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Supplementary Tables - PDF file 148K, Table S1. Characteristics of HER2-negative breast cancers, separated by HR status, TCGA Table S2. Characteristics of triple-negative breast cancers with residual disease post neoadjuvant chemotherapy and univariate Table S3. Bimodal analysis of metabolism-related genes ranked by bimodality index (BI)

Supplementary Figures - PDF file 440K, Figure S1. Figure S1. Validation the IHC protocol for LDHB using FFPE MDAMB231 cells with stable knockdown of LDHA or LDHB. Reduced staining for LDHB was detected only in the LDHB knockdown line. Control cells were infected with a non-silencing shRNA. Figure S2. LDHB, when present, substantially contributed to the total LDH activity in cell lines. Figure S3. A, verification of LDHA or LDHB knockdown by LDH activity in stable isogenic cell lines, MDAMB231 and HCC1937. Figure S4. LDHB association with PAM50 intrinsic subtype in primary breast cancers. A, LDHB mRNA expression separated by intrinsic subtype: Perou GSE10893 (8) Figure S5. High LDHB was associated with triple-negative breast cancer. LDHB mRNA expression of HER2 (by IHC/FISH)-negative disease separated by clinical classification Figure S6. LDHB mRNA expression within PAM50 intrinsic subtypes for HR-positive/HER2-negative breast cancers. Figure S7. LDHB mRNA expression within PAM50 intrinsic subtypes for triple-negative breast cancers Figure S8. LDHB mRNA expression was highly associated with cell cycle proliferation marker, CCNB1, for basal-like cancers within the triple-negative group. Figure S9. Association between mRNA expression and copy number for LDHB for the breast invasive carcinoma cohort separated by (A) basal and (B) luminal A/B subtypes for TCGA "manuscript samples" within the cBio Cancer Genomics Portal

Figure showing the NG-CHM Generator in the Galaxy bioinformatics platform.

Supplementary Data - PDF file 89K, Supplementary Methods Tissue microarray (TMA) of triple-negative breast cancers

Purpose: The current study evaluated associative effects of breast cancer cells with the tumor microenvironment and its influence on tumor behavior.Experimental Design: Formalin-fixed, paraffin-embedded tissue and matched protein lysates were evaluated from two independent breast cancer patient datasets (TCGA and MD Anderson). Reverse-phase protein arrays (RPPA) were utilized to create a proteomics signature to define breast tumor subtypes. Expression patterns of cell lines and normal breast tissues were utilized to determine markers that were differentially expressed in stroma and cancer cells. Protein localization and stromal contents were evaluated for matched cases by imaging.Results: A subtype of breast cancers designated “Reactive,” previously identified by RPPA that was not predicted by mRNA profiling, was extensively characterized. These tumors were primarily estrogen receptor (ER)-positive/human EGF receptor (HER)2-negative, low-risk cancers as determined by enrichment of low-grade nuclei, lobular or tubular histopathology, and the luminal A subtype by PAM50. Reactive breast cancers contained high numbers of stromal cells and the highest extracellular matrix content typically without infiltration of immune cells. For ER-positive/HER2-negative cancers, the Reactive classification predicted favorable clinical outcomes in the TCGA cohort (HR, 0.36; P < 0.05).Conclusions: A protein stromal signature in breast cancers is associated with a highly differentiated phenotype. The stromal compartment content and proteins are an extended phenotype not predicted by mRNA expression that could be utilized to subclassify ER-positive/HER2-negative breast cancers. Clin Cancer Res; 22(20); 5068–78. ©2016 AACR.

Classification of RPPA platform antibodies as "stromal" or ER-pos "cancer" enriched (Excel sheet)

Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well-understood and may predict response to chemotherapy. This study aimed to evaluate metabolic genes as individual predictive biomarkers in breast cancer.Experimental Design: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes—those with highest potential for robust high/low classification in clinical assays. Metabolic function was evaluated in vitro for the highest scoring metabolic gene, lactate dehydrogenase B (LDHB). Its expression was associated with neoadjuvant chemotherapy response and relapse within clinical and PAM50-derived subtypes.Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Stable knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using patient datasets, LDHB was highly expressed in basal-like cancers and could predict basal-like subtype within clinical groups [OR = 21 for hormone receptor (HR)-positive/HER2-negative; OR = 10 for triple-negative]. Furthermore, high LDHB predicted pathologic complete response (pCR) to neoadjuvant chemotherapy for both HR-positive/HER2-negative (OR = 4.1, P < 0.001) and triple-negative (OR = 3.0, P = 0.003) cancers. For triple-negative tumors without pCR, high LDHB posttreatment also identified proliferative tumors with increased risk of recurrence (HR = 2.2, P = 0.006).Conclusions: Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes independently of standard prognostic markers and PAM50 subtyping. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for patients with breast cancer receiving neoadjuvant chemotherapy. Clin Cancer Res; 19(13); 3703–13. ©2013 AACR.

