Journal articles on the topic 'Mafia infiltration'
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1
Mirenda, Litterio, Sauro Mocetti, and Lucia Rizzica. "The Economic Effects of Mafia: Firm Level Evidence." American Economic Review 112, no. 8 (August 1, 2022): 2748–73. http://dx.doi.org/10.1257/aer.20201015.
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We analyze the effects of Mafia infiltration in the legal economy. Combining information from investigative records with panel data on firms’ governance and balance sheets, we build an indicator of infiltration in firms located in an area with no tradition of Mafia. We show that Mafia targets young and less efficient firms and that infiltration generates a significant rise in firms’ revenues, with no proportionate growth in production inputs and a deterioration of the firm’s financial situation leading to market exit. These findings are consistent with a story of predatory behavior in which infiltration is used for money laundering or rent extraction. (JEL D22, G32, G34, K42, L25)
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Ravenda, Diego, Michele Giuranno, Maika Valencia-Silva, Josep M. Argiles-Bosch, and Josep García-Blandón. "The Effects of Mafia Infiltration on Public Procurement Performance." Academy of Management Proceedings 2020, no. 1 (August 2020): 10038. http://dx.doi.org/10.5465/ambpp.2020.253.
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Ravenda, Diego, Michele G. Giuranno, Maika M. Valencia-Silva, Josep M. Argiles-Bosch, and Josep García-Blandón. "The effects of mafia infiltration on public procurement performance." European Journal of Political Economy 64 (September 2020): 101923. http://dx.doi.org/10.1016/j.ejpoleco.2020.101923.
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Champeyrache, Clotilde. "A Commonsian approach to crime: the Mafia and the economic power to withhold." Cambridge Journal of Economics 45, no. 3 (April 14, 2021): 411–25. http://dx.doi.org/10.1093/cje/beab006.
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Abstract This paper is a plea for an institutionalist approach to crime. The argument is based on the Italian Mafia’s infiltration of legitimate businesses. The focus is on the power dimension of this infiltration. I begin by emphasising how the traditional branch of crime economics is unable to correctly address this issue. I then use the tools provided by Commons, especially his definition of property and the capacity to withhold and his distinction between will-in-vacuo and will-in-action. Access to property rights over productive entities for Mafiosi provides a perfect illustration of how the capacity to hold rights turns into a power to withhold them from others. Legal Mafia-owned enterprises should not be seen as a step toward normalisation of the Mafia, but rather as a mark of the extension of their criminal power.
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Dagnes, Joselle, Davide Donatiello, Valentina Moiso, Davide Pellegrino, Rocco Sciarrone, and Luca Storti. "Mafia infiltration, public administration and local institutions: A comparative study in Northern Italy." European Journal of Criminology 17, no. 5 (October 8, 2018): 540–62. http://dx.doi.org/10.1177/1477370818803050.
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Nuanced explanations of the factors underpinning the mafia’s movements across territories have recently been proposed. However, more light must be shed on the mechanisms through which mafiosi try to infiltrate the legal economy in non-traditional territories. Accordingly, this study aims to micro-found interactions and exchanges that mainly involve mafiosi, politicians and economic actors in expansion areas. Focusing on the local level, we will show how the misuse of several administrative tools generates a profitable opportunity structure for mafiosi. To this end, we present an in-depth comparative case study of three events involving the construction industry that took place in Northern Italy. The main findings show that: (i) mafiosi are skilled at smoothing social relations, enlarging and consolidating opaque networks predating their arrival; (ii) they give rise to different types of mutual exchanges and network structures.
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Checchi, Valeria Virginia, and Michele Polo. "Blowing in the Wind: The Infiltration of Sicilian Mafia in the Wind Power Business." Italian Economic Journal 6, no. 2 (March 6, 2020): 325–53. http://dx.doi.org/10.1007/s40797-020-00126-z.
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Becucci, Stefano. "Criminal infiltration and social mobilisation against the Mafia. Gela: a city between tradition and modernity." Global Crime 12, no. 1 (February 13, 2011): 1–18. http://dx.doi.org/10.1080/17440572.2011.548961.
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Acconcia, Antonio, Giancarlo Corsetti, and Saverio Simonelli. "Mafia and Public Spending: Evidence on the Fiscal Multiplier from a Quasi-Experiment." American Economic Review 104, no. 7 (July 1, 2014): 2185–209. http://dx.doi.org/10.1257/aer.104.7.2185.
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A law issued to combat political corruption and Mafia infiltration of city councils in Italy has resulted in episodes of large, unanticipated, temporary contractions in local public spending. Using these episodes as instruments, we estimate the output multiplier of spending cuts at provincial level—controlling for national monetary and fiscal policy, and holding the tax burden of local residents constant—to be 1.5. Assuming that lagged spending is exogenous to current output brings the estimate of the overall multiplier up to 1.9. These results suggest that local spending adjustment may be quite consequential for local activity. (JEL D72, E62, H71, K42)
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Occhiuzzi, Filomena. "The Dissolution of Municipal Councils due to Organized Crime Infiltration." European Journal of Interdisciplinary Studies 5, no. 2 (May 31, 2019): 45. http://dx.doi.org/10.26417/ejis-2019.v5i2-284.
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: The paper proposal is focused on the evolution of a specific legal instrument, which consists of the Central government’s power to “dissolve” municipal councils in the case of infiltrations by organized crime. In Italian administrative legislation, local councils may be dissolved for several reasons such as the ongoing violation of the law and the neglect of duty, but one of the most debated causes is the interference and the pressure that organized crime may exercise on the members of municipal councils. This specific administrative law instrument is defined in art. 143 T.U.E.L. and is part of a series of public anti-mafia policies. It was introduced in 1991 as an emergency law to cope with the risk of maladministration due to local authorities’ subjugation to criminal power (Mete, 2009). The aim of the dissolution of local councils is to preserve constitutional and fundamental values such as democracy and the rule of law, but it is a very severe legal tool as it affects a democratically elected community. This instrument is also closely related to the prevention of corruption in the public sector, as often the infiltrations by organized crime in municipalities are due to the corruption of public officials. The institution in charge of applying this legal tool is the Prefect, which has the power to enforce the orders of the central government and oversees local authorities. The procedure for the adoption of this instrument involves the major constitutional bodies such as the Parliament, the Ministry of Interior and the President of the Republic.
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Occhiuzzi, Filomena. "The Dissolution of Municipal Councils due to Organized Crime Infiltration." European Journal of Interdisciplinary Studies 5, no. 2 (May 31, 2019): 45. http://dx.doi.org/10.26417/ejis.v5i2.p45-53.
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: The paper proposal is focused on the evolution of a specific legal instrument, which consists of the Central government’s power to “dissolve” municipal councils in the case of infiltrations by organized crime. In Italian administrative legislation, local councils may be dissolved for several reasons such as the ongoing violation of the law and the neglect of duty, but one of the most debated causes is the interference and the pressure that organized crime may exercise on the members of municipal councils. This specific administrative law instrument is defined in art. 143 T.U.E.L. and is part of a series of public anti-mafia policies. It was introduced in 1991 as an emergency law to cope with the risk of maladministration due to local authorities’ subjugation to criminal power (Mete, 2009). The aim of the dissolution of local councils is to preserve constitutional and fundamental values such as democracy and the rule of law, but it is a very severe legal tool as it affects a democratically elected community. This instrument is also closely related to the prevention of corruption in the public sector, as often the infiltrations by organized crime in municipalities are due to the corruption of public officials. The institution in charge of applying this legal tool is the Prefect, which has the power to enforce the orders of the central government and oversees local authorities. The procedure for the adoption of this instrument involves the major constitutional bodies such as the Parliament, the Ministry of Interior and the President of the Republic.
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Radaelli, Giovanni, Marco Guerci, Federica Cabras, and Nando Dalla Chiesa. "How are professionals recruited by external agents in misconduct projects? The infiltration of organized crime in a university." Human Relations 72, no. 9 (July 20, 2018): 1407–35. http://dx.doi.org/10.1177/0018726718782616.
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Private firms, crime organizations or states may successfully recruit professionals in misconduct projects. How they do so remains, however, under-investigated. Past studies mostly take professionals’ perspective, or limit the organizational initiative of external agents to perverse incentives and threats. Our study shows instead how external agents may penetrate governance bodies and professional events to recruit and control professionals, who are both aware of and reluctant toward misconduct. Our longitudinal case study used judicial and non-judicial sources to analyse how a mafia clan infiltrated Troy University, and controlled the trade of exams and admissions for decades. The clan selected Troy University because of the presence of professors pre-disposed toward misconduct. The clan infiltrated the pre-disposed professors inside governance bodies and students inside academic events to recruit the reluctant professors with peer pressures, situated threats and administrative controls. It then exploited a generalized code of silence to control professionals for years. Overall, the study highlights the combination of perverse and pervasive mechanisms to recruit professionals; the role of corrupt professionals as linchpin between external agents and reluctant peers; and the perverse exploitation of normal professional practices of autonomy, trusteeship and multiple embeddedness.
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Dickie, John. "Fuori dal Comune: Lo scioglimento delle amministrazioni locali per infiltrazioni mafiose (Out of the Municipality: Suspending Local Government in Italy as a Response to Mafia Infiltration)." South European Society and Politics 15, no. 2 (June 2010): 330–32. http://dx.doi.org/10.1080/13608746.2010.503413.
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Eboli, Mario, Andrea Toto, and Andrea Ziruolo. "Mafia infiltrations in Italian municipalities: two statistical indicators." Applied Economics 53, no. 24 (April 11, 2021): 2693–712. http://dx.doi.org/10.1080/00036846.2020.1866157.
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Barnes, Stephen J., Valentina Taranovic, John M. Miller, Glenn Boyce, and Steve Beresford. "Sulfide Emplacement and Migration in the Nova-Bollinger Ni-Cu-Co Deposit, Albany-Fraser Orogen, Western Australia." Economic Geology 115, no. 8 (August 24, 2020): 1749–76. http://dx.doi.org/10.5382/econgeo.4758.
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Abstract The Nova-Bollinger Ni-Cu sulfide deposit is associated with a small chonolith (tube-shaped) intrusion emplaced at lower crustal depths into granulite facies migmatite gneisses. The deposit comprises disseminated and net-textured ores within the intrusions and a high proportion of massive, semimassive, and breccia exocontact ores within the underlying country rocks. Internally disposed endocontact ores show typical magmatic textures including conventional net texture, leopard net texture characterized by the presence of centimeter-sized clots of olivine and intercumulus phases, and globular ores. Some of the globular ores show an association of sulfide blebs with clinopyroxene-carbonate intergrowths that may represent infilling of original CO2-rich vapor bubbles. The exocontact ores have an assemblage of textures indicative of emplacement into hot, soft country rocks at a large-scale melting-infiltration front. Characteristic features range from hard-walled extensional vein arrays to complex infiltrations of disseminated sulfide within chaotically folded paragneiss. Sulfide infiltration was accompanied by partial melting of the country rock, producing felsic leucosomes, some of them strongly enriched in garnet, mainly occupying vein walls and interpreted as the result of counterflow of displaced silicate partial melt. Coarse-grained pentlandite-chalcopyrite-pyrrhotite loop textures are characteristic of all ore types, down to the scale of the infiltrating sulfides within the gneisses, and are regarded as diagnostically magmatic textures generated by sulfide liquid fractionation and growth of high-temperature pentlandite by peritectic reaction between fractionated sulfide melt and early crystallized monosulfide solid solution. The highly distinctive features of the Nova-Bollinger ores are a consequence of their emplacement in the mid to lower crust under peak granulite facies conditions. Under these unusual conditions the timescales for cooling between the silicate solidus and sulfide solidus temperatures were of the order of millions of years, being controlled by the temperature-time path for the exhumation of the orogen as a whole. Sulfides solidified over a time period three orders of magnitude greater than the thousand-year timescale for the solidification of the host silicate magmas. Furthermore, timescales for deformation matched those for cooling and solidification, allowing the country rocks to undergo deformation during ore emplacement. Fluctuating strain rates during and after initial emplacement of the carrier magmas into the host intrusion caused episodes of brittle extension, allowing unusually efficient penetration of partially molten sulfide into heterogeneous, partially molten silicate country rock, resulting in an unusually extensive thermomechanical aureole compared with other mafic intrusion-hosted nickel systems globally.
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Liu, Dehua, Chenyu Sun, Nahyun Kim, Chandur Bhan, John Pocholo Whitaker Tuason, Yue Chen, Shaodi Ma, et al. "Comprehensive Analysis of SFRP Family Members Prognostic Value and Immune Infiltration in Gastric Cancer." Life 11, no. 6 (June 3, 2021): 522. http://dx.doi.org/10.3390/life11060522.
