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INTRODUCTION: Following resection of pancreatic acinar cell carcinoma (PACC) distant recurrence remains high. We utilized the national cancer database (NCDB) to evaluate the role of systemic therapy in early-stage resected PACC. METHODS: We queried the NCDB registry from 2004 to 2015 for patients with pathologic stage I-IIB PACC. For each stage, patients who underwent surgery alone (SA) were compared to patients who received systemic and/or radiation therapy in addition to surgery (surgery + therapy [S + T]). RESULTS: A total of 271 patients (101 pI, 81 pIIA, and 89 pIIB) were analyzed. Of all clinically node positive patients (n = 41), the majority (n = 32, 78%) had node-positive disease at resection (pIIB). SA was performed in 112 patients (41.3%), whereas 159 (58.7%) patients received S + T. There was no difference in overall survival (OS) between S + T and SA with respect to pI or pIIA disease. In pIIB disease, S + T was associated with improved OS compared to SA (34.9 vs. 16.9 months, p = 0.031). Single-agent chemotherapy was associated with improved OS for pIIB disease when compared to SA (hazard ratio: 0.38, 95% confidence interval: 0.16, 0.83). CONCLUSION: In resectable PACC, the survival benefit of adjuvant therapy is limited to pathologic stage IIB disease. This benefit is evident even in patients treated with single-agent chemotherapy.

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Background Lymph node involvement is a significant prognostic factor for melanoma. Both number of positive nodes and disease burden within a lymph node affects survival. However, the significance of few tumor cells within a single node and subsequent optimal management remains without consensus. We investigated the implications of minimal nodal disease on clinical outcomes. Methods We reviewed 752 patients who underwent lymph node sampling at time of primary melanoma resection at our institution over 15 years. We deemed patients who had 1 node with 1 to 4 atypical cells staining positive for either Melan-A or Sox-10 as having “picomets.” We examined the initial clinicopathological features, subsequent management, and outcomes. Results Thirty-three patients (4%) met criteria for having picomets. The most common number of positively staining atypical cells was 1 (n = 13). Nodal staging at initial pathology review varied, and overall stage ranged from IA to IIIC. Four patients underwent further therapy, none of whom had recurrent disease. Of the 29 patients undergoing observation/surveillance only, 5 had disease recurrence (17%). Conclusion Although patients with picomets had better outcomes than historical stage matched cohorts, a small subset had recurrent disease. Staging patients with picomets as “N0” may not reflect the true negative prognostic significance of picomets. A larger population of patients meeting picomets criteria is needed to draw further conclusions.

BackgroundIndividual response to immune checkpoint inhibition (ICI) in patients with metastatic melanoma varies from 10–40% for monotherapy and 50–60% with combination therapy [1]. Identification of adjuncts to ICI to further bridge treatment response to cure is imperative. We focus on caloric restriction (CR) as an adjunct to anti-PD-1 ICI given its inexpensive nature, relative ease of application, and increased tolerability as compared to fasting.Methods12-week C57BL/6J mice were inoculated with Yale University Mouse Melanoma (YUMM 1.7), randomized into diet groups and further randomized into αPD-1 and control (IgG) groups on day 12 (D12). Full diet mice ad lib fed while CR mice were 40% calorically restricted based on average daily food intake. Tumors were measured every 3 days with digital calipers (q3d). αPD-1 or control was intraperitoneally injected starting D12 continuing q3d for 7 injections. Mice were sacrificed and tumors harvested on D31. RNA sequencing was performed on CD45+ CD3+ T cells.ResultsUnder CR conditions, mice treated with αPD-1 had significantly smaller tumor volumes compared to the full diet cohort treated with αPD-1 (D22, 271.15 m3 vs. 336.72 m3, p=0.031) and persisted to harvest (D31, 600.96 m3 vs. 1039.84 m3, p=0.034). A significant difference in tumor volumes between CR αPD-1 and CR control treated cohorts was observed starting at D28 (439.34 m3 vs. 667.63 m3, p=0.005) and persisted to harvest (D31, 600.96 m3 vs. 884.08 m3, p=0.009). However, no significant difference in tumor growth under full diet conditions in murine cohorts treated with αPD-1 or control or separately between CR and full diet cohorts treated with control was observed.On pathway enrichment analysis inflammatory response, cytokine-mediated, response to interferon-gamma, and cell proliferation pathways were downregulated in the CR + αPD-1 cohort. Notable genes found in these pathways include B-cell linker protein (BLNK), tyrosine-protein kinase Lyn (LYN), SYK (spleen tyrosine kinase), toll-like receptor (TLR) TLR4, TLR7, and TLR8.ConclusionsCaloric restriction significantly sensitizes YUMM 1.7 murine melanoma to anti-PD-1 therapy resulting in decreased tumor growth. We show significant modulation of tumor growth in a murine tumor cell line, which has previously demonstrated limited response to αPD-1. In the present study, caloric restriction may decrease inflammation via downregulation of cytokine and toll-like receptor mediated pathways. Furthermore, caloric restriction may reverse the immunosuppressive tumor microenvironment and provide an inexpensive means to increase treatment response to anti-PD-1 therapy.ReferencesWard WH, Farma JM. Cutaneous Melanoma: Etiology and Therapy. Brisbane (AU): Codon Publications. 2017; Chapter 8.Ethics ApprovalThis study was approved by the University Committee on Animal Resources (UCAR), UCAR-2018-014.

Background Medical literature states that a global longitudinal strain rate (GLS) Purpose To analyze the sensitivity (S) and specificity (Sp) of GLS Methods Patients were prospectively assessed with a cardiac echoDoppler + GLS at baseline, every 3 months during the first year and every 4 months thereafter. We assessed the S and Sp of GLS 10%, >15% and >20% reduction form baseline after treatment with A with or without T as predictors of cardiotoxicity (defined as a >10 percentage points decrease of left ventricular ejection fraction to a value below the lower normal limit with respect to baseline). Results 136 out of 884 patients (16%) had GLS measured at each visit: 83 patients (60%) and 53 patients (40%) treated with A or A+T respectively. Patients were followed up to 31±6 months. Mean age was 51±12 years. The table shows the baseline characteristics of both groups. 10 out of 83 patients in group A (12%) and 18 out of 53 P in group A+T (34%) developed cardiotoxicity. Baseline left ventricular ejection fraction and GLS were 61±4,7% and −20,18±2,6% in group A, and 58,7±5,8% and −19,5±2,6 post treatment. In this group, GLS S and Sp were 50 and 80%, respectively. In the group A+T, the best GLS cutoff was −19%, with a 60% sensitivity and 78% specificity. Conclusions In our non-selected cohort of patients, nor GLS or its percentage reductions along follow up predicted the reduction of left ventricular ejection fraction and the developing of cardiotoxic ventricular dysfunction in breast cancer patients receiving adjuvant treatment with A with or without T. The systematic use of this tool should be further investigated and validated at each center to help establish its usefulness in daily practice. Funding Acknowledgement Type of funding sources: None. Baseline characteristics