Proteins differentially expressed in Reactive subtype (Excel sheet).

Influenza pandemic of the human lung was caused by the Influenza A (H1N1) over 100 years ago in 1918, but it recurred in pandemic fashion in 2009. Understanding the pathobiology of this infectious agent in the human lung could lead to adjuvant therapies that are relatively non-toxic and reduce the mortality of the human host. Overall, our objective was to apply morphoproteomics to pulmonary lung sections from an autopsied victim so that we may better define its biology from the perspective of its interaction with the host and provide options for therapeutic targets.Morphoproteomic analysis from a case study of this Influenza A (H1N1) pulmonary infection included immunohistochemical probes to detect the expressions of fatty acid synthase (FAS), CD163Representative sections of the Influenza A (H1N1) victim's lung showed: cytoplasmic expression of FAS in most of the sloughed and atypical alveolar pneumocytes; abundance of intra-alveolar and alveolar interstitial CD163Morphoproteomics and microanatomical features coincide with the etiopathogenic features of pulmonary Influenza A (H1N1) infection and the host response. This plus data mining of the medical literature suggests that adjunctive, targeted therapy such as metformin and vitamin D3 could address the biology of Influenza A (H1N1) pneumonia, enhance the host immune response, and prevent its progression to a life-threatening, ventilator-dependent clinical situation.

Representing the largest and most culturally influential religious body of the era, the Congregational Church was the foundational institution of early American evangelicalism. It was the location of the earliest strands of revivalist religious experience and provided the pivotal theological architects and promoters of evangelical Christianity. By the early nineteenth century, its leaders stood at the forefront of nearly every important social reform movement in the country and helped to found many of its most important missions agencies, both domestic and foreign. It also produced some of the strongest backlash against evangelicalism, chiefly manifested in the institutional development of American Unitarianism. Evangelical impulses in Congregationalism were used to advance the social equality of marginalized groups such as women, African Americans, and poor Whites, as well as to buttress the hierarchical status quo. It was the seedbed of some of the most original, imaginative, and important theological movements in early America.

Post-wildfire erosion and the slope instability issues associated with it are a global problem that can negatively affect transportation corridors, the environment, and human life. Currently, mulch treatments are commonly used means of stabilizing wildfire-burnt hillslopes; however, mulch, especially agricultural straw mulch, can pose environmental concerns related to invasive plants. An environmentally friendly treatment, xanthan gum (XG), and a commercial polyacrylamide (PAM) were evaluated as alternatives for stabilizing surficial silty soil that was burnt by the 2018 Mesa Fire in central Idaho to reduce runoff-dominated erosion. Indoor rainfall experiments were conducted to simulate three wet-dry cycles. Runoff and infiltration were measured after each wetting and drying event, and used to compare the effectiveness of the admixture. The total runoff at the end of three wetting events increased slightly, by ~ 4% for PAM and ~ 12% for XG. These results indicate that both PAM and XG decrease soil loss and infiltration, but that neither seals the soil surface completely. The soil loss during each wetting event was found to be dependent on the water content before wetting and the corresponding regime in the soil water retention curve. PAM and XG maintained the unsaturated state in soil, with water contents consistently around 30% before the second and third wetting events. This resulted in similar runoffs and statistically significant reductions in soil loss. At the end of three events, the soil loss was reduced by 2.9 times for XG and 6.9 times for PAM, compared to the soil loss from untreated soil.

This article begins with a consideration of the putative parallels between the presidencies of Andrew Jackson, the nation’s 7th president, and Donald Trump, the 45th. Underlying Trump’s and his supporters’ partisan case for his Jacksonian populism and similarly volatile temperament is another argument explored in this article: that such a Jacksonian framing implicitly situates Trump in the pantheon of the nation’s greatest, most consequential presidents who have expanded the powers of the office itself. Several standards of judgment are adduced for the critical consideration of the Trump presidency as it nears the completion of its first term. The consequentialism of the Trump presidency is weighed against standards of ethics and the personality trait known as Machiavellianism.