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Gastric cancer (GC) is the fifth most common cancer globally. Secreted frizzled-related proteins (SFRP) are important elements associated with the Wnt signaling pathway, and its dysregulated expression is found in multiple cancers. However, the function of distinct SFRPs in GC remains poorly understood. We investigated the differential expression, prognostic value, and immune cell infiltration of SFRPs in gastric cancer patients from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan–Meier plotter, cBioPortal, STRING, Gene-MANIA, DAVID, MethSurv, and TIMER databases. We found that the expression levels of SFRP2 and SFRP4 were significantly increased in GC tissues, whereas the SFRP1 and SFRP5 expressions were reduced. SFRP1, SFRP2, and SFRP5 were significantly correlated with the clinical cancer stage in GC patients. Higher expression of SFRPs was associated with short overall survival (OS) in GC patients. Besides, high SFRPs methylation showed favorable OS in GC patients. The functions of SFRPs were primarily related to the Wnt signaling pathway, immune system development, and basal cell carcinoma. The expression of SFRPs was strongly correlated with immune infiltrating cells, including CD4+ T cells and macrophages in GC. Our study indicated that SFRPs could be potential targets of precision therapy and prognostic biomarkers for the survival of GC patients.
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Neumann, Else-Ragnhild. "Ultramafic and mafic xenoliths from Hierro, Canary Islands: evidence for melt infiltration in the upper mantle." Contributions to Mineralogy and Petrology 106, no. 2 (January 1991): 236–52. http://dx.doi.org/10.1007/bf00306436.
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Marques, Rodrigo Diniz, and Mauro Kumpfer Werlang. "PRECIPITAÇÃO E PERDA DE SEDIMENTOS NA ENCOSTA ITAGIBA, ZONA NORTE DE SANTA MARIA - RS." Ciência e Natura 35, no. 1 (October 22, 2013): 1. http://dx.doi.org/10.5902/2179460x9597.
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Occupation in risk areas in the Brazilian cities happens, mainly, because of social segregation and space management. In the city of Santa Maria, occupation in risk areas also occurs. One of these areas is the Itagiba slope, located in the neighborhood of Chácara das Flores, nor- thern zone of the city. The route of the Santa Maria-Uruguaiana railroad, designed by the Belgium Consortium, in 1890, has lead to changes in the north side of Kennedy Town. By modifying the conformation of the landscape, the sectioning of the slope changed the topography. In this sense, this work aims to contribute to the understanding of the erosive process in the slope and establish the relationship between precipitation and total loss of sediment. Aiming at this goal, the volumes of total precipitation and the amount of sediment removed in each event of precipitation were monitored over a period of two years. For this evaluation, the pedological volumes in the Itagiba slope were analyzed in terms of texture and consistency limits. Along a toposequence was also evaluated the coefficient of infiltration. Results showed a positive correlation between the volume of precipitation and the loss of sediments. Higher volume of loss was observed in pedological volumes with higher silt content. The coefficient of infiltration decreased with increasing depth, clay content, and plasticity. The evaluation of the toposequence shows that the increase in depth causes the increase of horizontal flows, and that the conformation of the slope profile is controlled by this process.
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Johnstone, Peter, and Mark Jones. "The Facilitation of Money Laundering Through Western Europe and the United States by Russian Organised Crime Groups." Journal of Money Laundering Control 3, no. 3 (January 1, 2000): 199–203. http://dx.doi.org/10.1108/eb027230.
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Over the past decade the Russian Mafia has established itself as capable of causing serious disruptions within the world's financial markets. Organised crime groups control a substantial number of the banks within Russia and as a consequence they are capable of infiltrating major sources of money supply and taking control of legitimate businesses, both foreign and domestic. Once an organised crime group has entered the banking structure, it can expand its operations by using the veneer of legitimacy provided by the bank as a source of utility for further criminal ventures. The laundering of illegal proceeds, both national and international, has now become one of the major activities conducted by Russian organised crime groups in the former Soviet Union.
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Huszno, Joanna, and Zofia Kołosza. "Checkpoint Kinase 2 (CHEK2) Mutation in Renal Cell Carcinoma: A Single-Center Experience." Journal of Kidney Cancer and VHL 5, no. 1 (April 18, 2018): 19–23. http://dx.doi.org/10.15586/jkcvhl.2018.101.
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Renal cell carcinoma (RCC) occurs in sporadic and heritable forms. Genetic mutations have been identified as risk factors in 1–2% of RCC. The aim of this study was to evaluate I157T and CHEK2*1100delC mutations of checkpoint kinase 2 (CHEK2) gene in RCC. Medical records of 40 clear cell RCC patients who had genetic tests and consultation at the Genetic Outpatient Clinic, Maria Sk?odowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Poland, were reviewed retrospectively. Mutation profile was assessed by ASA-PCR and RFLP-PCR techniques. Only three female patients had CHEK2 mutation (I157T). No CHEK2*1100delC was observed in any of the patients. These tumors were N0, and two were Grade 3. One showed capsular infiltration. No blood vessel infiltration or metastases was observed. Overall, RCC from patients with CHEK2 mutation did not display any special characteristics when compared with those without the mutation. While no association between CHEK2 mutation and RCC could be established, all three patients with CHEK2 mutation developed second neoplasms many years after first diagnosis. Further studies, especially regarding CHEK2 mutation as a predictive factor for second neoplasm in RCC patients, are warranted.
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Pan, Y., M. E. Fleet, and F. J. Longstaffe. "Melt-related metasomatism in mafic granulites of the Quetico subprovince, Ontario: constraints from O-Sr-Nd isotopic and fluid inclusion data." Canadian Journal of Earth Sciences 36, no. 9 (September 1, 1999): 1449–62. http://dx.doi.org/10.1139/e99-041.
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Mafic granulites in the Archean Quetico subprovince, north of Manitouwadge, Ontario, occur as isolated lenses or discontinuous layers in spatial association with tonalitic leucosomes in metasedimentary rocks and exhibit concentric zoning from a biotite-rich margin to an orthopyroxene-rich outer zone and a clinopyroxene-rich central zone, with internal orthopyroxene-bearing leucosomes and, rarely, patches of relict amphibolites within the clinopyroxene-rich zone. Microstructural and microchemical evidence suggests that the mafic granulites formed from amphibolites by combined infiltration-diffusion processes in the presence of a P-F-bearing silicate melt ((P2O5)melt = 0.24-0.28 wt.%) and a CO2-rich (hypersaline?) fluid. The whole-rock and mineral δ18O values of the mafic granulites (8-9 V-SMOW) indicate oxygen-isotope equilibration between amphibolites (6.6-6.9) and associated tonalitic leucosomes (9.5-10) at 700-800°C. Strontium- and Nd-isotope data and U-Pb zircon ages confirm isotopic homogenization at the leucosome-amphibolite boundaries during the peak granulite-facies metamorphism at about 2650 Ma. Texturally, early CO2-rich fluid inclusions in quartz and garnet yield P-T conditions similar to those of the peak granulite-facies metamorphism. Hypersaline fluid inclusions occur in textural coexistence with the early CO2-rich inclusions, but are invariably low in homogenization temperatures (178-234°C). This study shows that silicate melts not only provide a conduit for CO2-rich fluids but also interact directly with country rocks for the formation of granulites. Also, the O-Sr-Nd isotope data show that the documented mobility of rare-earth elements in the Quetico granulite zone is localized in scale and related to anatexis of local metasedimentary rocks during the granulite-facies metamorphism.
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Zhou, Yifan, Yusra B. Medik, Bhakti Patel, Daniel B. Zamler, Sijie Chen, Thomas Chapman, Sarah Schneider, et al. "Abstract 5545: Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5545. http://dx.doi.org/10.1158/1538-7445.am2022-5545.
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Abstract Immunotherapies such as anti-CTLA-4 immune checkpoint blockade (ICB) have revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by off-target tissue damage or immune-related adverse events (irAEs). At present, there is limited understanding of irAE mechanisms, hampering development of approaches to mitigate their damage. We addressed this problem by generating animal models of intestinal irAE. Our results show that disruption of homeostatic immunity by genetic predisposition to intestinal inflammation or acute gastrointestinal infection sensitizes mice to anti-CTLA-4-mediated intestinal toxicity. Inflammation-prone mice treated with anti-CTLA-4 showed neutrophil accumulation, systemic interleukin-6 (IL-6) release, and dysbiosis. Significantly, IL-6 blockade combined with antibiotic treatment improved anti-CTLA-4 therapeutic efficacy and reduced intestinal irAEs. Immune signatures were validated in biopsies from patients who developed colitis during ICB, supporting the utility of our models. This study provides new pre-clinical models, mechanistic insight into irAEs, and potential approaches to enhance ICB efficacy while mitigating irAEs. Citation Format: Yifan Zhou, Yusra B. Medik, Bhakti Patel, Daniel B. Zamler, Sijie Chen, Thomas Chapman, Sarah Schneider, Rachel L. Babcock, Taylor T. Chrisikos, Laura M. Kahn, Allison M. Dyevoich, Elizabeth M. Park, Alexandria P. Cogdill, Daniel H. Johnson, Sarah B. Johnson, Khalida M. Wani, Debora A. Ledesma, Courtney W. Hudgens, Jingjing Wang, Md Abdul Wadud Khan, Aron Y. Joon, Weiyi Peng, Haiyan S. Li, Reetakshi Arora, Ximing Tang, Maria Gabriela Raso, Xuegong Zhang, Wai Chin Foo, Michael T. Tetzlaff, Gretchen E. Diehl, Karen Clise-Dwyer, Elizabeth M. Whitley, Matthew M. Gubin, James P. Allison, Patrick Hwu, Nadim J. Ajami, Adi Diab, Jennifer A. Wargo, Stephanie S. Watowich. Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration [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 5545.
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Gavrielatou, Niki, Ekaterina Fortis, Aris Spathis, Maria Anastasiou, Panagiota Economopoulou, Maria Gkotzamanidou, Sylvie Rusakiewics, et al. "Abstract 1256: B-cell infiltration is associated with survival outcomes in nivolumab-treated head and neck squamous cell carcinoma (HNSCC): NCT 03652142." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1256. http://dx.doi.org/10.1158/1538-7445.am2022-1256.
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Abstract Background: Efficacy of Programmed Death1 inhibitor pembrolizumab in HNSCC demonstrates a positive correlation with PD-L1 expression, and PD-L1 positivity (CPS ≥1) is the only clinically approved biomarker for patient (pt) selection to this day. The primary objective of the current study is to prospectively explore candidate biomarkers from the tumor and tumor microenvironment for associations with clinical response to nivolumab in patients with recurrent/metastatic HNSCC treated with nivolumab. Methods: Longitudinal tissue biopsies were collected from recurrent and/or metastatic HNSCC patients treated with nivolumab. Biopsies were taken at baseline, 24-72 hours after the second cycle of nivolumab and at progression. Biomarker analysis employing IHC/IF and flow cytometry was conducted. PD-L1 CPS was assessed for 47 cases. Utilizing IF staining, immune cell populations (CD3+/CD8+/CD20+/FOXP3+), were quantified in stromal and tumor segments of 44 evaluable baseline, 29 post-treatment and 9 PD biopsies. Flow cytometry for immune sub-phenotypes was also performed on 57, 29 and 13 samples at the same timepoints, respectively. Results were correlated with response by RECIST 1.1 and survival outcomes. Results: High baseline CD20+ B cell density in stroma was associated with prolonged progression-free survival (PFS) (p=0.011) and the same trend was observed for overall survival (OS) (p=0.072). Intra-tumoral CD20+ did not demonstrate the same effect. None of the other immune-cell subtypes, in neither tissue compartment, were correlated with outcome. Increase in the post-treatment unswitched memory IgD/IgM+ B cell population in peripheral blood was also linked to improved OS (p=0.017). PD-L1 CPS ≥1 in baseline biopsies was associated with longer OS (p=0.001) but not PFS (p=0.12) and CD20+ B cell density was independent of PD-L1 positivity (p=0.121). When cases were stratified into 3 groups based on PD-L1 positivity and CD20+ B cell density, the “PD-L1/CD20+ double +/high” subgroup was associated with both improved PFS (p=0.013) and OS (p=0.028) in contrast with the “PD-L1/CD20+ single +/high” and “PD-L1/CD20+ double -/low” subgroups. Conclusions: Overall, our findings uncover the implication of infiltrating CD20+ B cells in HNSCC nivolumab outcomes and underscore their ability to enhance the predictive value of PD-L1 CPS and thus further refine patient selection. Citation Format: Niki Gavrielatou, Ekaterina Fortis, Aris Spathis, Maria Anastasiou, Panagiota Economopoulou, Maria Gkotzamanidou, Sylvie Rusakiewics, Ioannis Vathiotis, Thazin Nwe Aung, Ioannis Kotsantis, Elena Mihal Vagia, Ioannis Panayiotides, David Rimm, George Coukos, Periklis Foukas, Amanda Psyrri. B-cell infiltration is associated with survival outcomes in nivolumab-treated head and neck squamous cell carcinoma (HNSCC): NCT 03652142 [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 1256.