Background There is overwhelming volume of confirmed cases of COVID-19, despite this numerous knowledge gaps remain in the diagnosis, management, and prognostication of this novel coronavirus infection, making prevention and control a challenge. Methods This retrospective cohort study included patients with real-time reverse transcriptase polymerase chain reaction (rRT-PCR)-confirmed COVID-19. Binary logistic regression was used to determine the association between the cardiac biomarkers and in-hospital mortality. ROC, AUC, and cutoff analyses were used to determine optimal cutoff values for the cardiac biomarkers. Results A total of 90 subjects with a complete panel of cardiac biomarkers out of the 224 rRT-PCR confirmed cases were included. The median age was 57 years (IQR, 47–67 years), majority were males. Sixty-six (77.6%) subjects survived while 19 (22.4%) expired. The most common presenting symptom was fever (75.6%), and the most common comorbidity was hypertension (67.8%). Spearman rho correlation analysis showed moderate positive association of high sensitivity troponin I (hsTnI) with in-hospital mortality (R, 0.434, p = Conclusion High sensitivity troponin I level was a good tool with a very high negative predictive value in significantly predicting in-hospital mortality among rRT-PCR positive COVID-19 patients. Funding Acknowledgement Type of funding sources: None. ROC Curve

Adoptive cell therapy (ACT) with tumor-infiltrating T cells (TILs) has emerged as a promising therapy for the treatment of unresectable or metastatic solid tumors. One challenge to finding a universal anticancer treatment is the heterogeneity present between different tumors as a result of genetic instability associated with tumorigenesis. As the epitome of personalized medicine, TIL-ACT bypasses the issue of intertumoral heterogeneity by utilizing the patient’s existing antitumor immune response. Despite being one of the few therapies capable of inducing durable, complete tumor regression, many patients fail to respond. Recent research has focused on increasing therapeutic efficacy by refining various aspects of the TIL protocol, which includes the isolation, ex vivo expansion, and subsequent infusion of tumor specific lymphocytes. This review will explore how the therapy has evolved with time by highlighting various resistance mechanisms to TIL therapy and the novel strategies to overcome them.

Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance.

Introduction: First line anti-PD-1 immune checkpoint inhibition (αPD-1 ICI) induces objective responses in less than 50% of metastatic melanoma patients. Aspirin (ASA) use is associated with improved responsiveness to ICI, with inhibition of myeloid-induced immunosuppression in the tumor microenvironment (TME) a purported mechanism. Cyclooxygenase modulators ASA (pharmacologic inhibitor) and dietary fish oil (FO, substrate) shift myeloid and T cell populations to anti-inflammatory, pro-resolution phenotypes in immunity and cancer. Methods: C57-BL6/J mice were injected with YUMM 1.7 melanoma in the flank. Mice were fed control chow and water (CTL) or omega-3 rich (FO) chow (10% w/w, 30%kcal/kcal), given ASA in drinking water (600 ug/mL), or FO/ASA combined (COMBO) starting 12 days post tumor implantation, the same day as starting intraperitoneal αPD1 or IgG2a vehicle (q3-4 days). An alternative cohort received pre-αPD-1 treatment ASA and FO starting day 7. Tumors were assessed for growth, harvested, and characterized via flow cytometry on day 32. Results: When diets and water were started concurrent with αPD-1/IgG2a, FO decreased tumor volume vs. CTL for both vehicle (28%) and αPD-1 (27%) treatments; ASA and COMBO (p = 0.0501) did not. Compared to CTL, FO and COMBO increased monocytes (CD45+, CD11b+, Ly6C+, Ly6G-) and PD-L1+ monocytes in the TME with no effect on tumor associated macrophages (TAMS); ASA decreased the percent of Arginase 1+, CD206+ TAMs. ASA increased PD1+ CD8 T cells, while COMBO increased CD4 and CD8 T cells including LAG3+ and PD1+ CD8 T cells. When diets and water were started on day 7, FO + αPD-1 decreased tumor volume (21%) vs. αPD-1 controls; ASA and COMBO did not. Compared to CTL, FO and COMBO similarly altered immune populations as above, with FO additionally increasing total CD3+ T-cells, PD-L1+ CD4 T cells, and PD-1+ CD8 T cells; COMBO increased dendritic cells (CD11c+, MHCII+, F4/80-). TAMS were not assessed. Results significant (p< 0.05) by ANOVA or t-test unless specified. Food eaten, water imbibed, and weight did not vary between groups. Conclusions: Dietary fish oil impaired in vivo melanoma tumor growth with and without αPD-1 ICI despite increases in classically deleterious monocyte populations, while aspirin decreased M2-like macrophages in the TME without alterations in tumor growth. Modulation of the cyclooxygenase axis may be a cost-effective method to skew TME immune populations to favor αPD-1 immunotherapy responses in metastatic melanoma. Citation Format: Alexander C. Chacon, Shuyang S. Qin, Alexa D. Melucci, Katherine M. Jackson, Paul R. Burchard, Yatee A. Dave, Rachel Jewell, Brian A. Belt, William Tabayoyong, David C. Linehan, Peter A. Prieto. Dietary fish oil and aspirin to augment anti-PD-1 immunotherapy in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 254.

PD-1 (programmed cell death protein-1) blockade, an immunotherapy that re-stimulates antitumor CD8 T cell response, has revolutionized the treatment of metastatic melanoma. However, the majority of melanoma patients eventually acquire therapy resistance. The emergence of resistant metastases likely results from de novo somatic mutations secondary to inherent tumor genetic instability. We hypothesize that intertumoral genetic differences introduce immunosuppressive mechanisms, such as inducing myeloid-derived suppressor cell differentiation, that dampen existing antitumor immune responses. As all metastases share one host immune system, we investigated the local and systemic effects of intertumoral heterogeneity on antitumor immunity and PD-1 immunotherapy response in mice with multiple, synchronous melanoma metastases. To recapitulate intertumoral heterogeneity, we simultaneously injected PD-1 blockade-resistant YUMM 1.7 and its UVB-irradiated, PD-1 sensitive, derivative YUMMER 1.7 melanoma cell lines into opposite flanks of the same C57BL/6J mouse. We previously demonstrated that tumor-specific de novo somatic mutations, in combination with the host immune response, generate distinct microenvironments in synchronous YUMMER (immunologically active) and YUMM (immunologically inactive) tumors. Our novel murine synchronous melanoma model demonstrated that the presence of immunologically inactive YUMM tumors changes systemic antitumor immunity, including the induction of host splenic myelopoiesis. This phenomenon is accompanied by an increase in YUMMER intratumoral M-CSF (macrophage colony stimulating factor) concentration and an influx of immunosuppressive PD-L1+ (PD-1 ligand) macrophages into YUMMER tumors as assessed by flow cytometry and Luminex analyses. Furthermore, compared to control CD8 T cells, synchronous YUMMER-infiltrating CD8 T cells exhibit reduced functionality, with increased surface PD-1 persistence and failure to respond to PD-1 blockade. As a result, the presence of YUMM tumors are able to confer PD-1 blockade resistance to the normally PD-1 sensitive YUMMER tumors. Our results suggest that intertumoral heterogeneity leads to a “reverse abscopal effect,” where immunologically “cold” tumors can alter systemic myeloid immune responses to suppress antitumor CD8 T cell function in immunologically “hot” tumors. As such, the addition of myeloid-altering agents to PD-1 immunotherapy are likely to improve treatment efficacy and prevent acquired therapy resistance in patients with metastatic melanoma. Citation Format: Shuyang S. Qin, Booyeon J. Han, Alexander C. Chacon, Alexa D. Melucci, Alyssa R. Williams, Rachel Jewell, Minsoo Kim, David C. Linehan, Scott A. Gerber, Peter A. Prieto. "Reverse abscopal effect": Immunologically cold tumors alter systemic immunity and confer PD-1 resistance to immunologically hot tumors in synchronous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1605.