BACKGROUND AND AIMS The role of the intestinal microbiome in alcoholic hepatitis is not established. The aims of this study were to (1) characterize the fecal microbial ecology associated with alcoholic hepatitis, (2) relate microbiome changes to disease severity, and (3) infer the functional relevance of shifts in microbial ecology. APPROACH AND RESULTS The fecal microbiome in patients with moderate alcoholic hepatitis (MAH) or severe alcoholic hepatitis (SAH) was compared with healthy controls (HCs) and heavy drinking controls (HDCs). Microbial taxa were identified by 16S pyrosequencing. Functional metagenomics was performed using PICRUSt. Fecal short chain fatty acids (SCFAs) were measured using a liquid chromatography-mass spectrometry platform. A total of 78 participants (HC, n = 24; HDC, n = 20; MAH, n = 10; SAH, n = 24) were studied. HDC had a distinct signature compared with HC with depletion of Bacteroidetes (46% vs. 26%; P = 0.01). Alcoholic hepatitis was associated with a distinct microbiome signature compared with HDC (area under the curve = 0.826); differential abundance of Ruminococcaceae, Veillonellaceae, Lachnospiraceae, Porphyromonadaceae, and Rikenellaceae families were the key contributors to these differences. The beta diversity was significantly different among the groups (permutational multivariate analysis of variance [PERMANOVA] P

Overexpression of transcription factor 3 in alveolar soft part sarcoma(ASPS) results in upregulation of cell proliferation pathways. No standard treatment algorithm exists for ASPS; multikinase inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint inhibitors (ICI) have shown clinical benefit. To date, no studies have reported on management strategies or sequencing of therapy. We evaluated ASPS treatment patterns and responses in an experimental therapeutics clinic. Genomic and morphoproteomic analysis was performed to further elucidate novel targets. We retrospectively reviewed patients with ASPS treated on clinical trials. Demographic and clinical next-generation sequencing (NGS) profiles were collected. AACR GENIE database was queried to further evaluate aberrations in ASPS. Morphoproteomic analysis was carried out to better define the biology of ASPS with integration of genomic and proteomic findings. Eleven patients with ASPS were identified; 7 received NGS testing and mutations in CDKN2A (n = 1) and hepatocyte growth factor (n = 1) were present. Ten patients were treated with TKIs with stable disease as best response and 4 patients with ICI (three partial responses). Within GENIE, 20 patients were identified harboring 3 called pathogenic mutations. Tumor mutation burden was low in all samples. Morphoproteomic analysis confirmed the expression of phosphorylated c-Met. In addition, fatty acid synthase and phosphorylated-STAT3 were detected in tumor cell cytoplasm and nuclei. Patients with ASPS have a quiescent genome and derive clinical benefit from VEGF-targeting TKIs. Morphoproteomic analysis has provided both additional correlative pathways and angiogenic mechanisms that are targetable for patients with ASPS. Our study suggests that sequential therapy with TKIs and immune checkpoint inhibitors is a reasonable management strategy.

Large wildfires can have profound and lasting impacts not only from direct consumption of vegetation but also longerterm effects such as persistent soil erosion. The 2002 Hayman Fire burned in one of the watersheds supplying water to the Denver metropolitan area; thus there was concern regarding hillslope erosion and sedimentation in the reservoirs. The efficacy of various treatments for reducing erosion was tested, including hand scarification on contour, agricultural straw mulch, wood mulch, burned controls and unburned reference plots. Simulated rill erosion experiments were used both immediately after the fire and again 10 years post fire. To better understand untreated recovery, the same experiments were applied to control plots in post-fire years 1, 2, 3 and 4, and in unburned reference plots in years 4 and 10. Results indicate that control and scarified plots produced significantly greater sediment flux rates - 1.9 and 2.8 g s-1 respectively – than the straw and wood mulch treatments - 0.9 and 1.1 g s-1 - immediately after the fire. Mulch treatments reduced runoff rate, runoff velocity, and sediment concentration and flux rate. The straw mulch cover was no longer present, whereas the wood mulch was still there in year 10. Vegetation regrowth was slow and mulch treatments provided effective cover to reduce sediment right after the fire. In post-fire year 10, there were no significant differences in sediment flux rates across treatments; it is notable, however, that the wood mulch treatment (0.09 g s-1) most closely approached the unburned condition (0.07 g s-1). The burned control plots had high sediment flux rates until post-fire year 3, when flux rates significantly decreased and were statistically no longer higher than the unburned levels from year 4 and 10. These results will inform managers of the longer-term post-fire sediment delivery rates and of the ability of post-fire emergency hillslope treatments to mitigate erosion rates.