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Vho, Alice, Pierre Lanari, Daniela Rubatto, and Jörg Hermann. "Tracing fluid transfers in subduction zones: an integrated thermodynamic and <i>δ</i><sup>18</sup>O fractionation modelling approach." Solid Earth 11, no. 2 (March 10, 2020): 307–28. http://dx.doi.org/10.5194/se-11-307-2020.
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Abstract. Oxygen isotope geochemistry is a powerful tool for investigating rocks that interacted with fluids, to assess fluid sources and quantify the conditions of fluid–rock interaction. We present an integrated modelling approach and the computer program PTLoop that combine thermodynamic and oxygen isotope fractionation modelling for multi-rock open systems. The strategy involves a robust petrological model performing on-the-fly Gibbs energy minimizations coupled to an oxygen fractionation model for a given chemical and isotopic bulk rock composition; both models are based on internally consistent databases. This approach is applied to subduction zone metamorphism to predict the possible range of δ18O values for stable phases and aqueous fluids at various pressure (P) and temperature (T) conditions in the subducting slab. The modelled system is composed of a mafic oceanic crust with a sedimentary cover of known initial chemical composition and bulk δ18O. The evolution of mineral assemblages and δ18O values of each phase is calculated along a defined P–T path for two typical compositions of basalts and sediments. In a closed system, the dehydration reactions, fluid loss and mineral fractionation produce minor to negligible variations (i.e. within 1 ‰) in the bulk δ18O values of the rocks, which are likely to remain representative of the protolith composition. In an open system, fluid–rock interaction may occur (1) in the metasediment, as a consequence of infiltration of the fluid liberated by dehydration reactions occurring in the metamorphosed mafic oceanic crust, and (2) in the metabasalt, as a consequence of infiltration of an external fluid originated by dehydration of underlying serpentinites. In each rock type, the interaction with external fluids may lead to shifts in δ18O up to 1 order of magnitude larger than those calculated for closed systems. Such variations can be detected by analysing in situ oxygen isotopes in key metamorphic minerals such as garnet, white mica and quartz. The simulations show that when the water released by the slab infiltrates the forearc mantle wedge, it can cause extensive serpentinization within fractions of 1 Myr and significant oxygen isotope variation at the interface. The approach presented here opens new perspectives for tracking fluid pathways in subduction zones, to distinguish porous from channelled fluid flows, and to determine the P–T conditions and the extent of fluid–rock interaction.
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Kathuria, Karan R., Binbin Chen, Michael S. Khodadoust, Niclas Olsson, Mark M. Davis, Joshua E. Elias, Ronald Levy, Russ B. Altman, and Arash A. Alizadeh. "Maria-I: A Deep-Learning Approach for Accurate Prediction of MHC Class I Tumor Neoantigen Presentation." Blood 134, Supplement_1 (November 13, 2019): 84. http://dx.doi.org/10.1182/blood-2019-129334.
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Background: Therapeutic cancer vaccines targeting neoantigens have shown promise in early phase clinical trials for inducing tumor-specific T-cell responses in diverse tumor types. Identification of the small number of optimal cancer vaccine targets is essential to limit cost and improve efficacy of patient-specific vaccine design. Therefore, there is a need to narrow neoantigen selection to those peptides with the highest potential to induce anti-tumor immune responses, and to maximize the associated clinical benefits. The presentation of these antigens by Major Histocompatibility Complex (MHC) class I is key for prioritizing candidates. Previous algorithms to predict antigen presentation have had limited success and have primarily been trained on in-vitro binding affinity assays, or are commercial platforms not widely available for use. Methods: We previously developed MARIA (MHC Analysis with Recurrent Integrated Architecture) as a method for predicting MHC-II neoantigens [Chen B et al. 2017 ASH, and Chen et al. 2019, Nature Biotechnology, in press]; here we adapt and develop the same MARIA design for MHC-I and benchmark its performance. Specifically, we used deep-learning for predicting the likelihood of neoantigen presentation trained on presented lymphoma peptides as identified by mass-spectrometry (LC-MS/MS). MARIA-I was initially trained on >47,000 ligands we previously identified by mass-spectrometry through antigen presentation profiling of patients with mantle cell lymphomas [Khodadoust et al. 2017, Nature]. Recurrent neural network (RNN) layers within MARIA-I integrate 4 key features: peptide sequence-MHC key residues relationship, peptide-MHC binding, peptide cleavage pattern, and gene expression. Results: We internally validated MARIA-I using 10-fold cross validation, where we observed an average AUC of 0.99 for the integrated model (Fig 1a); the peptide-MHC key residues relationships conferred the largest contribution to MARIA-I performance. We also further tested MARIA-I using an external dataset of ~19,000 diverse peptides from MHC-I antigen presentation profiles of four cancer cell lines (ACC1143, HCT116, HCC1937, and SUP-B15). MARIA-I maintains above 0.92 AUC across four diverse cancer types (AUC = 0.92, 0.92, 0.96, and 0.95, respectively). Since presentation of immunogenic peptides is essential for activation of T cell effector functions, we separately tested MARIA-I's ability to identify CD8 tumor infiltrating lymphocyte responses using corresponding data from 62 patients and 7587 neoantigens [Parkhurst et al. 2019, Cancer Discovery]. Despite MARIA-I not being trained on T cell reactivity data, neoantigens known to elicit positive T cell responses had significantly higher MARIA-I scores (Fig 1b, p=6.92e-5, Mann-Whitney U test). Conclusion: MARIA-I enables accurate prediction of neoantigen presentation for MHC class I at scale. Given its generalizability, we expect MARIA-I to yield insights for development of therapeutic cancer vaccines as well as applications in transplantation and autoimmune pathology. Figure 1. MARIA-I performance on antigen presentation and identifying immunogenic peptides. a) MARIA-I and sub-model predictors evaluated on 10% held-out validation set. Merging peptide sequence, gene expression, binding, and cleavage scores yielded improvements in performance as compared to each predictor's individual ability. b) MARIA-I assigns significantly higher scores to peptides known to elicit positive CD8 T cell response (p=6.92e-5, Mann-Whitney U test). Disclosures Khodadoust: Corvus Pharmaceuticals: Research Funding. Davis:Vir Biotechnology: Consultancy, Equity Ownership, Honoraria; PACT Bio: Consultancy, Equity Ownership, Honoraria; Adicet Inc: Consultancy, Equity Ownership, Honoraria; Chuga Pharmabody: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Atreca: Consultancy, Equity Ownership, Honoraria; Juno: Consultancy, Equity Ownership, Honoraria. Levy:Five Prime: Membership on an entity's Board of Directors or advisory committees; Corvus: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Sutro: Membership on an entity's Board of Directors or advisory committees; Checkmate: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Abpro: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; 47 Inc: Membership on an entity's Board of Directors or advisory committees; XCella: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees. Altman:Personalis: Consultancy; Pfizer: Consultancy; Karius: Consultancy.
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Sandeman, H. A., B. L. Cousens, and C. J. Hemmingway. "Continental tholeiitic mafic rocks of the Paleoproterozoic Hurwitz Group, Central Hearne sub-domain, Nunavut: insight into the evolution of the Hearne sub-continental lithosphere." Canadian Journal of Earth Sciences 40, no. 9 (September 1, 2003): 1219–37. http://dx.doi.org/10.1139/e03-035.
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The Paleoproterozoic Hurwitz Group of the western Churchill Province is an erosional remnant of an areally extensive, predominantly shallow-water intracratonic basin comprised of four major sequences. Sequence 2, forming the central part of the stratigraphy, contains the Ameto Formation, a sequence of pillowed and massive basaltic rocks and associated gabbro sills termed the Happotiyik Member that are interlayered with subordinate deep-water mudstones, siltstones, and diamictites. Whole-rock geochemical data for the mafic rocks reveals a suite of homogeneous tholeiitic basalts with affinities to both continental and volcanic-arc tholeiites. Compatible trace elements and large-ion lithophile elements exhibit scattered behavior, whereas all high field strength elements show a systematic increase with Zr. The rocks are large-ion lithophile and light rare-earth element enriched, and have parallel primitive mantle normalized extended trace element patterns with prominent negative Nb, Ta, and Ti anomalies. εNd(t=2200 Ma) values for the rocks range from 0.0 to +0.8. The data indicate that the parental magmas were derived from a heterogeneous, predominantly depleted mantle source that included a minor metasomatically enriched component. Contamination by Neoarchean, juvenile silicic upper crust during ascent was minimal. We envisage that the rocks of the Happotiyik Member were generated from sub-continental lithospheric mantle that was stabilized immediately after formation of the ca. 2680 Ma, Neoarchean Central Hearne sub-domain. This enrichment occurred via metasomatic infiltration of subduction-derived fluids and melts into the overlying lithosphere. A wide range of Paleoproterozoic intra-continental mafic rocks in the western Churchill Province exhibit comparable geochemical and isotopic signatures that suggest an origin in the lithospheric mantle. These observations imply that the Hearne sub-continental lithospheric mantle has endured since the Neoarchean and likely persists today.
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Jiemy, W. F., R. Reitsema, A. Zhang, M. Sandovici, A. Boots, P. Heeringa, E. Brouwer, and K. Van der Geest. "OP0015 PROINFLAMMATORY MONOCYTES AND MACROPHAGES IN SYNOVIAL FLUID AND BURSAL TISSUE OF PATIENTS WITH POLYMYALGIA RHEUMATICA: POTENT PRODUCERS OF IL-6 AND GM-CSF." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 8.3–9. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4396.
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BackgroundPolymyalgia rheumatica (PMR) is a common, rheumatic inflammatory disease. Inflammation of bursae and tendon sheaths is a characteristic finding in patients with PMR. Glucocorticoid treatment remains the mainstay treatment for PMR. A study published in 1996 reported that macrophages dominate the inflammatory infiltrates in the glenohumeral synovium of PMR patients1, suggesting the importance of these cells in the immunopathology of PMR. However, the functional and phenotypical heterogeneity of the tissue-infiltrating macrophages in PMR remains obscure. Although treatment with anti-IL-6 receptor (tocilizumab) has shown promising results2, it is unclear whether macrophages contribute to IL-6 production in PMR. Additionally, anti-GM-CSF receptor therapy (mavrilimumab), recently shown to be efficacious in the closely related disease giant cell arteritis3, may also be useful for the treatment of PMR. Knowledge on the functional heterogeneity of monocytes/macrophages in PMR may aid in identifying novel therapeutic targets for this condition.ObjectivesTo determine the phenotype of monocyte/macrophages in peripheral blood, bursal/tenosynovial fluid and bursal tissue of patients with PMR.MethodsPaired peripheral blood (PB), bursal/tenosynovial fluid (SF) and bursal tissue biopsy samples from 11 PMR patients were included in our study. Bursal and tenosynovial samples were obtained from the shoulder. Distribution of the monocyte subsets (classical, intermediate and non-classical monocytes) was determined based on the level of CD14 and CD16 expression by flow cytometry. To study monocyte activation status, markers of ‘M1’ like (CD80 and CD64) and ‘M2’ like (CD206 and FRβ) macrophage polarization were included in the flow cytometry analysis. Immunohistochemistry of bursal tissue biopsies was focused on macrophage markers (CD68, CD86, CD64, CD206 and FRβ) andproinflammatory cytokines (IL-6 and GM-CSF), which were scored semi-quantitatively. Double immunofluorescence stainings were performed to determine the expression of IL-6 and GM-CSF by tissue-infiltrating macrophages in bursal tissue.ResultsMonocytes were detected in the SF of PMR patients. The proportion of classical monocytes was significantly lowered (p=0.001) in SF versus PB, while the proportion of intermediate monocytes was significantly elevated (p=0.001). The expression of CD206 was significantly elevated (p=0.001) but not FRβ in SF monocytes, suggesting GM-CSF skewed phenotype. In bursal tissue, macrophages displayed mixed ‘M1’/’M2’ traits with high expression of all macrophage polarization markers. Proinflammatory cytokines IL-6 and GM-CSF were highly expressed throughout the bursal tissue biopsies. Double immunofluorescence staining confirmed the expression of IL-6 and GM-CSF by the infiltrating macrophages.ConclusionSF monocytes and bursal tissue macrophages show a pro-inflammatory phenotype in PMR. Moreover, tissue-infiltrating macrophages show a prominent IL-6 and GM-CSF response in PMR. Our data add to the rationale of targeting IL-6 and GM-CSF as treatment options in PMR.References[1]Meliconi R, Pulsatelli L, Uguccioni M, et al. Leukocyte infiltration in synovial tissue from the shoulder of patients with polymyalgia rheumatica. Quantitative analysis and influence of corticosteroid treatment. Arthritis Rheum. 1996;39(7):1199-1207.[2]Devauchelle-Pensec V, Berthelot JM, Cornec D, et al. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. Ann Rheum Dis. 2016;75(8):1506-1510.[3]Cid MC, Unizoni S, Pupim L, et al. Mavrilimumab (anti GM-CSF Receptor α Monoclonal Antibody) Reduces Time to Flare and Increases Sustained Remission in a Phase 2 Trial of Patients with Giant Cell Arteritis [Abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10).AcknowledgementsThis work was supported by a research grant from FOREUM Foundation for Research in Rheumatology. The PMR Research On disease Mechanisms In Synovium (PROMIS) study was also funded by the Rheumatology Grant (Dutch Society for Rheumatology) and Mandema Stipend (University Medical Center Groningen).Disclosure of InterestsWilliam Febry Jiemy: None declared, Rosanne Reitsema: None declared, Anqi Zhang: None declared, Maria Sandovici: None declared, Annemieke Boots: None declared, Peter Heeringa: None declared, Elisabeth Brouwer Speakers bureau: E. Brouwer reports speaker and consulting fees from Roche in 2017-2018, outside the submitted work, Consultant of: E. Brouwer reports speaker and consulting fees from Roche in 2017-2018, outside the submitted work, Kornelis van der Geest Consultant of: K. van der Geest reports personal fees from Roche, outside the submitted work.