e21564 Background: Less than half of metastatic melanoma patients experience objective responses to first line anti-PD-1 immune checkpoint inhibition (αPD-1 ICI). Omega-3 fatty acids in dietary fish oil (FO) shift myeloid and T-cell populations to anti-inflammatory, pro-resolution phenotypes in immunity and cancer. We investigated whether dietary FO supplementation could augment tumor microenvironment (TME) immune profiles and improve ICI response in melanoma. Methods: C57-BL6/J mice were injected with YUMM 1.7 melanoma in the flank. Mice were fed control chow (CTL) or omega-3 rich (FO) chow (10% w/w, 30%kcal/kcal) starting 7 days post tumor implantation. Intraperitoneal αPD1 or IgG2a vehicle were injected q3-4 days starting day 12. To assess the temporal flux of TME immune populations, tumors from mice in analogous experiments were assessed for growth, harvested on day 12, day 22, or day 32, and characterized via flow cytometry. Results: In multiple models, FO decreased YUMM tumor growth vs. CTL by day 32 (> 21% for all models). FO halved tumor associated macrophage content, including M2 macrophages (Arg1+, CD206+, CD68+, F480+), at day 12. Conversely, FO increased M2 macrophages at day 22, leveling even with CTL at day 32. At all three timepoints, FO increased TME monocytes (Ly6C+, Ly6G-). In the T cell compartment, FO decreased TME CD4 and CD8 T cell content (including PD1+ CD4 and PD1+ CD8) at day 12, an effect which was reversed by day 22 (increased CD4 and CD8s vs CTL). FO increased PD-L1+ CD4 T cells and CD8+ T cells, including PD1+ CD8 T cells, on day 32. When fish oil diets were started on day 12 (concurrent with immunotherapy), FO decreased tumor volume, increased monocytes (and PD-L1+ monocytes), and increased CD4 and PD1+ CD8 T cells by day 32, all less significantly than when starting diets 5 days prior to initiation of immunotherapy. All results significant (p < 0.05) by 2-way ANOVA or t-test unless specified. Food eaten, water imbibed, and weight change did not vary between groups. Conclusions: Fish oil impairs in vivo murine melanoma tumor growth with and without αPD-1 ICI. Fish oil modulated myeloid and T cell lineages via delaying M2 macrophage and CD4 / CD8 T-cell appearance in the tumor microenvironment, with concomitant increases in monocytes and key T cell effectors involved in αPD-1 ICI responsiveness by the time decrements in tumor growth were noted. Dietary fish oil may benefit patients with advanced melanoma treated with αPD-1 immunotherapy; further study in humans is warranted.

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

606 Background: Standard of care for early-stage resectable pancreatic cancer (PC) includes a combination of surgical resection and chemotherapy. Frequently, CA 19-9 is used as a biomarker to monitor treatment effect and has prognostic significance. We evaluated the impact of CA 19-9 on overall survival (OS) in patients with clinical stage I PC (cT1N0 and cT2N0) utilizing the National Cancer Database (NCDB). Methods: The NCDB was queried between 2010 and 2014 to identify patients with clinical stage I PC. Patients who had missing or undocumented CA 19-9 value at diagnosis were excluded. Demographic and clinical characteristics were analyzed. Patients were stratified into two cohorts based on the CA 19-9 value at diagnosis – CA 19-9 < 98 U/mL and CA 19-9 > 98 U/mL. Univariable and multivariable analyses were performed, and variables associated with OS were identified. Kaplan-Meier survival curves were computed to compare the OS between the two cohorts. Results: A total of 12,480 patients met our inclusion criteria. A majority of patients were female (51.9%), white (84.4%), with a median age of 70 years. Nearly, half the patients received care in an academic/research program (49.5%). A majority of patients had tumors located in the head of the pancreas (71.9%), and received single-agent (35.1%) or multiagent (22.9%) chemotherapy. Over half the patients (6505 patients, 52.1%) had a CA 19-9 value > 98 U/mL. A CA 19-9 value > 98 U/mL in patients predicted a significantly shorter median OS of 12.1 months compared to 19.4 months in patients with a CA 19-9 < 98 U/mL, p 98 U/mL compared to a 5-year OS rate of 18.1% for patients with a CA 19-9 value < 98 U/mL. On multivariable analysis, CA 19-9 > 98 compared to CA 19-9 < 98 (HR 1.53, p

The number of overdose deaths are on the rise all over the world. An estimate of 93,000 drug overdose deaths have been estimated in the United States in 2020. COVID-19 pandemic has exacerbated the drug crisis. Factors, such as existing health disparities among underserved communities, lack of resources for people of color, lack of belief in available resources, social isolation and economic burden, limited access to treatment, regulatory barriers in telehealth, and stress from the on-going COVID-19 pandemic have been identified as some of the key factors behind the acute health effects of people with substance use disorder. These interrelated factors exacerbate the impact of already existing disparities in the underserved communities. Policy and regulatory changes around telehealth and access of treatment for substance use disorder are warranted. Evidence-based strategies and other safer drug practices should be implemented to mitigate the impact on human health. Investment in programs that increase access to treatment, will be useful for potential future pandemics, where increasing mental health services and overall access to healthcare in disadvantaged communities would lessen the disparities in physical and mental ailments. In this review, we are evaluating and summarizing the acute health effects of the ongoing COVID-19 pandemic on individuals with substance use disorder.