Diffuse large B-cell lymphoma (DLBCL) is the most aggressive form of non-Hodgkin's lymphoma.We applied morphoproteomics to a tissue microarray of DLBCL cases to uncover commonalities in its biology with therapeutic implications. Morphoproteomic analysis of 9 individual cases of classic DLBCL included immunohistochemical probes to detect silent mating type information regulation 2 homolog 1 (SIRT1), enhancer of Zeste homolog 2 (EZH2) and C-X-C chemokine receptor 4 (CXCR4) and their cellular compartmentalization by bright field microscopy.We detected the expression of SIRT1 in the majority (50%) of the tumoral nuclei of 8 of 9 cases of DLBCL and of EZH2 expression in the majority (50%) of the tumoral nuclei in 9 of the 9 cases; and the expression of the tumoral stem cell marker, CXCR4 in the cytoplasmic and/or plasmalemmal compartment at50% of the tumor cells in all 9 cases of DLBCL. The morphoproteomic findings of SIRT1 and EZH2 expression in DLBCL, for the most part, parallel the morphoproteomic findings in B-cell acute lymphoblastic leukemia. This concordance has pharmacogenomic and therapeutic implications. Similarly, the fact that EZH2 can enhance the expression of tumoral stem cell marker, CXCR4 implies that there is a block in differentiation in DLBCL.By targeting the Sirt1, EZH2 and CXCR4 pathways using relatively non-toxic adjuvant therapeutic agents such as metformin, melatonin, curcumin, sulforaphane, vitamin D3 and plerixafor, we should be able to target the biology of DLBCL.

As wildland fires amplify in size in many regions in the western USA, land and water managers are increasingly concerned about the deleterious effects on drinking water supplies. Consequences of severe wildfires include disturbed soils and areas of thick ash cover, which raises the concern of the risk of water contamination via ash. The persistence of ash cover and depth were monitored for up to 90 days post-fire at nearly 100 plots distributed between two wildfires in Idaho and Washington, USA. Our goal was to determine the most ‘cost’ effective, operational method of mapping post-wildfire ash cover in terms of financial, data volume, time, and processing costs. Field measurements were coupled with multi-platform satellite and aerial imagery collected during the same time span. The image types spanned the spatial resolution of 30 m to sub-meter (Landsat-8, Sentinel-2, WorldView-2, and a drone), while the spectral resolution spanned visible through SWIR (short-wave infrared) bands, and they were all collected at various time scales. We that found several common vegetation and post-fire spectral indices were correlated with ash cover (r = 0.6–0.85), however, the blue normalized difference vegetation index (BNDVI) with monthly Sentinel-2 imagery was especially well-suited for monitoring the change in ash cover during its ephemeral period. A map of the ash cover can be used to estimate the ash load, which can then be used as an input into a hydrologic model predicting ash transport and fate, helping to ultimately improve our ability to predict impacts on downstream water resources.

Chemotherapy originated in the early 1960s. The initial chemotherapeutic agents focused on blocking metabolic pathways and found substantial success in certain types of tumors, but they are generally considered toxic to all normal and tumor cells, and they have significant side effects. As more scientific studies began to identify many new, specific targets and mutations, along with a multitude of growth pathways in tumor cells, new agents targeting cell growth pathways began to emerge in the late 1990s and early 2000s. In 2003, a method called morphoproteomics was developed to evaluate the immunohistochemical protein expressions of target markers in tumors, and it has been considered a pioneering method for guiding targeted therapy. Subsequently, many genomic techniques have been established for identifying specific mutations and tumor markers in order to guide the targeted therapy. More recently, immuno-oncology therapy targeting specific immune markers has been rapidly developed, and the immunohistochemical evaluation of specific immune markers such as PD-L1 demonstrates further expansion of oncologic morphoproteomics. This brief review will focus on the role of pathologists in developing various techniques and guiding targeted therapies during the era of personalized medicine.