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Benkó, Zsolt, Aberra Mogessie, Ferenc Molnár, Steven Hauck, Mark Severson, and Karl Ettinger. "The Influence of Thermal Differences and Variation of Cl–F–OH Ratios on Cu-Ni-PGE Mineralization in the Contact Aureole of the South Kawishiwi Intrusion, Duluth Complex." Geosciences 8, no. 12 (December 12, 2018): 474. http://dx.doi.org/10.3390/geosciences8120474.
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In the contact metamorphic aureole of the Duluth Complex, Cu-Ni-PGE mineralization occurs locally up to 100 m from the intrusion-footwall contact (Spruce Road area), whereas elsewhere (Dunka Pit deposit) the footwall granite and metapelite (Serpentine deposit) are barren. This study aimed to understand the effect of temperature and halogen fugacity variations on the presence or absence of mineralization in these footwall units. The mafic mineral assemblages, two-pyroxene, titanium-in-quartz, and biotite-apatite thermometers indicate that temperatures could be as high as 920 °C in the mineralized areas of the footwall, whereas the maximum temperature was lower by about 100 °C in the unmineralized part of the intrusion. Variation of the halogen concentrations and fugacities was monitored with the analysis of halogen concentrations in biotite and apatite. Fluorine and chlorine concentrations in biotite increase as a function of the distance from contact in the mineralized drill core and decrease in the unmineralized zones. Chlorine concentrations in apatite increase parallel with the distance from contact in the mineralized zones, whereas fluorine concentrations show only minor variation. Concentrations of these elements may have had subtle effect on the partial melting in the footwall units and indirectly facilitated the infiltration of the sulfide liquid into the footwall.
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Rodrigues, Valdemir Antonio, Manuel Esteban Lucas-Borja, José Maria Tarjuelo, Antonio Ruiz Canales, and Rodrigo Máximo Sánchez-Román. "INTERCEPTAÇÃO DA PRECIPITAÇÃO PELAS COPAS EM Pinus halepensis Mill - ALBACETE - ESPANHA." IRRIGA 21, no. 4 (October 6, 2016): 736–49. http://dx.doi.org/10.15809/irriga.2016v21n4p736-749.
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INTERCEPTAÇÃO DA PRECIPITAÇÃO PELAS COPAS EM Pinus halepensis Mill - ALBACETE - ESPANHA VALDEMIR ANTONIO RODRIGUES1; JOSE MARIA TARJUELO2; MANUEL ESTEBAN LUCAS-BORJA2; ANTONIO RUIZ CANALES3 E RODRIGO MÁXIMO SÁNCHEZ-ROMÁN1 (1) Professores da Faculdade de Ciências Agronômicas - Universidade Estadual Paulista. FCA - UNESP. Botucatu - São Paulo – Brasil, valdemirrodrigues@fca.unesp.br , rmsroman@fca.unesp.br(2) Professores da Escuela Superior de Ingeniería Agrícola - Universidad Castilla La Mancha. UCLM. Albacete. Espanha, jose.tarjuelo@uclm.es; manuelesteban.lucas@uclm.es(3) Professor da Escuela Politécnica Superior de Orihuela - Universidad Miguel Hernández de Elche. UMH. Orihuele Espanha, aruizcanales@gmail.com 1 RESUMO Os processos hidrológicos são fundamentais no entendimento da redistribuição da água no ecossistema florestal. Os objetivos do trabalho foram avaliar a precipitação, interceptação pelas copas, a precipitação efetiva, infiltração da água no solo, escoamento superficial e carreamento de sedimentos do solo. Os estudos foram realizados no ano hídrico (2014/2015), com Pinus halepensis de 32 anos de idade, situado no Centro Regional de Estudios del Água (CREA) na Universidad Castilla de La Mancha, em Albacete – Espanha. As avaliações da redistribuição das precipitações foram feitas utilizando 03 pluviômetros externo e 64 sob o dossel das copas das árvores, interceptômetro de tronco e infiltrômetro no solo. Em dados médios as precipitações foram de 329,2mm, a precipitação efetiva de 229,6mm e a interceptação pelas copas de 30%, sendo 70% da precipitação que atinge o solo. Houve alta capacidade de infiltração de 66,4% com baixo escoamento superficial de 10,9mm e, sedimentos de solos carreados de 5,3 ton/ha/ano. Conclui-se que com baixa intensidade de precipitação ocorreu alta interceptação pelas copas, diminuição da precipitação efetiva e infiltração total da água no solo. Já com alta intensidade de precipitação ocorreu diminuição da interceptação e aumento da precipitação efetiva, com infiltração de água no solo de 218,7 mm/ano, o que contribui notavelmente com o reabastecimento da água subterrânea. Palavras- chave: Pinus halepensis, precipitação, precipitação interna, interceptação pelas copas. RODRIGUES, V. A.; TARJUELO, J. M.; LUCAS-BORJA, M. E.; RUIZ CANALES, A.; ROMÁN, R. M. S.EVALUATION OF PRECIPITATION, THROUGHFALL AND INTERCEPTATION BY CANOPIES TREES IN Pinus halepensis - ALBACETE - SPAIN 2 ABSTRACT Hydrological processes are essential in understanding the redistribution of water in the forest ecosystem. The objectives were to evaluate the precipitation, interceptation by canopies, the effective rainfall, water infiltration, runoff and carrying of soil sediment. The studies were conducted in the water year 2014/2015, with Pinus halepensis Mill 32 years old, located in the Regional Centre de Estudios del Agua (CREA) at the Universidad de Castilla La Mancha in Albacete - Spain. Assessments of redistribution of precipitation were made using 03 external and 64 rain gauges under the canopy of the trees, trunk interceptômetro and infiltrometer on the ground. Data on average precipitation were 329,2mm, effective precipitation 229,6mm and the intercepting the tops of 30% and 70% of the precipitation that hits the ground. There was a high 66.4% of infiltration capacity with low runoff 10,9mm with carrying of 5,3 ton/ha/year. It is concluded that low intensity of precipitation was high intercept the tops, decreased effective precipitation and the total water infiltration into the soil. Already with high intensity, rainfall occurred decreased interceptation and increasing effective rainfall, water infiltration into the soil of 218.7 mm/year, which contributes significantly to the replenishment of groundwater. Keywords: Pinus halepensis, precipitation, throughfall, interceptation by canopies trees.
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Oza, Harsh, Victoria Grabinski, Hector Ibanez, Ines Godet, Daniele Gilkes, Ashley Cimino-Mathews, Edward Gabrielson, et al. "Abstract P2-20-14: Relationship of HIF-1α and tumor infiltrating lymphocytes in patients with HER2-negative early-stage breast cancer treated with neoadjuvant chemotherapy." Cancer Research 83, no. 5_Supplement (March 1, 2023): P2–20–14—P2–20–14. http://dx.doi.org/10.1158/1538-7445.sabcs22-p2-20-14.
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Abstract Title: Relationship of HIF-1α and tumor infiltrating lymphocytes in patients with HER2-negative early-stage breast cancer treated with neoadjuvant chemotherapy Authors: Grabinski VF, Oza HH, Gilkes DM, Shah MY, Cimino-Mathews A, Gabrielson E, Zhi I, Pipa Z, Lehman J, Ibanez HE, Ke S, Tsai HL, Stearns V, Santa-Maria CA Introduction: Hypoxia inducible factor 1α (HIF-1α) is an oxygen-dependent transcription factor expressed in areas of hypoxia associated with regulation of immune escape mechanisms, metabolism (CAIX), and results in cancer treatment resistance. High stromal tumor infiltrating lymphocytes (sTILs) are associated with pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) in breast cancer. We investigated associations between HIF-1α, sTILs and their relationship with pCR after NACT in patients with HER2-negative early-stage breast cancer. Methods: We identified patients with early-stage HER2-negative breast cancer at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center from 2000-2009 who received NACT, and had accessible breast tissue from biopsy and/or surgery. A pathologist scored nuclear HIF-1α (0, 1, 2, or 3), membranous CAIX (0, 1, 2, or 3), sTILs (0-100) from baseline (ie pre-NACT) and surgical tissue (if non-pCR). Statistical analysis considered the following variables: age, histology, race, menopausal status, tumor size, and node status. Chemotherapy regimens were divided into either anthracycline AND taxane versus anthracycline OR taxane. Wilcoxon rank-sum, Fisher exact, and Jonckheere trends tests were utilized to assess differences between groups. Results: 43 patients met the predefined criteria and were included in the analysis, 16% (n=7) obtained a pCR. Patient race, ethnicity, clinical tumor size, histology, clinical subtype (estrogen receptor positive (ER+) vs. triple negative (TN)), and NACT regimen were not associated with pCR. Older age (p=0.019), postmenopausal status (p=0.009), smaller surgical tumor size (p < 0.001), and surgical node-negative status (p < 0.001) were associated with pCR. Mean TILs score was 32.5% in patients achieving pCR versus 20% in those with non-pCR (p=0.46); mean HIF-1α was 2.42 in pCR group versus 2.57 in non-pCR (p=0.84). There was a trend of lower baseline sTILs with increasing nuclear HIF-1α score (p=0.085). Membranous CAIX was not associated with nuclear HIF-1α or baseline TILs, however, in the small proportion of patients (n=11) with CAIX scoring, higher membranous CAIX score at baseline (1 vs. 0) was associated with pCR (p=0.024). Conclusions: We observed that patients with pCR had a numerically higher sTILs level at baseline consistent with other studies, but did not find a correlation of HIF-1α and pCR. Patients with higher HIF-1α scores tended to have lower sTILS, suggesting that hypoxia may be leading to an immunosuppressive tumor microenvironment. Further characterizing the HIF-1α pathway and its effects on the immune microenvironment may help identify resistance mechanisms to chemotherapy and immunotherapy. Citation Format: Harsh Oza, Victoria Grabinski, Hector Ibanez, Ines Godet, Daniele Gilkes, Ashley Cimino-Mathews, Edward Gabrielson, Mirat Shah, W. Iris Zhi, Zoe Pipa, Jennifer Lehman, Suqi Ke, Hua-Ling Tsai, Vered Stearns, Cesar Augusto Santa-Maria. Relationship of HIF-1α and tumor infiltrating lymphocytes in patients with HER2-negative early-stage breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-14.
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Stecklum, Maria, Annika Wulf-Goldenberg, Bernadette Brzezicha, Wolfgang Walther, and Jens Hoffmann. "Abstract 1650: Humanized mouse models for preclinical evaluation of novel immune cell therapies, checkpoint inhibitors, and immune cell engagers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1650. http://dx.doi.org/10.1158/1538-7445.am2022-1650.