BackgroundDespite recent advancements in systemic therapy, only a minority of metastatic patients develop meaningful clinical responses to immune checkpoint inhibitors. Inherent genetic instability of melanoma generates genomically and microenvironmentally distinct metastases. These different tumor microenvironments (TMEs) contain numerous T cell suppression mechanisms, such as upregulation of the PD-1/PD-L1 exhaustion pathway. However, as synchronous metastases share one host immune system, intertumoral heterogeneity may result in increasing cross-talk between metastases that impairs systemic antitumor immunity and promotes PD-1 immunotherapy resistance.MethodsYUMM 1.7 (less immunogenic) and YUMMER 1.7 (more immunogenic cell line derived from YUMM following UVB irradiation) melanoma cell lines were simultaneously injected into opposite flanks of the same mice as a model of synchronous melanoma. We assessed tumor growth in wildtype, interferon-gamma (IFN-γ) knockout, and CD8-depleted mice as well as in response to PD-1 inhibitor. We characterized the TME with flow cytometry and performed TCR sequencing on tumor-infiltrating CD8 T cells.ResultsDistinct TMEs were observed for YUMM and YUMMER tumors simultaneously grown in the same mouse. The presence of the less immunogenic YUMM tumor allows the more immunogenic YUMMER tumors to escape IFN-γ and CD8 T cell-mediated rejection, despite abundant tumor-infiltrating, clonally expanded CD8 T cells. Identical immunodominant CD8 T cell clones were found in both YUMM and YUMMER tumors within the same mouse. Synchronous YUMMER-infiltrating CD8 T cells exhibit suppressed phenotypes, including increased persistence of surface PD-1 and decreased surface CD107a expressions. Simultaneously, these synchronous YUMMER tumors additionally upregulate macrophage surface PD-L1 expression, which potentially contributes to tumor immune escape. Lastly, synchronous YUMMER tumors become resistant to PD-1 inhibition, in direct contrast to control YUMMER tumors.ConclusionsIn a host with multiple melanoma lesions, immunogenicity of all tumors contribute to the systemic antitumor immune response. We show that two synchronous tumors with synonymous mutations (AcknowledgementsWe would like to thank Dr. Marcus Bosenberg from the Department of Dermatology at Yale University for kindly gifting us with the YUMMER 1.7 murine melanoma cell line.Ethics ApprovalAnimal experiments were approved by the University Committee on Animal Resources and performed in accordance with University of Rochester approved guidelines.

BackgroundOnly 30–40% of metastatic melanoma patients experience objective responses to first line anti-PD-1 immune checkpoint inhibition (αPD-1 ICI). Cyclooxygenase (COX-1/2) inhibition with aspirin (ASA) and other non-steroidal anti-inflammatory drugs has been associated with prolonged time to recurrence and improved responsiveness to ICI in human melanoma,1 with inhibition of myeloid-induced immunosuppression in the tumor microenvironment (TME) a purported mechanism.2 Similarly, dietary omega-3 fatty acids metabolized by COX-2 elicit downstream effects on T-cell differentiation akin to ASA administration, abrogating murine melanoma and human breast cancer progression. Mechanisms of ICI resistance remain unclear, and adjunct therapies look to bridge the gap from current response rates to cure.MethodsYUMM 1.7 melanoma cells were injected into flanks of C57-BL6/J mice. Mice were fed control diets or supplemented with omega-3 rich fish oil (FO) chow (10% weight/weight, 30%kcal/kcal), ASA in drinking water (ASA, LO – 300, MED – 600, HI - 1000 ug/mL), or the combination of these agents (COMBO, with ASA-MED) starting at day 7 post tumor implantation. Intraperitoneal αPD1 was administered every 3–4 days starting at day 12. Tumors were assessed for growth, harvested at day 32 (day 26 for ASA LO/HI), and characterized with flow cytometry. All significant results (pResultsFO resulted in lesser tumor volume at day 32 in αPD-1 treated mice, while ASA-HI resulted in lesser tumor volume in mice not treated with αPD-1 but did not synergize with αPD-1. ASA-MED and COMBO groups trended towards decreased tumor size (p = 0.07 and 0.07 respectively) by day 32 in αPD-1 treated mice. FO and COMBO increased total CD3+ T-cells and monocytes (CD45+, CD19-, CD11b+, Ly6C+, Ly6G -) in the TME. FO increased PD-L1 + CD4+ T-cells, while COMBO increased total CD8+ T-cells and PD1+ CD8+ T-cells. ASA-HI increased monocytes and the proportion of PD-1+, CD8+ T-cells in the TME.ConclusionsMyeloid-induced suppression of T-cell function in tumors may contribute to immune checkpoint inhibition resistance. In the present study, both fish oil and aspirin altered melanoma tumor growth, with only fish oil synergizing with anti-PD-1 at the doses assessed. Both fish oil and aspirin augmented monocyte populations in the tumor microenvironment, with differential effects on T-cell populations. The partially synergistic mechanism between substrate-limited (FO) and pharmacologic (ASA) inhibition of cyclooxygenase-2 may provide a cost-effective avenue to combat immune escape in melanoma patients treated with anti-PD-1 immune checkpoint inhibition, requiring further investigation in humans.ReferencesWang SJ, et al. Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer. J Immunother Cancer 2020;8(2).Zelenay S, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 2015;162(6):1257–70.

3601 Background: A minimum of 12 lymph nodes are required during colectomy to accurately stage colon cancer. Prior studies in stage II colon cancer patients demonstrate association of inadequate lymph node examination (LNE) with worse overall survival (OS). No large-scale analogous studies related to LNE have been completed in stage I colon cancer patients. We evaluated patients with stage I colon cancer to determine the association between lymph node yield and OS. Methods: We reviewed the National Cancer Database between 2004-2015 to identify patients with pathologic stage I colon cancer (pT1N0 or pT2N0) who underwent definitive surgical resection. Patients who received radiation therapy or had missing values were excluded. Clinical and demographic characteristics were analyzed. Based on LNE, patients were stratified into 4 cohorts (LNE, 0-5, 6-11, 12-19, 20+) and 2 cohorts (0-11, 12+). Univariable and multivariable analyses were performed to identify variables associated with OS. Kaplan-Meier survival curves were computed to compare the cohorts. Results: We included 81,909 patients for analyses. Median age at diagnosis was 69. A majority were female (51.1%), white (83.8%), received care in a community cancer program (59.5%), and had a Charlson-Deyo score of 0 (66.6%). Only 0.7% of patients had a margin positive resection with a 2.5cm median tumor size. Patients were similarly split between pT1 and pT2. Suboptimal LNE was noted in 27.8% of patients. Patients with LNE were distributed - 10.7% (0-5), 17.1% (6-11), 43.4% (12-19) and 28.9% (20+). Postoperative 30-day mortality was 1.9%. 521 (0.7%) received systemic therapy. Ten-year survival in patients with 0-5 LNE was 52.8% compared to 60.1% with 20+ LNE. On multivariable analyses, patients aged ≥ 69, male sex, increasing tumor size (quartile), pT2 staging and a higher Charlson-Deyo score independently predicted worse OS (p < 0.001). LNE categories were significantly associated with OS (p < 0.001) (Table). On regrouping into 0-11 and 12+ LNE groups, 0-11 LNE group predicted worse OS (HR 1.22, p < 0.001). On multivariable analysis, the above variables continued to show similar association with OS (p < 0.001). Conclusions: Our study demonstrates that lymph node yield is associated with overall survival in patients with stage 1 colon cancer undergoing surgical resection. Furthermore, patients with suboptimal lymph node yield are associated with an inferior overall survival compared to those with optimal lymph node yield. Moreover, this study finds that a large number of patients ( > 25%) continue to have suboptimal lymph node yields. Future efforts should focus on improving the lymph node yield with optimal efforts by the surgeon and pathologist. Future studies should examine the role of systemic therapy in patients with inadequate lymph node yield.[Table: see text]