Wildfire ash is a mixture of pyrogenic organic and inorganic materials with high concentration in nutrients and potential contaminants that is easily mobilized by runoff. Ash has been identified as a major threat to water quality since it can impact aquatic life and disrupt water treatment operations when is washed off into water bodies. The ability to modelling ash transport, however, is in its infancy. One reason for this is that the relationship between runoff and ash transport for concentrated flow has not been described yet, limiting the capabilities of current runoff-erosion models to predict ash transport and delivery in fire-affected areas.To fill this knowledge gap, we conducted a series of laboratory experiments on ash transport using concentrated flow on flumes. Ash collected from US conifer forest burned at high severity was applied at two different rates (corresponding to layers of 1 and 3 cm thickness) to an artificial substrate of gravel and sand attached to the bottom of the flumes that simulates soil roughness. Three different flow rates were consecutively applied to each flume in all possible combinations (6 flow rate combinations and 6 replicates per combination and ash thickness).The results show that ash is easily transported by concentrated flow, confirming previous observations on ash mobility. The runoff rate required to start transporting the ash was close to 0 (0.005 L min-1 for both 1 and 3 cm ash layers) and the average concentration of ash in the runoff once this process started was considerably high (120 and 176 g L-1 for 1 and 3 cm ash layers respectively), probably due to the low density and cohesion of this fire by-product. The results also show that ash depletion is a critical process when modelling ash transport and, thus, that ash transport by concentrated flow is better modelled using a variable sediment transport rate to account for ash decay with consecutive rainfall events. This is especially true for the 1 cm ash layer. The relationships between runoff and ash transport for concentrated flow obtained here for the evaluated ash type and loads are critical parameters to predict ash transport and will be used to refine ash transport capabilities of WEPPcloud-WATAR, a new tool aimed at predicting ash contamination risks after wildfires.

Jonathan Edwards’s exegesis brought together a remarkable constellation of issues in early modern thought and biblical interpretation. Although he lived on the frontier of the British empire, he lived intimately with the core philosophical and theological issues at the heart of that society. The Bible’s status as an unquestioned religious and social authority was under scrutiny during his lifetime, with many concluding that it was hopelessly primitive and outmoded. Edwards sought to fashion an interpretive approach that took seriously modern historical, scientific, and anthropological discoveries, while maintaining a high degree of confidence in the Bible as the revelation of God. Thus, he adapted much of his interpretation to modern categories of thought, while at the same time employing traditional modes of theological interpretation such as typology, miracles, and the analogy of faith. His exegesis served to underwrite all of his major theological treatises.

Post-primary tuberculosis (TB) disease is characterized by paucibacillary necrosis of the early lesion, tuberculous pneumonia, in the adult human lung. The mechanism is speculated to be a strong localized delayed type hypersensitive response (DTH). However, up to this date, no one has been able to identify the source of the large accumulation of MTB antigens required for the DTH response. Although it is known and accepted that the pathogen

Correlation analysis is a fundamental technique to determine potential relationships within biological processes. However, many biological processes have been shown to function in a periodic manner. When modeling correlations, the fluctuations that are associated with periodicity cause significant issues. We have implemented a Phase Shift Correlation (PSC) algorithm, with a corresponding value PSCrho, to address the periodicity and phase variance associated with features that vary with the same frequency -- but are phase shifted. The phase shift could well indicate causality with one feature’s quantitative change leading to the change in the other feature.We applied the PSC algorithm to Ulcerative Colitis (UC) microbiome data and compared the resulting feature relationships with the equivalent Spearman correlation function results. PSC located many instances of higher phase shifted correlations, where the corresponding Pearson correlation was low.

The COVID-19 pandemic has challenged the world economically and medically. Understanding and defining the biology of this specific coronavirus infection may lead to targeted therapies to lessen its virulence and expand the host resistance. This study's objective was to apply morphoproteomics to pulmonary lung sections from a forensic autopsy of an untreated COVID-19 victim, so that we may better define its biology from the perspective of its interaction with the host and provide options for therapeutic targets.Morphoproteomic analysis from a case study of this COVID-19 pulmonary infection included immunohistochemical probes to detect phosphorylated p-STAT3 (Tyr 705), as part of the interleukin (IL)-6 pathway; cyclooxygenase (COX)-2, CD8+ cytotoxic lymphocytes, Programmed Death (PD)-1 receptor+ lymphoid cells, CD56+ NK lymphoid cells, CD163+ (M2 polarized monocytes/macrophages), and programmed death-ligand 1 (PD-L1) expression as part of the host response to interaction with the COVID-19 virus.Representative sections of the COVID-19 victim's lung showed: nuclear expression of p-STAT3 (Tyr 705) in many of the alveolar pneumocytes and in occasional endothelial cells; COX-2 expression in the alveolar pneumocytes; a relative paucity of CD8+ cytotoxic lymphocytes; absence of CD56+ NK lymphoid cells; abundance of intra-alveolar and alveolar interstitial CD163+ macrophages/monocytes; PD-L1 expression on occasional macrophages, focally on collections of alveolar pneumocytes, and on cells in the alveolar interstitium; and rare PD-1+ lymphocytes in similar regions as CD8+ lymphocytes.Morphoproteomics and microanatomical features coincide with the etiopathogenic features of pulmonary coronavirus infection and the host response. This suggests that a targeted therapy could address the biology of COVID-19 pneumonia, enhance the host immune response and prevent its progression to a life-threatening, ventilator-dependent clinical situation.