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Abstract Background The preclinical evaluation of novel immune therapies demands humanized mouse models with functional human immune cells. In previous studies we have demonstrated, that either peripheral blood mononuclear cells (PBMC), subsets of PBMCs like T- and NK-cells or hematopoietic stem cells (HSC) can be used to establish a humanized immune system with functional T-, B-, and NK cells, as well as monocytes and dendritic cells in immunodeficient mice. By transplantation of cell-line-derived (CDX) or patient-derived (PDX) tumor xenografts on humanized mice, we successfully generated a full human tumor-immune-cell model for different tumor entities. Finally, we validated the functionality of these models using checkpoint inhibitors like Ipilimumab (Ipi), Nivolumab (Nivo), Pembrolizumab (Pembro), cell therapies and immune cell engagers. Methods HSC-humanized mice were generated by i.v. transplantation of CD34+stem cells to immunodeficient NOG mice. PBMC or isolated T- or NK-cell preparations were used to humanize mice by single or multiple i.v. injections. CDX and PDX from different entities (i.e. lymphoma, neuroblastoma, and breast cancer) were transplanted on those humanized mice. These models were used to evaluate novel immune therapies. Blood and tumor samples were analysed by FACS for immune cell infiltration and activation. Results The transplanted HSCs engrafted in mice and established a functional human immune system with proliferation and differentiation. 14 weeks after HSC inoculation up to 20% of the human immune cells in the blood were functional T-cells, characterized by a high PD-1 expression. The selected CDX and PDX tumors successfully engrafted on humanized mice without significant differences in tumor growth compared to non-humanized mice. Checkpoint inhibitor treatments induced tumor growth delay in selected models. FACS analysis of tumors revealed an increased percentage of tumor infiltrating T-cells. We identified a set of CDX and PDX models without interference with parallel injection of PBMC, T- or NK-cell preparations for the evaluation of immune cell engagers and other cell therapies. Conclusions We established human tumor-immune-cell models of different entities using CDX or PDX in combination with different donor derived immune cell subsets as effector cells. We demonstrated successful engraftment of HSC on immunodeficient mouse strains, generating mice with a functional human hematopoiesis. These models have been employed for preclinical evaluation of novel checkpoint inhibitors, cell therapies and immune cell engagers. Our models allow preclinical, translational studies on tumor immune biology as well as evaluation of new therapies, drug combinations and biomarker identification and validation. Citation Format: Maria Stecklum, Annika Wulf-Goldenberg, Bernadette Brzezicha, Wolfgang Walther, Jens Hoffmann. Humanized mouse models for preclinical evaluation of novel immune cell therapies, checkpoint inhibitors, and immune cell engagers [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 1650.
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Cobb, Dustin A., Lixia Liu, Barbara Dziegielewska, Philip Mollica, Maria Lee, and Daniel W. Lee. "Abstract 577: Control of solid tumors by alphav beta3 CAR T cells is accompanied by profound tumor penetration and prevention of metastasis in pre-clinical models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 577. http://dx.doi.org/10.1158/1538-7445.am2022-577.
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Abstract Purpose: Using in vitro and xenograft models we aimed to determine the efficacy of αvβ3 CAR T cells deployed against melanoma and breast cancer tumors, two malignancies previously recognized for harnessing the αvβ3 pathway for angiogenic and invasion purposes. Procedures: CAR T cells expressing an anti-αvβ3 scFv containing either a CD28 or 4-1BB co-stimulatory domain and CD3zeta were generated by retroviral transduction. In vitro cytotoxicity of αvβ3 CAR T cells was assessed by co-culture with melanoma or breast tumor cells assayed with bioluminescent- and impedance-based methods and effector cytokine production by ELISA. Xenograft studies, including melanoma (SK-MEL-28) and orthotopic breast tumors (MD-AMB-231), were carried out in NSG mice to evaluate in vivo efficacy of systemically administered αvβ3 CAR T cells. Immunohistochemistry was performed to evaluate T cell infiltration of melanoma tumors and changes within the tumor microenvironment. NSG mice harboring orthotopic breast tumors were monitored for disease progression, development of metastases using bioluminescent imaging and flow cytometry analysis of lung tissue, and overall survival. Results: αvβ3 CAR T cells exhibited robust cytotoxicity and cytokine production against several melanoma and triple-negative breast tumor cell lines. Systemic administration of αvβ3 CAR T cells potently inhibited growth of SK-MEL-28 melanoma xenografts as demonstrated by significant differences in tumor volume relative to CD19 CAR treatment. Immunohistochemical analysis of tumors at the experimental endpoint revealed striking infiltration of residual tumors by human T cells in mice administered αvβ3.28z CARs, but to a lesser extent in αvβ3.BBz CAR-treated xenografts. This T cell infiltration was accompanied by marked expression of PD-L1 that was mostly absent in tumors of CD19 CAR-treated controls, suggesting treatment-induced up-regulation of PD-L1. In orthotopic xenografts of MD-AMB-231 breast tumors, αvβ3 CAR T cells were able to control tumor growth, prevent the formation of lung metastases, and resulted in enhanced overall survival. Conclusions: These pre-clinical studies highlight a renewed potential for targeting integrins, specifically αvβ3, for the treatment of solid tumors. Data from this study suggests that αvβ3 CAR T cell therapy for melanoma may be further improved by combination therapy with checkpoint inhibition. Together with our prior work demonstrating robust efficacy of αvβ3 CAR T cells to treat glioblastoma and DIPG xenografts, these results highlight the broad applicability of utilizing CAR T cells targeting αvβ3 for treatment of multiple cancer types with reduced risk of on-target, off-tumor toxicity due to the restricted expression of αvβ3 in normal tissues. Results of these studies warrant further development of αvβ3 CAR T cells for clinical use. Citation Format: Dustin A. Cobb, Lixia Liu, Barbara Dziegielewska, Philip Mollica, Maria Lee, Daniel W. Lee. Control of solid tumors by alphav beta3 CAR T cells is accompanied by profound tumor penetration and prevention of metastasis in pre-clinical models [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 577.
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Deshpande, Atul, Melanie Loth, Dimitrios Sidiropoulos, QingFeng Zhu, Genevieve Stein-O'Brien, NIkhil Rao, Cedric Uytingco, et al. "Abstract 2130: Uncovering the spatial landscape of tumor-immune interactions using latent spaces from spatial transcriptomics." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2130. http://dx.doi.org/10.1158/1538-7445.am2022-2130.
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Abstract Recent advances in spatial transcriptomics (ST) enable us to measure gene expression from cancer tissues while retaining their spatial context. We present a novel bioinformatics pipeline to infer molecular changes from tumor and immune cell interactions in the tumor microenvironment (TME) from ST data. Latent space methods enable inference of biological patterns from ST without the need for spot deconvolution into cell-based spatial features. While linear latent space methods yield interpretable biological patterns, interactions between tumor and immune cells can be nonlinear. To enable comprehensive inference of the pathways in the TME, we developed novel algorithms to characterize biological patterns from ST data using linear latent space methods and further nonlinear effects from their interactions. For any given set of genes, the patternSpotter tool visualizes the spatial variation in the relative contribution of individual patterns to the aggregate expression at each location in the tumor sample. Application of this tool to latent features identified using CoGAPS non-negative matrix factorization on a Visium ST (10x Genomics) data from a lymph node with pancreatic cancer metastasis confirms its known immune cell architecture. Furthermore, we develop a patternMarker algorithm to identify sets of coexpressed genes associated with the patterns, which help us to pinpoint the underlying biological processes and cell types. Further analyzing a breast cancer sample with invasive carcinoma and multiple precursor lesions demonstrates that this approach can uncover tumor and immune regions without prior reliance on pathology annotations from H&E imaging. In this case, an ensemble-based factorization of multiple dimensions enhances our resolution of intra-tumor heterogeneity and identifies distinct hormone receptor pathways in different precursor lesions with the patternMarker algorithm. Additional latent features are associated with immune cells, revealing further heterogeneity in immune infiltration between the invasive carcinoma and distinct precursor lesions. Still, the molecular interactions resulting from this infiltration induce a further non-linear alteration to transcription not captured through the inferred latent spaces. To resolve this, we develop a further interactionMarker statistic to identify regions of inter-pattern interaction and the associated genes. We apply this approach to detect additional intra-tumor heterogeneity in immune signaling from infiltration suggestive of differences in immune attack of invasive lesions. Altogether, our pipeline for latent space analysis of ST can identify the location and context-specific molecular interactions within the TME, broadly applicable to a better understanding of the key drivers of tumorigenesis and resistance to immune attack in cancer. Citation Format: Atul Deshpande, Melanie Loth, Dimitrios Sidiropoulos, QingFeng Zhu, Genevieve Stein-O'Brien, NIkhil Rao, Cedric Uytingco, Stephen Williams, Cesar Santa-Maria, Daniele M. Gilkes, Lei Zhang, Elizabeth Jaffee, Robert Anders, Ludmila Danilova, Luciane T. Kagohara, Elana J. Fertig. Uncovering the spatial landscape of tumor-immune interactions using latent spaces from spatial transcriptomics [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 2130.
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Silva, Sérgio Ricardo da, Nairam Félix de Barros, Liovando Marciano da Costa, and Fernando Palha Leite. "Soil compaction and eucalyptus growth in response to forwarder traffic intensity and load." Revista Brasileira de Ciência do Solo 32, no. 3 (June 2008): 921–32. http://dx.doi.org/10.1590/s0100-06832008000300002.
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During timber exploitation in forest stands harvesting machines pass repeatedly along the same track and can cause soil compaction, which leads to soil erosion and restricted tree root growth. The level of soil compaction depends on the number of passes and weight of the wood load. This paper aimed to evaluate soil compaction and eucalyptus growth as affected by the number of passes and wood load of a forwarder. The study was carried out in Santa Maria de Itabira county, Minas Gerais State - Brazil, on a seven-year-old eucalyptus stand planted on an Oxisol. The trees were felled by chainsaw and manually removed. Plots of 144 m² (four rows 12 m long in a 3 x 2 m spacing) were then marked off for the conduction of two trials. The first tested the traffic intensity of a forwarder which weighed 11,900 kg and carried 12 m³ wood (density of 480 kg m-3) and passed 2, 4, and 8 times along the same track. In the second trial, the forwarder carried loads of 4, 8, and 12 m³ of wood, and the machine was driven four times along the same track. In each plot, the passes affected four rows. Eucalyptus was planted in 30 x 30 x 30 cm holes on the compacted tracks. The soil in the area is clayey (470 clay and 440 g kg-1 sand content) and at depths of 0-5 cm and 5-10 cm, respectively, soil organic carbon was 406 and 272 g kg-1 and the moisture content during the trial 248 and 249 g kg-1. These layers were assessed for soil bulk density and water-stable aggregates. The infiltration rate was measured by a cylinder infiltrometer. After 441 days the measurements were repeated, with additional analyses of: soil organic carbon, total nitrogen, N-NH4+, N-NO3-, porosity, and penetration resistance. Tree height, stem diameter, and stem dry matter were measured. Forwarder traffic increased soil compaction, resistance to penetration and microporosity while it reduced the geometric mean diameter, total porosity, macroporosity and infiltration rate. Stem dry matter yield and tree height were not affected by soil compaction. Two passes of the forwarder were enough to cause the disturbances at the highest levels. The compaction effects were still persistent 441 days after forwarder traffic.
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Rodrigues, Valdemir Antonio, Rodrigo Máximo Sánchez-Román, José Maria Tarjuelo, Maria Márcia Pereira Sartori, and Antonio Ruiz Canales. "AVALIAÇÃO DO ESCOAMENTO E INTERCEPTAÇÃO DA ÁGUA DAS CHUVAS." IRRIGA 1, no. 1 (June 12, 2015): 01–13. http://dx.doi.org/10.15809/irriga.2015v1n1p01.