Simple Summary Metastatic melanoma patients may present with multiple, simultaneous metastases that are genetically different. This intertumoral heterogeneity can cause these tumors to respond differently to the same systemic therapy. Progression of any one tumor, even when others regress, eventually leads to therapy termination. The mechanism underlying these mixed responses remains unknown due to a lack of clinically representative animal models. In a novel murine model of synchronous melanoma that recapitulates human intertumoral heterogeneity, we show that intertumoral genetic heterogeneity leads to the simultaneous generation of distinct tumor immune microenvironments within the same mouse. Furthermore, each tumor can independently regulate local PD-1 (programmed cell death protein 1) and PD-L1 (PD-1 ligand) expressions, an immunosuppressive axis targeted by popular checkpoint immunotherapies. This model is useful for furthering the study of intertumoral heterogeneity and of lesion-specific therapeutic responses. Abstract Metastatic melanoma portends a poor prognosis and patients may present with multiple, simultaneous tumors. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond, or exhibit lesion-specific responses wherein some metastases respond as others progress within the same patient. While intertumoral heterogeneity has been clinically associated with these mixed lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates this intertumoral genetic and microenvironmental heterogeneity. We show that genetic differences between tumors are sufficient to generate distinct tumor immune microenvironments (TIME) simultaneously in the same mouse. Furthermore, these TIMEs lead to the independent regulation of PD-1/PD-L1 (programmed cell death protein 1/PD-1 ligand), a popular axis targeted by immune checkpoint therapy, in response to ongoing anti-tumor immunity and the presence of interferon-gamma. Currently, therapeutic selection for metastatic melanoma patients is guided by a single biopsy, which may not represent the immune status of all tumors. As a result, patients can display heterogeneous lesion-specific responses. Further investigations into this synchronous melanoma model will provide mechanistic insight into the effects of intertumoral heterogeneity and guide therapeutic selection in this challenging patient population.

Background: Resistance to BRAF V600E inhibitors (dabrafenib) and MEK inhibitors (trametinib) occurs in 6-8 months in the majority of melanoma patients with the target V600E mutation. For this reason, combination targeted therapy (TT) offers reliable but often non-durable responses. A translatable model exhibiting de novo resistance to TT with response to checkpoint inhibition (ICB) may offer an avenue for exploring mechanisms of TT resistance, responses in combined TT/ICB, and modes of treatment salvage. Methods: C57/BL6J mice flanks were injected with Yumm 1.7 melanoma. After 14 days, mice were subjected to TT with dabrafenib/trametinib chow. A select few tumors (3/40) exhibited resistance to TT. Tumors from resistant mice were harvested, morcellized, and cultured to isolate a Yumm 1.7 cell line (Y1.7 BrafR) with a resistant phenotype and passaged to ensure uniform clonality. Y1.7 BrafR was assessed for growth characteristics, morphology, and response to dabrafenib/trametinib in vitro. In a synchronous mouse melanoma model, Yumm 1.7 and Y1.7 BrafR were injected into opposing flanks, allowed 14 days growth, and mice were subjected to either TT, ICB (aPD-1/aCTLA-4 combined therapy), TT + ICB, or vehicle for 5 days. Results: Y1.7 BrafR exhibited in vitro resistance to dabrafenib at 0.1, 1, and 10uM after 72 hr exposure (12%, 32%, and 47% growth depletion vs untreated cells, Yumm 1.7 with 67%, 61%, and 84%). This effect was not noted with trametinib except at 10uM (84% vs 92% growth depletion). Both lines succumbed to combination TT of varying doses by 72 hours. Y1.7 Braf R exhibits a doubling time of 18.14 hr vs. 12.35 hr for Yumm 1.7, with no appreciable differences in morphology on 40x light microscopy, as both lines extend dendritic processes while forming dense nests. Despite slower in vitro growth, Y1.7 BrafR exhibits markedly greater growth in vivo after 14 days incubation and 5 days treatment (1.16 v 0.44 cm^3 in vehicle mice), with less response to TT chow (51% tumor volume depletion from vehicle vs. 90% in Yumm1 .7) and TT/ICB (data not shown) and greater response to ICB (15% volume depletion vs 24% volume increase in Yumm 1.7). All data are statistically significant (2-tail t-test, p Conclusions: Our results show the development of a TT-resistant mouse melanoma model. This model is clinically relevant for patients who have initially potent, but non-durable responses to TT. Future studies will focus on mechanisms of dabrafenib resistance, tumor nutrition and metabolism, modes of salvage, and efficacy of T-cell recruitment to the tumor microenvironment in this de novo TT-resistant line. Citation Format: Alexander Chacon, Katherine Jackson, Shuyang Qin, Alyssa Williams, Rachel Jewell, Peter Prieto. Development of a translatable targeted therapy-resistant melanoma model [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO029.

Scope Mild dietary zinc (Zn) deficiency is wide-spread in human populations, but the effect on Zn-dependent processes of immune function and healing are not well understood. The consequences of mild dietary Zn restriction were examined in two mouse models of inflammation and recovery. Methods and results Male C57BL/6 mice were fed a Zn adequate diet (ZA, 30 mg Zn/kg diet), or diets containing sub-optimal Zn levels (ZM, 15 mg Zn/kg diet; ZD, 10 mg Zn/kg diet) for 30 days before a thioglycollate peritonitis challenge. Plasma lipid profiles were distinct, with greater Zn restriction resulting in a greater impact on metabolites. The milder ZM diet was selected for immune studies. Peritoneal macrophages from ZM mice displayed increased phagocytosis and amplified pro-inflammatory cytokine (IL-1β, IL-6, and TNFα) release compared to ZA, at baseline and after a secondary LPS challenge. Splenocytes isolated from ZM mice displayed an increase in IL-6 and a reduction in anti-inflammatory IL-4 compared to ZA. Cytokine levels in plasma were unaltered. Following mechanical manipulation of the intestines to induce ileus, ZM mice had delayed intestinal transit compared to ZA. Conclusion Mild Zn deficiency enhances local inflammatory responses, amplifying macrophage functions and delaying recovery from acute insults within the peritoneum.