Undifferentiated colorectal cancer (UCRC) has a well-documented CD44 cancer stem cell (CSC) component. CXCR4 (C-X-C motif receptor 4) also is a CSC marker and with its ligand, stromal-derived factor (SDF)-1 alpha has been shown to act in concert with CD44 to promote cancer cell invasion. To date, CXCR4 has not been reported in the MEDLINE (PubMed) literature with respect to UCRC. Morphoproteomic analysis, utilizing bright field microscopy, can visualize the intensity and cell location of protein analytes with a patient's tumor including CXCR4 expression and was applicable to this case study. Using morphoproteomic analysis we identified chromogenic expression of both CD44 on the plasmalemmal aspect of the majority of the undifferentiated colorectal cancer foci and CXCR4 expression on the plasmalemmal or cytoplasmic aspect in up to 50% of the tumor cells in some regions and also on the intratumoral endothelial cells in the patient's UCRC. Moreover, both CSC markers were retained in the foci showing incomplete mucinous differentiation. In the context of data mining of the scientific literature, these findings suggest a collaboration between CXCR4 and CD44 in promoting tumor invasion and angiodependent metastasis in UCRC. Therapies designed to inhibit both the CD44 and the CXCR4 pathways are available and could reduce the metastatic potential of UCRC.

Wildfires naturally occur worldwide, however the potential disruption to ecosystem services from subsequent post-fire flooding and erosion often necessitates a response from land managers. The impact of high severity wildfire on infiltration and interrill erosion responses was evaluated for five years after the 2003 Hot Creek Fire in Idaho, USA. Relative infiltration from mini-disk tension infiltrometers (MDI) was compared to rainfall simulation measurements on small burned and control plots. Vegetation recovery was slow due to the severity of the fire, with median cover of 6-8% on burned sites after 5 years. Consequently, interrill sediment yields remained significantly higher on the burned sites (329-1200 g m-2) compared to the unburned sites (3-35 g m-2) in year 5. Total infiltration on the burned plots increased during the study period, yet were persistently lower compared to the control plots. Relative infiltration measurements made at the soil surface, and 1- and 3-cm depths were significantly correlated to non-steady state total infiltration values taken in the first 10 minutes of the hour-long rainfall simulations. Significant correlations were found at the 1-cm (ρ = 0.4-0.6) and 3-cm (ρ = 0.3-0.6) depths (most p-values

Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice. Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 + 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection. Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P = 0.023 and 0.024, respectively). Increased TNFα levels correlated positively with SD at week 8 (P < 0.01). Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes. Clin Cancer Res; 24(16); 3845–56. ©2018 AACR.

Background Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein, which regulates cell proliferation and facilitates intracellular transport of albumin bound particles including chemotherapeutic agents such as Nab-paclitaxel/ABI-007. Therefore the presence of SPARC may achieve higher intra-tumoral drug concentration with lower dosage and thus reduce systemic side-effects. Several trials of ABI-007, in melanoma, show promising clinical activity. Design Fifty-four cases of dermal based neoplasms were retrieved including 24 angiosarcomas (AS), 10 hemangiomas, 9 nodular melanomas, 4 Kaposi sarcomas (KS), 3 leiomyosarcomas (LMS), 3 atypical fibroxanthomas (AFX) and 1 spindle cell squamous cell carcinoma (SSCC). SPARC immunohistochemistry (IHC) was performed with a mouse monoclonal antibody. Results SPARC expression was detected in a majority of AS (17/24), melanomas (8/9), AFX (3/3), LMS (3/3) and KS (4/4) with some expression in hemangiomas (3/10), while being negative in SSCC (0/1); and was significantly associated with tumor group (p = 0.017). Although a significant difference in overall survival was observed between SPARC expression groups (positive vs. negative) for all patients, there was no significant difference noted among angiosarcoma patients. Conclusion We have confirmed the presence of SPARC expression in melanoma, KS, LMS and AS and also detected it for the first time in AFX. Since paclitaxel has shown some effectiveness in AS, melanoma and KS, ABI-007 could also be beneficial in these patients.