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AVALIAÇÃO DO ESCOAMENTO E INTERCEPTAÇÃO DA ÁGUA DAS CHUVAS VALDEMIR ANTONIO RODRIGUES1; RODRIGO M. SÁNCHEZ-ROMÁN1; JOSÉ MARIA TARJUELO2; MARIA MÁRCIA PEREIRA SARTORI1 E ANTONIO RUIZ CANALES3 (1)Faculdade de Ciências Agronômicas -Universidade Estadual Paulista. UNESP. Botucatu - SP - Brasil.(2)Escuela Superior de Ingeniería Agrícola - Universidad CastillaLa Mancha. UCLM. Albacete. Espanha.(3)Escuela Politécnica Superior de Orihuela - Universidad Miguel Hernández de Elche, Orihuele Espanha.E-mails: valdemirrodrigues@fca.unesp.br, rmsroman@fca.unesp.br, jose.tarjuelo@uclm.es,mmpsartori@fca.unesp.br, aruizcanales@gmail.com, 1 RESUMO Os objetivos foram quantificar o escoamento superficial em diferentes coberturas do solo; analisar a função da vegetação na interceptação da água e controle da erosão; discutir os fatores que alteram a dinâmica da água em parcelas experimentais. O trabalho foi realizado na fazenda São Manuel, no estado de São Paulo (FCA/UNESP), em parcelas de solos com: cobertura vegetal, gramíneas, sem cobertura vegetal e solo impermeabilizado. As simulações de chuvas foram realizadas com quatro tempos de duração. Os tipos de cobertura do solo, intensidade das precipitações, influenciaram no escoamento superficial com maior sedimentação, enquanto que no solo com vegetação ocorreu interceptação pelas copas e menor mobilização de sedimentos. O coeficiente de escoamento superficial foi baixo na presença de vegetação resultando em maior infiltração e melhor regularidade da vazão. Enquanto que a erosão e sedimentos aumentaram nos solos desprotegidos alterando a dinâmica hidrológica em microbacias. Palavras - chave: precipitação, vegetação, erosão do solo, microbacia. RODRIGUES, V. A.; ROMÁN, R. M. S.; TARJUELO, J. M.; SARTORI, M. M. P;RUIZ CANALES, A.EVALUATION OF RUNOFF AND INTERCEPTION OF RAINFALL 2 ABSTRACT The objectives of this study were to quantify the surface runoff in different soil covers; analyze the effect of the forest on water interception and on erosion control; discuss the factors affecting water dynamics in experimental plots. The study was conducted at the São Manuel farm, São Paulo State - FCA/UNESP, in soil plots as follows: with vegetative cover, grasses, without vegetative cover and impervious soil. Rainfall simulations were performed using four time periods. The types of soil covering and rainfall intensity affected surface runoff causing higher sedimentation, whereas interception by the canopies and lower sediment mobilization were found in soil with vegetation. The coefficient of surface runoff was low in the presence of vegetation, leading to higher infiltration and better flow regularity, whereas erosion and sediments increased in unprotected soils affecting hydrological dynamics in micro watersheds. Keywords: precipitation, vegetation, soil erosion, micro watershed.
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Morin, David, Réjean Hébert, and Louise Corriveau. "Mesoproterozoic deep K-magmatism recorded in a megacryst- and xenolith-bearing minette dyke, western Grenville Province." Canadian Journal of Earth Sciences 42, no. 10 (October 1, 2005): 1881–906. http://dx.doi.org/10.1139/e05-083.
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The 1.07 Ga Rivard minette dyke transported thousands of exotic (xenoliths) and cogenetic (cognate nodules) clasts from deep lithospheric levels of the Grenville Province. Nodules related to the clinopyroxene- and biotite-phyric host consist of megacrystic clinopyroxene and K-feldspar and mica-rich pyroxenite. Clinopyroxene megacrysts record high-pressure and high-temperature crystallization, crystal recycling, or magma mixing, whereas Ba-rich K-feldspar megacryst possibly represent near-solidus phenocrysts crystallized from evolved K-rich magmas. Mica-pyroxenite xenoliths are interpreted as products of magma mixing or infiltration of K-rich melt in pyroxene cumulate. Partial replacement of pyroxenes by strained phlogopite attests to mica crystallization before or during plastic deformation and prior to xenolith incorporation in the minette. The minette is mafic, ultrapotassic, and enriched in large-ion lithophile elements and light rare-earth elements. It experienced limited fractionation and crustal contamination but has been exposed to magma mixing. High K, La, and Cr contents suggest partial melting of a K-metasomatized mantle source. The Rivard minette shares the age, mineralogy, and chemistry with the 1.091.07 Ga KensingtonSkootamatta potassic alkaline suite and forms part of a common K-rich magmatic event taking its source in an enriched mantle. Source heterogeneity, conditions of partial melting, crystal fractionation, magma mixing, and crustal contamination all contributed, to various extents, to the complex chemistry of the K-rich intrusions of the KensingtonSkootamatta suite. Collectively, this suite records extensive and diverse magmatic batches derived from partial melting of a mantle metasomatized during subduction events prior to emplacement.
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Ghent, Edward D., Benjamin R. Edwards, and James K. Russell. "Pargasite-bearing vein in spinel lherzolite from the mantle lithosphere of the North America Cordillera." Canadian Journal of Earth Sciences 56, no. 8 (August 2019): 870–85. http://dx.doi.org/10.1139/cjes-2018-0239.
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Basanite lavas near Craven Lake, British Columbia, host a spinel lherzolite xenolith containing cross-cutting veins with pargasitic amphibole (plus minor apatite). The occurrence of vein amphibole in spinel lherzolite is singular for the Canadian Cordillera. The vein crosscuts foliated peridotite and is itself cut by the basanite host. The amphibole is pargasite, which is the most common amphibole composition in mantle peridotite. Rare earth element concentrations in the pargasite are similar to those for mafic alkaline rocks across the northern Cordilleran volcanic province (light rare earth elements ∼50× chondrite and heavy rare earth elements ∼5× chondrite). Two-pyroxene geothermometry suggests that the vein and host peridotite were thermally equilibrated prior to sampling by the basanite magma. Calculated temperature conditions for the sample, assuming equilibration along a model steady-state geotherm, are between 990 and 1050 °C and correspond to a pressure of 0.15 GPa (∼52 ± 2 km depth). These conditions are consistent with the stability limits of mantle pargasite in the presence of a fluid having XH2O < ∼0.1. The pargasite vein and associated apatite provide direct evidence for postaccretion fracture infiltration of CO2–F–H2O-bearing silicate fluids into the Cordilleran mantle lithosphere. Pargasite with low aH2O is in equilibrium with parts per million concentrations of H2O in mantle olivine, potentially lowering the mechanical strength of the lithospheric mantle underlying the Cordillera and making it more susceptible to processes such as lithospheric delamination. Remelting of Cordilleran mantle lithosphere containing amphibole veins may be involved in the formation of sporadic nephelinite found in the Canadian Cordillera.
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Ciruelos, Eva, Antonia Perelló, Santiago González-Santiago, Ana López, Francisco Javier Salvador Bofill, Cinta Albacar, Juan Miguel Cejalvo, et al. "Abstract OT2-08-02: SOLTI-1907 ATREZZO: Targeting hormonal receptor negative (HR-) or PAM50 non-luminal disease with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive metastatic breast cancer (MBC)." Cancer Research 83, no. 5_Supplement (March 1, 2023): OT2–08–02—OT2–08–02. http://dx.doi.org/10.1158/1538-7445.sabcs22-ot2-08-02.
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Abstract Background Today, there is no clear therapeutic algorithm for patients with metastatic HER2-positive (HER2+) breast cancer (BC) who have progressed to trastuzumab, pertuzumab, tyrosine kinase inhibitors and antibody-drug conjugates (ADC). Among the emerging strategies, the use of immune checkpoint inhibitors in combination therapy is showing promising clinical benefit in the advanced setting of HER2+ BC by overcoming immune resistance and enhancing antitumor cellular immunity. The intrinsic subtypes Basal-like and HER2-enriched (i.e PAM50 non-luminal tumors) represent approximately the 60% of HER2+ BC and are associated with higher expression of immune-related genes, tumor-infiltrating lymphocytes (TILs) presence and high tumor mutational burden (TMB), compared to luminal subtypes. Additionally, immune infiltration and TMB in HER2+ BC are associated with chemo/antiHER2 responsiveness and with potential benefit from anti-PD-1/PD-L1 inhibitors. We hypothesize that combining atezolizumab with trastuzumab and vinorelbine may improve outcomes in HR- or PAM50 non-luminal/HR-positive (HR+) disease within HER2+ MBC. Methods ATREZZO is an open-label, single-arm, Simon 2-stage, multicenter phase II study. The trial will include 55 pre- or post-menopausal female or male patients with unresectable locally advanced or metastatic HR- or PAM50 non-luminal/HR+ HER2+ BC and progressed to trastuzumab-based chemotherapy and anti-HER2 ADC. Prior pertuzumab is allowed, but not required. Treatment consists of atezolizumab IV 1200 mg every 3 weeks combined with trastuzumab and vinorelbine. Patients with stable, progressing, or untreated brain metastasis not requiring immediate local therapy are eligible. The primary objective is to evaluate the Overall Response Rate (ORR) according to RECIST v 1.1 and secondary endpoints include ORR in patients with PD-L1 positive breast cancer, clinical benefit rate, overall survival and progression-free survival. The final recruited population will contain no more than 60 % of patients with PD-L1 negative tumors. Tumor assessments will be performed every 9 weeks. Incidence, duration and severity of adverse events, and further correlative molecular analyses will be also evaluated. An interim analysis will be conducted when 19 patients are evaluable for ORR and if the number of responses is ≥ 3, 36 additional patients will be included. As of July 15th, 2022, 48 patients were screened and 15 were included in sixteen Spanish sites. This study was funded by Roche Farma SA. Trial identification: NCT04759248 Citation Format: Eva Ciruelos, Antonia Perelló, Santiago González-Santiago, Ana López, Francisco Javier Salvador Bofill, Cinta Albacar, Juan Miguel Cejalvo, Santiago Escrivá-de-Romani, Isabel Blancas, Sonia Pernas, Olga Martínez-Sáez, Josefina Cruz, Jose Ponce, Sonia Servitja, Maria-Eva Perez-Lopez, Juan A Guerra, Esther Sanfeliu, Cesar A Rodríguez, Guillermo Villacampa, Lorea Villanueva, Pablo Tolosa, Tomás Pascual, Aleix Prat. SOLTI-1907 ATREZZO: Targeting hormonal receptor negative (HR-) or PAM50 non-luminal disease with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-08-02.
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Humphreys, M. C. S., J. Zhang, G. F. Cooper, C. G. Macpherson, and C. J. Ottley. "Identifying the ingredients of hydrous arc magmas: insights from Mt Lamington, Papua New Guinea." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 377, no. 2139 (January 7, 2019): 20180018. http://dx.doi.org/10.1098/rsta.2018.0018.
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Volcanism is the surface expression of magma intrusion, crystallization, assimilation and hybridization processes operating throughout the crust over a range of time periods. Many magmas, including those erupted at subduction zones, have complex textures that reflect these processes. Here, we use textural and geochemical characteristics of calcic amphiboles to help identify multiple ingredients of subduction zone magmatism at Mt Lamington volcano, Papua New Guinea. Our approach uses existing trace element partitioning schemes to calculate the compositions of amphibole equilibrium melts (AEMs). The AEM compositions show that Mt Lamington andesites and plutonic enclaves are dominated by fractionation of amphibole + plagioclase + biotite, with assimilation of plagioclase and zircon. Magnesiohastingsite crystals in the andesite and diktytaxitic mafic enclaves reflect multiple episodes of recharge by more primitive, geochemically variable melts. The andesite also contains clots with rounded grains and melt on grain boundaries. These features indicate slow crystallization, and the retention of melt films could significantly enhance the potential for remobilization of crystals by infiltrating melts or during magma mixing. Variations in crystallization conditions could thus significantly affect the mush microstructure. We suggest that this could result in a significant bias of the volcanic record towards the preferential incorporation of more slowly cooled plutonic material from the lower crust or from more thermally mature plumbing systems. This article is part of the Theo Murphy meeting issue ‘Magma reservoir architecture and dynamics’.
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Francini, Edoardo, Fang-Shu Ou, Stefano Lazzi, Roberto Petrioli, Andrea Giovanni Multari, Guido Pesola, Luciana Messuti, et al. "CD3+ tumor-infiltrating lymphocytes (TILs) as prognostic in patients (pts) with stage II colon cancer (CC) not treated with adjuvant chemotherapy (ADJ)." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 167. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.167.
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167 Background: Previous studies have reported high TILs are a favorable prognostic factor in stage II CC. However, whether the impact of TILs on overall survival (OS) differs among pts who did or did not receive ADJ is still to be determined. We assessed the prognostic value of CD3+ TILs in pts with stage II CC according to whether they received ADJ or not (no-ADJ). Methods: Pts treated with curative surgery for stage II CC (2002-2013) were identified through the Santa Maria alle Scotte Hospital database. CD3+ TILs at the invasive front, center of tumor, and stroma, were determined by immunohistochemistry and manually quantified as the rate of TILs/total tissue areas. High TILs (H-TILs) was defined as > 20%. Pts were classified as high or low TILs (L-TILs) and ADJ or no-ADJ. Cox models were used to assess OS with hazard ratio estimates (95% CI). Results: Of the 678 pts included (356 deaths), 137 (20%) received ADJ while 541 (80%) did not. ADJ comprised fluoropyrimidine +/- oxaliplatin. Median follow-up was 8.5 years. The distributions of the 4 groups were: 16% (L-TIL/ADJ), 64% (L-TIL/no-ADJ), 5% (H-TIL/ADJ), 15% (H-TIL/no-ADJ). Compared to H-TILs/no-ADJ, ADJ pts had a significantly longer OS (P < .0001) regardless of the TILS rate while L-TILs/no ADJ had significantly shorter OS and higher risk of death (HR = 1.41; 95% CI, 1.06-1.88; P < .0001) [See table]. On multivariable analysis, adjusting for perforation, obstruction, T-stage, grade, < 12 lymph nodes resected, lymphovascular and perineural invasion, the adverse prognostic impact of L-TILs (vs H-TILs) in no-ADJ pts was confirmed (HR = 1.36; 95% CI 1.02, 1.82; P = .0373). Conclusions: Low CD3+ TILs rate was independently associated with shorter OS in stage II CC pts who did not receive ADJ, but was not prognostic among pts who had ADJ. These data suggest a potentially different impact of TILs in chemo-treated vs -untreated stage II CC which could affect clinical decision making. [Table: see text]
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Leal, Clarice Maria, Aderson Soares de Andrade Júnior, Valdemício Ferreira de Sousa, Enio Farias de França e Silva, and Edson Alves Bastos. "QUALIDADE DA ÁGUA SUBTERRÂNEA PARA FINS DE IRRIGAÇÃO NA MICRORREGIÃO DE TERESINA, PIAUÍ." IRRIGA 14, no. 3 (September 30, 2009): 276–88. http://dx.doi.org/10.15809/irriga.2009v14n3p276-288.