Restoration of joint stability during total shoulder arthroplasty can be challenging in the face of severe glenoid retroversion. A novel technique of humeral head component anterior-offsetting has been proposed to address posterior instability. We evaluated the biomechanical benefits of this technique in cadaveric specimens. Total shoulder arthroplasty was performed in 14 cadaveric shoulders from 7 donors. Complementary shoulders were assigned to either 10° or 20° glenoid retroversion, with retroversion created by eccentric reaming. Two humeral head component offset positions were tested in each specimen: The anatomic (posterior) and anterior (reverse). With loads applied to the rotator cuff and deltoid, joint contact pressures and the force and energy required for posterior humeral head translation were measured. The force and energy required to displace the humeral head posteriorly increased significantly with the anterior offset position compared to the anatomic offset position. The joint contact pressures were significantly shifted anteriorly, and the joint contact area significantly increased with the anterior offset position. Anterior offsetting of the humeral head component increased the resistance to posterior humeral head translation, shifted joint contact pressures anteriorly, and increased joint contact area, thus, potentially increasing the joint stability in total shoulder arthroplasty with simulated glenoid retroversion.

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample., Latin Americans trace their ancestry to the admixture of Native Americans, Europeans and Sub-Saharan Africans. Here, the authors develop a novel haplotype-based approach and analyse over 6,500 Latin Americans to infer the geographically-detailed genetic structure of this population.

19 Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths, with the incidence expected to rise in the coming years. Despite conventional chemotherapy and advances in immune checkpoint blockade, 5 year survival remains a dismal 8%. Intratumoral accumulation of granulocytic myeloid derived suppressor cells (G-MDSC) pose a significant barrier to treatment as they contribute to immune evasion by PDAC and correlate with poor prognosis. The ELR+ CXC chemokine receptors CXCR1 and CXCR2 (CXCR1/2) contribute to peripheral neutrophil migration into tissues and have been implicated in tumor mediated G-MDSC recruitment to the tumor microenvironment. Here we present our findings using an orally dosed CXCR1/2 inhibitor, SX-682, in an orthotopic PDAC model. Methods: C57BL/6 mice underwent orthotopic injections with KP2 cells. Mice were randomized into five groups (Table) receiving three weeks of FOLFIRINOX with combinations of SX-682 and/or checkpoint inhibition (anti-PD1/anti-CTLA4). FOLFIRINOX was dosed weekly for three weeks. Checkpoint inhibition was administered twice weekly. Chow weights were monitored for consumption of SX-682. Results: The simultaneous administration of FOLFIRINOX with SX-682 combined with checkpoint inhibition (triple therapy) resulted in a significant increase in survival compared to other groups (p = 0.0001). Notably, there was a significant increase in survival with triple therapy versus FOLFIRINOX plus checkpoint alone (p = 0.0259). Median survival of the triple therapy group was 42.5 days, compared to 37 days with checkpoint inhibition (p =

565 Background: Cholangiocarcinoma (CCA) is the second most common primary liver malignancy, with increasing incidence. Currently, surgical resection offers the only chance for cure, however the prognosis remains poor in part due to high rates of unresectability, recurrence, and poor response to conventional therapy. Thus, new systemic therapies represent an unmet medical need. Few preclinical models exist for identifying and testing new targeted or immune based therapies. Here we present our findings of the immune infiltrate in human CCA tumor microenvironment (TME) and a spontaneous murine model that faithfully recapitulates human disease. Methods: Histology and immunohistochemistry (IHC) staining was performed on human CCA and adjacent normal liver. Mice with targeted hepatic Kras activation and loss of p53 (KPPC) spontaneously develop CCA. KPPC hepatic tumors and normal livers from littermate controls underwent histological and gene expression studies. Flow cytometric analysis was performed on bone marrow, spleen, peripheral blood, CCA tumors and normal littermate livers. Results: Digital IHC quantification of archival human CCA specimens demonstrated elevated levels of CD15+CXCR2+ granulocytic myeloid derived suppressor cells (G-MDSC) compared to adjacent normal liver (p = < 0.05). In addition, the CXCR2 ligand, CXCL5, was significantly elevated in CCA tumors compared to adjacent normal liver. In KPPC mice, flow cytometric analysis of hepatic tumors showed an abundance of CD45+ leukocytes comprised of immunosuppressive G-MDSC vs normal littermate controls (p = 0.0007) which recapitulates human disease. qRT-PCR demonstrated significantly increased expression of G-csf, Csf1, Cxcl1, Cxcl2, and Cxcl5 (p = < 0.0001) in CCA KPPC tumors compared to normal livers. Accordingly, granulocytes in KPPC mice were elevated in both the bone marrow and blood compared to normal littermate controls. Conclusions: These data suggest CCA co-opts the ELR+ cytokine/CXCR2 axes to mobilize and recruit immunosuppressive G-MDSC to the TME. Targeted therapy against tumor infiltrating neutrophils can be tested in this pre-clinical model to inform clinical translation.

Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality, with dismal 5-year prognosis of 8%, in part due to poor response to available therapies. Thus, new systemic cancer control therapies are in dire need. Semaphorin 4D (SEMA4D) is a soluble and membrane bound glycoprotein that binds its cognate Plexin B1/B2 receptors, expressed on monocytic and granulocytic leukocytes. Prior work has shown that increased expression of SEMA4D and Plexin B in resected PDAC patients is associated with lymph node and distant metastasis, as well as a worse prognosis. Additionally, SEMA4D blockade has conferred improved immune checkpoint blockade response in murine models of colorectal carcinoma and head and neck squamous cell carcinoma via abrogation of myeloid-derived suppressor cell recruitment and function, as well as enhanced T-cell recruitment and activity within the tumor microenvironment. Here we study the effects of SEMA4D blockade in a murine model of PDAC. Methods: C57b/6 mice were orthotopically injected with murine PDAC line (KP2) derived from KRASG12D,TP53Flox/Wt;P48-Cre autochthonous tumors. Mice were treated with Folfirinox (5-FU, irinotecan, oxaliplatin, weekly), immune checkpoint blockade (ICB) (anti-PD1, anti-CTLA-4 mAbs bi-weekly), and anti-SEMA4D mAB (biweekly). Peripheral blood and tumor-infiltrating leukocytes from patients with PDAC undergoing pancreaticoduodenectomy were assessed for Plexin B1 via flow cytometry. Results: Human PDAC demonstrates penetration of Plexin B1 positive leukocytes, most notably tumor-associated macrophages, neutrophils, and monocytes. Mice injected with KP2 developed tumors detectable via high-frequency ultrasound and exhibited longer survival when treated with the combination of Folfirinox, ICB, and anti-SEMA4D antibody, compared to Folfirinox alone, Folfirinox plus ICB, or Folfirinox plus anti-SEMA4D antibody. Conclusions: Plexin B1+ myeloid subsets penetrate human PDAC tumors, and treatment with SEMA4D-blocking antibody improved response to ICB in combination with standard-of-care Folfirinox in preclinical murine studies. Future work will focus on understanding the immune mechanism of improved therapeutic response, as well as further characterization of the prevalence and prognostic ramifications of the SEMA4D-Plexin B axis in PDAC. Citation Format: Luis I. Ruffolo, Katherine M. Jackson, Nicholas Ullman, Alexander Chacon, Alexa Melucci, Paul Burchard, Mary Georger, Rachel Jewell, Peter Prieto, Brian Belt, Crystal Mallow, Elizabeth Evans, Terrence Fisher, Maurice Zauderer, Christina Wu, Brian Olson, Gregory B. Lesinski, David C. Linehan. Targeting the semaphorin 4D-plexin B axis to augment FOLFIRINOX in a murine model of pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B48.