The relative ranking of cirrhosis-related deaths differs between high-/middle-income countries. Gut microbiome is affected in cirrhosis and is related to diet. Our aim was to determine the effect of differing dietary habits on gut microbiota and clinical outcomes. Outpatient compensated/decompensated patients with cirrhosis and controls from Turkey and the United States underwent dietary and stool microbiota analysis. Patients with cirrhosis were followed till 90-day hospitalizations. Shannon diversity and multivariable determinants (Cox and binary logistic) of microbial diversity and hospitalizations were studied within/between groups. Two hundred ninety-six subjects (157 U.S.: 48 controls, 59 compensated, 50 decompensated; 139 Turkey: 46 controls, 50 compensated, 43 decompensated) were included. Patients with cirrhosis between cohorts had similar Model for End-Stage Liver Disease (MELD) scores. American patients with cirrhosis had more men, greater rifaximin/lactulose use, and higher hepatitis C/alcohol etiologies. Coffee intake was higher in Americans whereas tea, fermented milk, and chocolate intake were higher in Turkey. The entire Turkish cohort had a significantly higher microbial diversity than Americans, which did not change between their controls and patients with cirrhosis. In contrast, microbial diversity changed in the U.S.-based cohort and was the lowest in decompensated patients. Coffee, tea, vegetable, chocolate, and fermented milk intake predicted a higher diversity whereas MELD score, lactulose use, and carbonated beverage use predicted a lower microbial diversity. The Turkish cohort had a lower risk of 90-day hospitalizations. On Cox and binary logistic regression, microbial diversity was protective against 90-day hospitalizations, along with coffee/tea, vegetable, and cereal intake. Conclusion In this study of patients with cirrhosis and healthy controls from the United States and Turkey, a diet rich in fermented milk, vegetables, cereals, coffee, and tea is associated with a higher microbial diversity. Microbial diversity was associated with an independently lower risk of 90-day hospitalizations. (Hepatology 2018;68:234-247).

Angiosarcomas account about 2-3% of adult soft tissue sarcomas. This is a rare form of malignancy with remarkable clinical heterogeneity in term of presentation and behavior and can occur in any location of the body. Although radiation and chemotherapy are the usual form of therapy, frequent recurrence and metastasis is observed. The prognosis of angiosarcoma is relatively poor, and the overall 5-year survival rate is approximately 35%. Previous studies have shown the SDF-1 (stromal derived factor-1)/CXCR4 pathway is involved in the progression and the metastasis of angiosarcoma. CXCR4 is a chemokine receptor involved in metastatic spread of malignant tumors and is upregulated by many factors, including hypoxia and the histone methyltransferase EZH2. CXCR4 in turn activates the JAK/STAT3 pathway, which regulates the immune environment by inducing an infiltrate of tumor associated macrophages (TAMs) of the M2 (immunosuppressive) phenotype. Sarcomas in general have increased TAMs of the M2 phenotype and accumulating evidence indicates that a high number of TAMs are associated with an unfavorable prognosis in a variety of malignancies including angiosarcoma. The monocyte chemokine CCL2 has already been documented previously in canine hemangiosarcoma as one of the primary chemoattractants for M2 macrophages. The SDF-1/CXCR4 pathway has also been documented in other malignancies as a regulator of M2 macrophage infiltration and the immunosuppressive environment. It has also been reported that blockade of CXCR4 selectively reduces M2-polarized macrophages. We studied the expression of EZH2, p-STAT3, CXCR4, and CD163 (M2 macrophage marker), in four known cases of angiosarcoma. Two cases involved right lower leg soft tissue and two cases involved tissues from aortic wall. In all of our four cases the tumor cells of angiosarcoma stained positive for EZH2, p-STAT3, CXCR4, and CD163. This supports our hypothesis that indeed in angiosarcoma the M2 macrophages has an association with CXCR4 and pSTAT3. Clinical implications of this are that plerixafor or other CXCR4 antagonists could be used to treat angiosarcoma. By blocking CXCR4, the progression and metastasis of angiosarcoma could be abrogated and the immunosuppressive environment can be normalized. Our study indicates that CXCR4 could be considered a therapeutic target in angiosarcoma and the CXCR4 antagonist plerixafor should be further investigated as a potential agent to improve patient outcomes. Citation Format: Anindita Ghosh, Robert E. Brown, Joan M. Bull, Shaimaa M. Elzamly, Jamie J. Buryanek. CXCR4 as a therapeutic target in angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2692.