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QUALIDADE DA ÁGUA SUBTERRÂNEA PARA FINS DE IRRIGAÇÃO NA MICRORREGIÃO DE TERESINA, PIAUÍ. Clarice Maria Leal1; Aderson Soares de Andrade Júnior1; Valdemício Ferreira de Sousa1; Ênio Farias de França e Silva2; Edson Alves Bastos1[1]Empresa Brasileira de Pesquisa Agropecuária do Meio Norte, Teresina, PI, clarice@cpamn.embrapa.br2Universidade Federal Rural de Pernambuco, Recife, PE. 1 RESUMO O presente estudo teve por objetivo a realização de um levantamento das características físicas, químicas e físico-químicas das águas subterrâneas da Bacia Sedimentar do Rio Parnaíba, em especial aquelas características relevantes para a determinação da qualidade dessas águas para fins de irrigação. Foram coletadas amostras de água em 270 poços georreferenciados localizados em 14 municípios da Microrregião de Teresina-PI. As amostras foram coletadas em duas épocas distintas, ou seja, nas estações secas de 2004 e de 2005. Nessas amostras foram realizadas determinações dos seguintes parâmetros: pH, NH4+, NO3-, Ca2+, Mg2+, CE, RAS, Na+, Cloretos, Bicarbonatos e Carbonatos. Os resultados foram interpoladosem um SIG (Sistemas de Informações Geográficas) – SPRING – com o objetivo de constituir mapas temáticos mostrando as classes de restrição das águas para fins de irrigação. Dentre os resultados obtidos, a análise conjunta de RAS e CE revelou potenciais problemas de infiltração da água no solo em mais da metade dos municípios, mostrando a necessidade de um manejo adequado da irrigação com vistas a mitigar os problemas nessas áreas. UNITERMOS: salinidade, infiltração, hidrogeologia, RAS, CE, SPRING LEAL, C. M.; ANDRADE JÚNIOR, A. S., de; SOUSA, V. F. de; SILVA, E. F. de F.; BASTOS, E. A. GROUNDWATER QUALITY TO IRRIGATION IN TERESINA REGION, PIAUI STATE, BRAZIL 2 ABSTRACT The objective of the present study was to analyze chemical and physical characteristics, of the groundwater of the Sedimentary Basin of Parnaíba River, especially those ones that are important to determine water quality for irrigation. Samples were collected in 270 georreferenced wells located in 14 municipal districts of Teresina Region, PiauiState. The samples were collected in 2004 and 2005 dry stations. The following parameters were determined: pH, NH4+, NO3-, Ca2+, Mg2+, CE, SAR, Na+, Chlorides, Bicarbonates and Carbonates. The results were interpolated in a GIS (Geographical Systems Information) - SPRING – in order to make theme maps showing the restriction classes of irrigation water. The analysis of sodium adsorption ratio (SAR) and electric conductivity (EC) showed water infiltration problems in the soil in most of the municipal districts, and the need of an appropriate irrigation management technique to mitigate the problems in those areas.KEYWORDS: salinity, infiltration, hydrogeology, SAR, EC, SPRING
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Connolly, Joseph J., Laura M. Spring, Alphonse G. Taghian, Michele Gadd, Laura Warren, Ana C. Garrido-Castro, Tari King, et al. "Abstract OT3-15-01: TBCRC-053: P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer." Cancer Research 83, no. 5_Supplement (March 1, 2023): OT3–15–01—OT3–15–01. http://dx.doi.org/10.1158/1538-7445.sabcs22-ot3-15-01.
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Abstract Background: The introduction of immune checkpoint inhibitors (ICI) to standard neoadjuvant chemotherapy regimens has been shown to significantly improve outcomes in patients with triple negative breast cancer and is being investigated for high-risk hormone receptor-positive (HR+)/human epidermal growth factor-2 negative (HER2-) breast cancer. Preclinical evidence suggests radiation therapy (RT) can stimulate intra-tumoral T cell infiltration and enhance the expression and immune detection of tumor-specific neoantigens. This phase II pilot randomized study (NCT04443348) aims to evaluate the safety and efficacy of two different doses of preoperative primary tumor RT boost when combined with neoadjuvant pembrolizumab, then followed by standard neoadjuvant chemotherapy. Dual co-primary endpoints include determining the pathologic complete response (pCR) rate in the non-irradiated and pathologically confirmed metastatic axillary lymph node(s) in each treatment arm and quantifying tumor-infiltrating T lymphocytes in on-treatment (C1D14) tumor biopsies. We hypothesize that high-dose RT will increase the proportion of tumors with high T cell infiltration (i.e., top quartile) from 25% to 55%. Secondary endpoints include measuring residual cancer burden, evaluating tolerability of the regimen, and assessing quality of life. Exploratory endpoints include evaluation of treatment-associated changes in the tumor immune microenvironment, circulating immune cell analyses, and circulating tumor DNA kinetics. Methods: The study plans to enroll 128 participants with either triple negative (n=80) or high-risk HR=/HER2- (n=48) breast cancer who will be randomized to receive no, low (9 Gy), or high (24 Gy) dose of preoperative RT boost, after which 24 participants of either breast cancer subtype will be enrolled to an exploratory high dose proton therapy boost cohort. The eligibility criteria include patients who have biopsy-proven, axillary lymph node-positive breast cancer that is either triple negative (defined as ER< 10%, PR< 10%, and HER2-negative) or high-risk HR+/HER2- (grade III or having a high-risk genomic assay score). Study treatment is given in 6-week cycles, with 400 mg Pembrolizumab given on day 1 of each cycle. For those participants randomized to receive a preoperative RT boost, treatment is delivered in 3 fractions (3 × 3 Gy or 3 × 8 Gy) over consecutive business days, where one of the fractions is given on the same day as C1D1 Pembrolizumab. Standard neoadjuvant chemotherapy begins on C1D15 with paclitaxel (plus carboplatin for triple negative) administered weekly for 12 weeks, and then starting on C3D15, dose-dense doxorubicin/cyclophosphamide is administered every 2 weeks for 8 weeks. Following neoadjuvant treatment, participants will receive standard breast surgery (including removal of the pathologically confirmed metastatic lymph node) followed by adjuvant pembrolizumab, radiation therapy, and standard-of-care systemic therapy as clinically indicated. Tissue samples from the primary tumor and biopsy-proven lymph node are taken at baseline, C1D14, and at the time of surgery. There are eleven blood collection timepoints throughout the neoadjuvant and adjuvant settings. Participants will be followed for 2 years after surgery to assess safety and durability of responses. Results: This study has accrued 12 participants to date, including 10 with triple negative breast cancer and 2 with high-risk HR+/HER2- breast cancer. Formal results for this study are forthcoming, as the trial is actively accruing at 6 institutions, with plans to open at 3 more within the year. For persons with a specific interest in this trial, please contact Joseph Connolly, Multi-Center Coordinator, at jconnolly28@mgh.harvard.edu. Citation Format: Joseph J. Connolly, Laura M. Spring, Alphonse G. Taghian, Michele Gadd, Laura Warren, Ana C. Garrido-Castro, Tari King, Elizabeth A. Mittendorf, Jose P. Leone, Dana L. Casey, Lisa Carey, Tiffany A. Traina, Yara Abdou, Atif Khan, George Plitas, Jean Wright, Cesar Augusto Santa-Maria, Lisa Jacobs, Rachel Blitzblau, E Shelley Hwang, Carey Anders, Ian Krop, Antonio C. Wolff, Alastair M. Thompson, Elyssa Denault, Gaorav Gupta, Alice Ho. TBCRC-053: P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-15-01.
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Prat, Aleix, Juan M. Cejalvo, Laia Pare, Olga Martínez-Sáez, Mireia Margelí Vila, Claudette Falato, Josefina Cruz, et al. "Abstract PD13-04: Activity of patritumab deruxtecan, a HER3-directed antibody drug conjugate, in early breast cancer according to ERBB3 expression: Interim analysis results of a window-of-opportunity study (SOLTI-1805 TOT-HER3)." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD13–04—PD13–04. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd13-04.
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Abstract Introduction Patritumab deruxtecan (U3-1402; HER3-DXd) is a HER3-directed antibody drug conjugate with demonstrated clinically meaningful antitumor activity and acceptable safety profile in heavily pre-treated metastatic breast cancer (BC) with high or low HER3 expression levels (Masuda et al. Cancer Res. 2019; Krop et al. SABCS 2020). Here, we report the interim efficacy and safety data of the TOT-HER3 trial (NCT04610528), the first window-of-opportunity study designed to assess whether a single dose of HER3-DXd may increase immune infiltration during short-term preoperative treatment in early BC. Methods This is a prospective, phase 0, multicenter, single arm trial planned to enroll 80 patients with treatment naïve hormone receptor positive, HER2 negative primary operable BC ≥1 cm by ultrasound. Patients are allocated to one of 4 cohorts based on centrally assessed levels of ERBB3 mRNA by the nCounter platform in a pre-treatment biopsy and receive HER3-DXd administered as a single dose of 6.4 mg/kg. Post-treatment biopsy at C1D21 is obtained to explore primary and correlative endpoints. The primary objective is to evaluate the median change in the CelTIL score (-0.8*tumor cellularity% + 1.3*tumor-infiltrating lymphocytes%) (Nuciforo et al. Ann Oncol. 2018) in paired pre- and post-treatment samples in the overall cohort. Change in CelTIL score and the expression of 67 genes across ERBB3 cohorts and PAM50 subtypes is also explored. Adverse events (AEs) are graded according to CTCAE v 5.0. Results As of April 21 2021, 30 patients (all women) received the study treatment and were evaluable for the primary endpoint. Mean age was 52 years (range 35-77 years); 19 patients were pre- and 11 were post-menopausal. Median tumor size was 20 mm (range 10-60 mm); cN0 70%; mean Ki67 35% (range 10-90%); grade 1-2 67%. According to ERBB3 expression, 6 (20%), 13 (43%), 5 (17%) and 6 (20%) patients were categorized as high, medium, low and ultra-low, respectively. CelTIL score increased, was stable and decreased in 17 (57%), 3 (10%) and 10 (33%) patients, respectively. Overall, a statistically significant increase in CelTIL was observed between paired samples (p=0.028). At C1D21, a total of 12 (44%) patients experienced a response (7 complete and 5 partial response) by clinical palpation. CelTIL significantly changed in responders (p=0.006) but not in patients with stable disease (p=0.61). Baseline ERBB3 levels did not correlate with CelTIL change or clinical response. Moreover, PAM50 subtype distribution was as follows: Luminal A 15 (50%), Luminal B 13 (43%), HER2-Enriched 1 (3.5%), Basal-like 1 (3.5%). CelTIL score did not change significantly between Luminal A and Luminal B tumors. Five (38.5%) Luminal B tumors switched to Luminal A at C1D21. Interestingly, baseline high PAM50 risk-of-recurrence was associated with higher CelTIL score at C1D21 (p=0.002). Patritumab deruxtecan induced high expression of immune-related genes including PD1, CD8a and CD19 and Luminal A signature and suppressed proliferation-related genes. Overall, 29 (97%) patients reported at least one AE and 98% of AEs were grade 1 or 2. The most common AEs were nausea, asthenia, abdominal pain, alopecia, vomiting, diarrhea, neutropenia, increased liver enzymes. A grade 3 treatment-related reversible AST increase occurred in 1 patient. Conclusion In this interim trial analysis, a single dose of patritumab deruxtecan was associated with clinical response and important biological changes irrespective of baseline ERBB3 expression. The safety profile was consistent with that previously reported for the drug. Citation Format: Aleix Prat, Juan M. Cejalvo, Laia Pare, Olga Martínez-Sáez, Mireia Margelí Vila, Claudette Falato, Josefina Cruz, Miriam Arumí de Dios, Maria J Vidal, Juan Antonio Guerra, Ana Maria Luna Barrera, Pablo Tolosa, Francisco Javier Salvador-Bofill, Sonia Pernas, Blanca Gonzáles-Farré, Esther Sanfeliu, Eva Ciruelos, Violeta Serra, Martin Espinosa-Bravo, Yann Izarzugaza, Stephen Esker, Pang-Dian Fan, Guillermo Villacampa, Juan M Ferrero-Cafiero, Tomás Pascual, Mafalda Oliveira. Activity of patritumab deruxtecan, a HER3-directed antibody drug conjugate, in early breast cancer according to ERBB3 expression: Interim analysis results of a window-of-opportunity study (SOLTI-1805 TOT-HER3) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-04.