The understanding of orbital hybridization and spin polarization at the organic-ferromagnetic interface is essential in the search for efficient hybrid spintronic devices. Here, using first-principles calculations, we report a systematic study of spin-split hybrid states of ${\mathrm{C}}_{60}$ deposited on various ferromagnetic surfaces: bcc-Cr(001), bcc-Fe(001), bcc-Co(001), fcc-Co(001), and hcp-Co(0001). We show that the adsorption geometry of the molecule with respect to the surface crystallographic orientation of the magnetic substrate as well as the strength of the interaction play a crucial role in the spin polarization of the hybrid orbitals. We find that a large spin polarization in vacuum above the buckyball can only be achieved if the molecule is adsorbed upon a bcc-(001) surface by its pentagonal ring. Therefore, bcc-Cr(001), bcc-Fe(001), and bcc-Co(001) are the optimal candidates. Spin-polarized scanning tunneling spectroscopy measurements on single ${\mathrm{C}}_{60}$ adsorbed on Cr(001) and Co/Pt(111) also confirm that the symmetry both of the substrate and of the molecular conformation has a strong influence on the induced spin polarization. Our finding may give valuable insights for further engineering of spin filtering devices through single molecular orbitals.

Background Recent studies suggest that purified omega-3 fatty acids may attenuate acute inflammation and hasten the transition to healing. In this study, we tested the hypothesis that pretreatment with omega-3–rich fish oil (FO) would promote resolution of peritoneal inflammation through production of specific lipid mediators. Methods C57/BL6 mice were given a daily 200-μL oral gavage of saline (CTL) or FO (1.0-1.5 g/kg/d docosahexaenoic acid and 1.3-2.0 g/kg/d eicosapentaenoic acid) for 7 d before chemical peritonitis was induced with thioglycollate. Peritoneal lavage fluid was collected before induction and at days 2 and 4 after peritonitis onset. Prostaglandin E2 (PGE2), Leukotriene B4 (LTB4), Resolvin D1 (RvD1), and the composition of immune cell populations were examined in peritoneal lavage exudates. Cells harvested from the peritoneum were assessed for macrophage differentiation markers, phagocytosis, and lipopolysaccharide-induced cytokine secretion profiles (interleukin [IL]-6, IL-10, IL-1β, TNFα). Results The ratio of RvD1 to pro-inflammatory PGE2 and LTB4 was increased in the peritoneal cavity of FO-supplemented animals. FO induced a decrease in the number of monocytes in the lavage fluid, with no change in the number of macrophages, neutrophils, or lymphocytes. Macrophage phagocytosis and M1/M2 messenger RNA markers were unchanged by FO with the exception of decreased PPARγ expression. FO increased ex vivo TNFα secretion after stimulation with lipopolysaccharide. Conclusions Our findings provide evidence that nutraceutically relevant doses of FO supplements given before and during chemical peritonitis shift the balance of lipid mediators towards a proresolution, anti-inflammatory state without drastically altering the number or phenotype of local innate immune cell populations.

Long-term control of triatomine bugs in Chagas endemic regions will depend on a full understanding of vector-parasite-host interactions. Herein we describe a cytochrome b multiplex polymerase chain reaction (PCR)-based strategy for blood meal source identification in bug foregut contents. This technique discriminates human from animal blood, and has been tested in five Triatoma species from México. Host identification has been validated for human, four rodent species, two bat species, dog, rabbit, sheep, and opossum. In addition, Trypanosoma cruzi can be identified simultaneously using S34/S67-specific kinetoplast DNA primers. Both host and parasite identification were possible as long as 10 weeks after bug feeding, and in samples stored up to 6 years. The blood meal identification procedure described here represents a powerful tool for large-scale studies identifying the biological, ecological, and environmental variables associated with Chagas disease transmission.

We concentrate here on the transition metal rich corner of the ternary R–M–B systems (R is a rare-earth elements, Y or Th and M is a transition metal element), where a series of R n +1 Co 3 n +5 B 2 n phases exist. This series of compounds derive from the RCo 5 crystal structure by an ordered substitution of boron for cobalt leading to a wide family of superstructures. The effects of boron for cobalt substitution on the magnetic properties such as the ordering temperatures or the magnetisation are discussed. The influence of the local environment on the magnitude of the Co magnetic moment is presented. Depending upon the number of boron layers as near neighbours the Co magnetic moment magnitude can vary from 1.8 down to 0 μ B . The effect of substituting Fe or Ni for Co is discussed in the light of neutron powder diffraction and X-ray anomalous diffraction, respectively. Whereas the Fe containing compounds are found to keep the original CeCo 4 B structure type, the Ni containing ones are exhibiting even more complex crystal structures. The preferential location of Fe on the Co 2 c site is presented. The magnetic properties of the YCo 4− x Ni x B compounds are investigated. The influence of Th for Y substitution in YCo 4 B is also presented.

Restoration of joint stability during total shoulder arthroplasty can be challenging in the face of severe glenoid retroversion. A novel technique of humeral head component anterior-offsetting has been proposed to address posterior instability. We evaluated the biomechanical benefits of this technique in cadaveric specimens. Total shoulder arthroplasty was performed in 14 cadaveric shoulders from 7 donors. Complementary shoulders were assigned to either 10° or 20° glenoid retroversion, with retroversion created by eccentric reaming. Two humeral head component offset positions were tested in each specimen: The anatomic (posterior) and anterior (reverse). With loads applied to the rotator cuff and deltoid, joint contact pressures and the force and energy required for posterior humeral head translation were measured. The force and energy required to displace the humeral head posteriorly increased significantly with the anterior offset position compared to the anatomic offset position. The joint contact pressures were significantly shifted anteriorly, and the joint contact area significantly increased with the anterior offset position. Anterior offsetting of the humeral head component increased the resistance to posterior humeral head translation, shifted joint contact pressures anteriorly, and increased joint contact area, thus, potentially increasing the joint stability in total shoulder arthroplasty with simulated glenoid retroversion.

