (all ps \u3e .05). A secondary analysis revealed an interaction between ST and lifetime trauma load on the left amygdala to visual cortex connectivity (peak Z value: −4.41, corrected p \u3c .02). Conclusions: Findings suggest that prior ST is associated with heightened posttraumatic dysfunction following a new trauma exposure but not increased amygdala activity. In addition, ST may interact with lifetime trauma load to alter neural circuitry in visual processing regions following acute trauma exposure. Further research should probe the relationship between trauma type and visual circuitry in the acute aftermath of trauma

Structural covariance of the ventral visual stream predicts posttraumatic intrusion and nightmare symptoms: a multivariate data fusion analysis

Visual components of trauma memories are often vividly re-experienced by survivors with deleterious consequences for normal function. Neuroimaging research on trauma has primarily focused on threat-processing circuitry as core to trauma-related dysfunction. Conversely, limited attention has been given to visual circuitry which may be particularly relevant to posttraumatic stress disorder (PTSD). Prior work suggests that the ventral visual stream is directly related to the cognitive and affective disturbances observed in PTSD and may be predictive of later symptom expression. The present study used multimodal magnetic resonance imaging data (n = 278) collected two weeks after trauma exposure from the AURORA study, a longitudinal, multisite investigation of adverse posttraumatic neuropsychiatric sequelae. Indices of gray and white matter were combined using data fusion to identify a structural covariance network (SCN) of the ventral visual stream 2 weeks after trauma. Participant\u27s loadings on the SCN were positively associated with both intrusion symptoms and intensity of nightmares. Further, SCN loadings moderated connectivity between a previously observed amygdala-hippocampal functional covariance network and the inferior temporal gyrus. Follow-up MRI data at 6 months showed an inverse relationship between SCN loadings and negative alterations in cognition in mood. Further, individuals who showed decreased strength of the SCN between 2 weeks and 6 months had generally higher PTSD symptom severity over time. The present findings highlight a role for structural integrity of the ventral visual stream in the development of PTSD. The ventral visual stream may be particularly important for the consolidation or retrieval of trauma memories and may contribute to efficient reactivation of visual components of the trauma memory, thereby exacerbating PTSD symptoms. Potentially chronic engagement of the network may lead to reduced structural integrity which becomes a risk factor for lasting PTSD symptoms

Lack of Trehalose Accelerates H2O2-Induced Candida albicans Apoptosis through Regulating Ca2+ Signaling Pathway and Caspase Activity

Trehalose is a non-reducing disaccharide and can be accumulated in response to heat or oxidative stresses in Candida albicans. Here we showed that a C. albicans tps1Δ mutant, which is deficient in trehalose synthesis, exhibited increased apoptosis rate upon H2O2 treatment together with an increase of intracellular Ca2+ level and caspase activity. When the intracellular Ca2+ level was stimulated by adding CaCl2 or A23187, both the apoptosis rate and caspase activity were increased. In contrast, the presence of two calcium chelators, EGTA and BAPTA, could attenuate these effects. Moreover, we investigated the role of Ca2+ pathway in C. albicans apoptosis and found that both calcineurin and the calcineurin-dependent transcription factor, Crz1p, mutants showed decreased apoptosis and caspase activity upon H2O2 treatment compared to the wild-type cells. Expression of CaMCA1, the only gene found encoding a C. albicans metacaspase, in calcineurin-deleted or Crz1p-deleted cells restored the cell sensitivity to H2O2. Our results suggest that Ca2+ and its downstream calcineurin/Crz1p/CaMCA1 pathway are involved in H2O2 -induced C. albicans apoptosis. Inhibition of this pathway might be the mechanism for the protective role of trehalose in C. albicans