Soils with high rock content are common in many US forests, and contain large amounts of stored C. Accurate measurements of soil bulk density and rock content are critical for calculating and assessing changes in both C and nutrient pool size, but bulk density sampling methods have limitations and sources of variability. Therefore, we evaluated the use of small-diameter soil cores (SD), irregular soil volume excavation (IR), and a nuclear density gauge (ND) to measure bulk density and rock content, and estimate C and N pools in three 10-cm increments to a 30-cm depth in a glacial till soil in northern Wisconsin. Total and fine bulk densities were lower when measured with SD cores than with larger soil volume IR and ND methods. No differences in C pools among bulk density sampling methods were found in the 10-cm increments, but when combined to 30 cm, the C pool estimate with IR (81.6 Mg ha–¹) was significantly higher than those of ND (75.3 Mg ha–¹) and SD (73.4 Mg ha–¹). No significant differences in N pools were detected in the 10-cm increments, but the 0- to 30-cm N pool estimates by IR (5.65 Mg ha–¹) and ND (5 Mg ha–¹) were higher than that of SD (4.22 Mg ha–¹). Surface rocks could lower soil C and N pools by 20% or more. Overall, the bulk density method had little effect on soil C and N pool estimates in the surface 20 cm of this soil but did when sampled to 30 cm soil depth.

Post-wildfire soil erosion can be caused by water or aeolian processes, yet most erosion research has focused on predominantly water-driven erosion. This study investigates the effectiveness of three agricultural mulches, with and without a tackifier, on aeolian sediment transport processes. A wind tunnel was used to simulate post-wildfire wind erosion at three wind speeds (6, 11 and 18 m s−1). Shallow trays containing soil collected after a wildfire were treated with chopped rice, wheat or chopped wheat mulch; mulch treatments were also compounded with liquid treatments, tackifier to water ratios of 1:6, 1:3 and water. The mulch treatments were generally easily moved at all wind speeds with cover reductions greater than 90% at the highest wind speed. As expected, sediment loss was greatest for the bare soil treatment, ranging from 6.5 g m−2 at the lowest wind speed which increases to 6258 g m−2 at the highest wind speed. Adding wheat or chopped wheat mulch significantly reduced sediment loss by an order or magnitude (698 and 298 g m−2, respectively) at the highest wind speed. Adding chopped rice straw reduced sediment loss by a half to 3573 g m−2 at the highest wind speed, but the effect was not significant due to mobilization of the mulch. The most effective sediment loss mitigation was achieved with liquid tackifier treatments when applied to bare soil and when compounded with various mulch treatments, particularly at the highest wind speed. These results may aid management decisions when mitigating aeolian sediment transport after wildfires.

The recent ascendency of Trumpism calls for a historical review of nativist movements and the social appeal they gained. This article will focus on talk-radio and how it shaped and influenced the American psyche and became a cornerstone for conservatism. The article illustrates common themes between contemporary talk-radio hosts and previous antiprogressive figures. Understanding the success of Rush Limbaugh, which started in the late 1980s, created a whole social movement that ought to be analyzed in order to understand the current mood of Trumpism. The author draws from historical events and personal anecdotes to analyze the nativist sentiments that keep reemerging in the public discourse.

Crystal Storing Histiocytosis (CSH) is a rare entity occurring in association with underlying lymphoproliferative disorders and plasma cell neoplasms. It denotes accumulation of immunoglobulin crystals in the histiocyte cytoplasm. In this study, we report a patient with plasma cell myeloma who presented with bilateral comminuted femur fractures. Histological examination of fracture tissue revealed hypercellular (~100%) marrow with extensive involvement by sheets of histiocytes with abundant eosinophilic cytoplasm admixed with scattered plasma cells. Intracytoplasmic diamond and rhomboid crystals within histiocytes were demonstrated by electron microscopy. Immunohistochemistry highlighted monotypic plasma cells with kappa restriction, representing 20-30% of marrow cellularity; however, non-polarizable cytoplasmic striations in histiocytes were negative for light chain expression. A diagnosis of crystal-storing histiocytosis associated with plasma cell myeloma was rendered. Further evaluation of these macrophages is positive for CD163 and COX2 and shows pSTAT3 with variable nuclear staining in some histiocytes. This case demonstrates that numerous M2 macrophages are present as crystal storing histiocytosis; and this knowledge might convey prognostic and therapeutic significance for the patients with crystal storing histiocytosis.