The Mossbauer spectra of the YCo4−xFexB compounds, where x is 1, 2 and 3, have been measured at 78 and 295 K and reveal relatively small iron hyperfine fields of about 15 T, relatively large quadrupole interactions of about +1.0 and −1.0 mm s−1 and very different spectra for YCo3FeB and YCo2Fe2B as compared with YCoFe3B. As a consequence, the spectra have been fitted with a full Hamiltonian by adjusting the hyperfine parameters of the iron 2c and 6i sites found in these compounds. The fits have used an asymmetry parameter, η, and Euler angles, θ and , that relate the hyperfine field to the iron electric field gradient axes of each iron site in an orientation that is consistent with the structural and magnetic properties of the site. The fits indicate that the relative areas of the spectral components assigned to the two iron 2c and 6i sites are in agreement with the iron occupancy of the sites as determined by neutron diffraction. The results of the fits also indicate both that the full Hamiltonian approach is required for physically reasonable spectral fits and that the small observed fields result from the presence of large orbital contributions which subtract from the Fermi contact contributions to the magnetic hyperfine fields of the two sites.

We demonstrate the capability to build zero and one-dimensional electroactive molecular nanostructures ordered over a macroscopic scale and stable under ambient conditions. To realize these arrays, we use the selective grafting of functionalized thiols (juglon and terthiophene based) on a self-organized metallic template. The nanoscale patterning of the molecular conductance is demonstrated and analyzed by scanning tunneling spectroscopy. Finally, the influence of the nanostructuring on electro-chemical properties is measured, paving the way to an all-bottom-up fabrication of nanostructured templates for nanosciences. (C) 2013 AIP Publishing LLC.

The morphology of cobalt, palladium, and platinum nanoclusters grown on a gold surface is analyzed from both thermodynamic and kinetic viewpoints. Although the thermodynamic equilibrium shape as a function of cluster size is similar for all three elements and shows a morphology transition from monolayer to bilayer, only Co clusters meet their stable state and undergo a transition. Atomistic simulations on a picosecond to nanosecond time scale evidence kinetic limitations for Pt and Pd, and allow us to understand the experimentally observed morphology for the different species. It is shown that stress relaxation, by strongly influencing the energy activation for atom hopping from first to second cluster layer and the magnitude of vibration of the atoms, is the determinant parameter for the existence or absence of the cluster morphology transition. DOI: 10.1103/PhysRevB.87.155404

The crystal and magnetic structures of the Ndn+1Co3n+5B2n (n=1, 2 and 3) compounds have been studied by high-resolution powder neutron diffraction at the Institut Laue Langevin. The results are compared to earlier measurements on the isotype Yn+1Co3n+5B2n compounds. The neutron-diffraction analysis shows that the magnetic moments are ferromagnetically ordered. The magnetic structures of NdCo4B, Nd3Co11B4 and Nd2Co7B3 confirm that a large variety of magnetic moments exist for the cobalt atoms. On the one hand, the magnetic behavior of the cobalt atoms situated in the 2c position is not significantly affected by the substitution of boron for cobalt. On the other hand, the cobalt atoms situated on the 3g, 6i1 and 6i2 positions are carrying significantly reduced magnetic moments in comparison with those of the Co (2c) ones. The Nd magnetic moments are also found to be sensitive to the boron content. Finally, the direction of easy magnetization is found to be unchanged upon boron for cobalt substitution and lies in the basal plane for NdCo4B, Nd3Co11B4 and Nd2Co7B3.

Several tens of chromium layers were deposited at 250 degrees C on a Cr(001) surface and investigated by spin-polarized scanning tunneling microscopy (SP-STM), Auger electron spectroscopy (AES) and scanning tunneling spectroscopy (STS). Chromium is found to grow with a mound-like morphology resulting from the stacking of several monolayers which do not uniformly cover the whole surface of the substrate. The terminal plane consists of an irregular array of Cr islands with lateral sizes smaller than 20 x 20 nm(2). Combined AES and STS measurements reveal the presence of a significant amount of segregants prior to and after deposition. A detailed investigation of the surface shows that it consists of two types of patches. Thanks to STS measurements, the two types of area have been identified as being either chromium pure or segregant rich. SP-STM experiments have evidenced that the antiferromagnetic layer coupling remains in the chromium mounds after deposition and is not significantly affected by the presence of the segregants.

International audience; We have studied the influence of Pt capping on the magnetic properties of self-organized Co nanodots by means of complementary structural and magnetic investigation techniques. The growth of monodisperse 5 nm diameter Co dots on a Au(111) surface and its progressive coverage by Pt were performed under ultrahigh vacuum conditions and imaged by scanning tunneling microscopy, revealing a weak mixing at room temperature. The Co/Pt core-shell structure was studied both by molecular-dynamics simulations and surface extended x-ray-absorption fine structure, showing a global dilatation of the Co core. Both magnetic moments and hysteresis cycles at various temperatures were measured using x-ray magnetic circular dichroism, revealing a slight increase of the magnetic moments and the out-of-plane magnetic anisotropy after Pt capping. Moreover, the variation of magnetic anisotropy as a function of capping was followed in situ by the magneto-optical Kerr effect. Our investigations demonstrate that interfacial hybridization between Co and Pt is dominant over magnetoelastic contribution in this system.

Using scanning tunneling microscopy and a diffraction experiment, we have discovered a new ordered surface alloy made out of two bulk-immiscible components, Fe and Au, deposited on a Ru(0001) substrate. In such a system, substrate-mediated strain interactions are believed to provide the main driving force for mixing. However, spin-polarized ab initio calculations show that the most stable structures are always the ones with the highest magnetic moment per Fe atom and not the ones minimizing the surface stress, in remarkable agreement with the observations. This opens up novel possibilities for creating materials with unique properties of relevance to device applications.

O ciclo biologico do Amblyomma dubitatum, que se alimentava experimentalmente em coelhos domesticos, foi avaliado em condicoes laboratoriais e comparado com dados recentemente obtidos de infestacoes experimentais em capivaras (Hydrochaeris hydrochaeris), hospedeiros naturais para essa especie. Os coelhos foram considerados hospedeiros experimentais adequados para larvas e ninfas porque quatro dos cinco parâmetros avaliados (numero de carrapatos que ingurgitaram, periodo de alimentacao, percentagem de carrapatos que realizaram muda e periodo de pre-muda) foram semelhantes aos resultados obtidos com capivaras. As percentagens diarias de desprendimento e de muda das larvas e ninfas confirmam os coelhos como hospedeiros experimentais adequados para esses estagios de A. dubitatum. Os resultados do experimento indicam que os coelhos sao hospedeiros inadequados para os adultos.

Summary form only given. Advances in lithography and thinner SiO/sub 2/ gate oxides have enabled the scaling of MOS (metal-oxide-semiconductor) technologies to sub-0.25 /spl mu/m feature size. High dielectric constant materials, such as Ta/sub 2/O/sub 5/, have been suggested as a substitute for SiO/sub 2/ as the gate material beyond t/sub ox/=25 /spl Aring/. However, the Si-Ta/sub 2/O/sub 5/ material system suffers from unacceptable levels of bulk fixed charge, high density of interface trap states, and low silicon interface carrier mobility. We present a solution to these issues through the synthesis of a SiO/sub 2/-Ta/sub 2/O/sub 5/-SiO/sub 2/ stacked dielectric. The fabricated transistors exhibit excellent I-V characteristics.