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Gawiński, Cieszymierz, Wojciech Michalski, Andrzej Mróz, and Lucjan Wyrwicz. "Correlation between Lymphocyte-to-Monocyte Ratio (LMR), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR) and Tumor-Infiltrating Lymphocytes (TILs) in Left-Sided Colorectal Cancer Patients." Biology 11, no. 3 (February 28, 2022): 385. http://dx.doi.org/10.3390/biology11030385.
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Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Novel markers are required in order to select high-risk patients and better adjust the treatment. Both peripheral and local markers of cancer-related inflammation (CRI) such as lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR) and tumor-infiltrating lymphocytes (TILs) have been thoroughly investigated in recent years and deemed to be highly prognostic. We hypothesized that there is an association between local and peripheral CRI indices and that blood-based biomarkers may serve as a surrogate of TILs. We retrospectively analyzed 87 patients with locally advanced left-sided CRC treated with radical-intent surgery in the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw, Poland, between January 2014 and December 2015. Fifty patients were found eligible for the study. The patients were divided in terms of pre-treatment values of systemic inflammatory response (SIR) markers into LMR/NLR/PLR-high and low groups. We evaluated the resected specimens by immunohistochemistry in order to assess the densities of CD3+ and CD8+ lymphocytes in the center of the tumor and in the invasive margin. We found that the level of CD3+ lymphocytes in the center of the tumor was statistically significantly higher in patients with low pre-treatment NLR (p = 0.044); however, no correlation between any of the SIR markers and CD3+ or CD8+ TILs was observed. Five-year overall survival (OS) was longer in patients with high LMR (p < 0.001), low NLR (p = 0.001) and low PLR (p = 0.095). No correlation between the density of TILs and OS was demonstrated. In conclusion, based on our study, peripheral blood-based markers and CD3+ and CD8+ TILs are not interrelated.
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Déléris, J., A. Nédélec, E. Ferré, G. Gleizes, R. P. Ménot, C. K. Obasi, and J. L. Bouchez. "The Pan-African Toro Complex (northern Nigeria): magmatic interactions and structures in a bimodal intrusion." Geological Magazine 133, no. 5 (September 1996): 535–52. http://dx.doi.org/10.1017/s0016756800007822.
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AbstractThe Toro Complex is one of the Pan-African Older Granites of Nigeria, first described as a reversely zoned pluton made of a central dioritic mass surrounded by a broad granitic rim. It has been thoroughly reinvestigated both from the petrographic and structural points of view, with the help of systematic anisotropy of magnetic susceptibility (AMS) measurements. The granite main body is a hornblende–biotite porphyritic monzogranite characterized by an early submagmatic fabric displaying a concentric pattern of foliations and west plunging lineations (stage 1). This fabric is overprinted by a later one due to solid-state strain along north-south subvertical dextral shear zones (stage 2). In the vicinity of the diorite, an evengrained granite displays magmatic structures that are contemporaneous with this strike-slip event. The diorite–granite contact is a complex zone where field, petrographic and geochemical data enable recognition of the effects of mixing and mingling between a mafic and a felsic magma. Tonalites cropping out within this contact zone are interpreted as hybrid rocks. The reverse zonation of the diorite itself is also the result of some hybridization process. Magmatic interactions mainly resulted from in situ infiltration of granitic liquid into the dioritic mass. The detailed history of this bimodal intrusion began with the emplacement of the granitic magma acquiring a first stage fabric. Before full crystallization of the granitic core, intrusion of the dioritic magma permitted reheating of the granitic magma that then crystallized with specific structural characters. The second stage structures, whether characterized by magmatic fabric near the diorite or by solid-state strain features in north–south shear zones elsewhere in the granite, are related to late Pan-African dextral strike-slip tectonics in the basement of northern Nigeria. The bimodal Toro Complex is therefore considered as a late Pan-African syntectonic pluton.
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Vernaci, Grazia Maria, Davide Massa, Ilaria Patuzzi, Alice Menichetti, Tommaso Giarratano, Gaia Griguolo, Federica Miglietta, et al. "Abstract P2-12-04: Characterization of gut microbiome composition in triple negative breast cancer patients treated with neoadjuvant chemotherapy." Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–12–04—P2–12–04. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-12-04.
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Abstract Background: Recent evidences showed intestinal microbiota to be implicated in carcinogenesis and response to chemotherapy and immune checkpoint inhibitors in solid tumors. Furthermore, antibiotics are known to deeply influence microbiome composition in healthy people and cancer patients. The role of gut microbiome in triple negative breast cancer (TNBC) is underexplored. Methods: In this pilot prospective study, we characterized the gut microbiome of 30 TNBC patients undergoing neoadjuvant chemotherapy at two Italian Institutions. Fecal samples were collected at 2 timepoints: at the baseline (t0) and at 1 week (t1) from CT. Microbiome was analyzed by 16S rRNA sequencing. Measures of α-diversity expressed by Richness and Simpson evenness were evaluated at the species level. β-diversity was calculated using PERMANOVA test according to UniFrac measures of dissimilarity at the species level.Tumor infiltrating lymphocytes (TILs) were assessed from diagnostic core biopsy and surgical specimen. Results: From September 2017 to March 2020, 30 TNBC patients were enrolled. Median age was 53 years, 43% were premenopausal, 43% were overweight or obese (BMI>25); 97% had a histologic G3 carcinoma, clinical nodal involvements was present in 57%; median TILs at diagnosis was 30%. All patients received anthracycline and taxane-based chemotherapy, including carboplatin in 23 patients (77%). A pCR was achieved in 15 (50%) patients. The overall rate of stool samples collection was 93%. With regards to t0, no differences in terms of α- and β-diversity were found.At t1, α-diversity was significantly higher in pCR group (Simpson evenness index, p=0.016). Considering clinical-pathological features, a BMI <24.9 was associated with higher microbiome richness (p=0.012). Measurements of β-diversity did not differ between groups.As 73% of patients during the treatment phase received antibiotics, with consequent potential microbiome impairment, we repeated analyses at t1 considering fecal samples collected >90 days after the end of antibiotic therapy (N=17). At this analysis, β-diversity evaluated with Unifrac measure was significantly correlated with pCR (p=0.035), with Haemophilus Influentiae being significantly enriched in non-pCR group. Conclusions: Fecal microbiome collection and analysis in this population is feasible and deserves further investigation with regards its association with response to chemotherapy. Citation Format: Grazia Maria Vernaci, Davide Massa, Ilaria Patuzzi, Alice Menichetti, Tommaso Giarratano, Gaia Griguolo, Federica Miglietta, Matteo Fassan, Edoardo Savarino, PierFranco Conte, Valentina Guarneri, Maria Vittoria Dieci. Characterization of gut microbiome composition in triple negative breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-04.
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Zeh, Armin, Allan H. Wilson, Dominik Gudelius, and Axel Gerdes. "Hafnium Isotopic Composition of the Bushveld Complex Requires Mantle Melt–Upper Crust Mixing: New Evidence from Zirconology of Mafic, Felsic and Metasedimentary Rocks." Journal of Petrology 60, no. 11 (November 1, 2019): 2169–200. http://dx.doi.org/10.1093/petrology/egaa004.
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Abstract The origin of magmas that formed the Bushveld Complex remains highly debated in spite of many decades of intense research. Previous geochemical–petrological studies have shown a strong mantle derivation resulting ultimately in highly economic ore bodies of platinum group elements and chromium. However, geochemistry also points to the contribution of a significant crustal component, which may have been derived singly or in combination from a number of different sources. These include subcontinental lithospheric mantle that was enriched prior to Bushveld magma formation, possibly by subduction, assimilation of lower and upper crust during magma ascent, and contamination during magma chamber accretion within sedimentary rocks of the enclosing Transvaal Supergroup. In this study, the contributions of these various reservoirs will be evaluated by employing Hf isotopic data of well-characterized zircon grains in mafic, felsic and metasedimentary rocks, together with Zr–Hf bulk-rock compositions. The results reveal that magmatic zircon grains in mafic cumulate rocks from the floor to the roof of the c. 9 km thick Rustenburg Layered Suite (RLS) show essentially the same variations in εHf2·055 Ga from −7·5 to −10·2 as those of metamorphic zircon grains and overgrowths in the immediate surrounding quartzite and metapelitic rocks, as well as in granitic melt batches, granophyres, and the upper Rooiberg volcanics. The same values are also obtained by estimating the average Hf isotopic compositions of detrital zircon grains in many quartzite and metapelitic rocks from the surrounding Magaliesberg (εHf2·055 Ga = −6·2 to −10·8, six samples, maximum deposition age at 2080 Ma) and Houtenbeck formations (εHf2·055 Ga = −7·1 to −8·9, three samples, maximum deposition age at 2070 Ma), and by a six-point isochron of a garnet-schist from the Silverton Formation (εHft = −6·6 ± 0·7; age = 2059·4 ± 2·7 Ma). Zircon morphologies, zoning patterns, Hf isotopic data and petrological constraints furthermore reveal that metamorphic zircon was precipitated from aqueous fluids and/or felsic melts at temperatures between 550 and 900 °C, and that the Hf isotopic composition became homogenized during fluid transport in the contact aureole. However, results of numerical modelling indicate that fluid infiltration had only a minor effect on the Zr–Hf budget and Hf isotopic composition of the RLS, and that these parameters were mainly controlled by the mixing of melts derived from three major sources: (1) the asthenospheric mantle (>20 %); (2) enriched subcontinental lithospheric mantle (<80 %); (3) assimilation of significant amounts of crust (up to 40 %). The modelling furthermore suggests that assimilation of lower Kaapvaal Craton crust was minor (<15 %) during B1 (high-Mg andesite) magma formation, but up to 40 % during B3 (tholeiite) magma formation. The minor variation in εHft of zircon throughout the entire stratigraphy of the RLS resulted from the interplay of three dominant contributing factors: (1) intrusion of hot (>1200 °C) mantle-derived magmas with relatively low Zr–Hf concentrations having a similar εHf2·055 Ga of −8·5 ± 1·9 to that of upper crust rocks surrounding the RLS; (2) significant assimilation of volcanic and metasedimentary rocks with high Zr–Hf concentration; (3) mingling, mixing and/or diffusive exchange of Zr and Hf between crust and mantle-derived melts and aqueous fluids prior to late-magmatic crystallization of zircon at temperatures between 700 and 900 °C. This study shows that the combination of Zr–Hf bulk-rock data with Hf isotopic data of well-characterized zircon grains provides a powerful tool to quantify various mantle and crustal reservoirs of mafic layered intrusions, and allows new insights into magma chamber and related contact metamorphic processes.
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Ramos-Paradas, Javier, David Gomez-Sanchez, Aranzazu Rosado, Alvaro Conrado Ucero, Nuria Carrizo, Ana Belen Enguita, Maria Teresa Muñoz, Esther Conde, Luis Paz-Ares, and Eva Maria Garrido-Martin. "Abstract 1245: Comprehensive analysis of non-small cell lung cancer identifies molecular genotype-immunophenotype associations and candidate biomarkers predictive of response to immunotherapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1245. http://dx.doi.org/10.1158/1538-7445.am2022-1245.
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Abstract Lung cancer has the second highest incidence and leads cancer mortality worldwide, being Non-Small Cell Lung Cancer (NSCLC) the most prevalent subtype. Immunotherapy with checkpoint blockers has shown outstanding benefits in a subset of NSCLC patients, which are not accurately identified due to the lack of robust biomarkers of response. We hypothesize that specific molecular alterations of NSCLC tumor cells impact the immune microenvironment. Defining this association could improve the prediction of response to immunotherapy. This work aims to identify a multiparametric biomarker signature. We studied 178 tumor samples from a cohort of early stage NSCLC with complete clinical annotation. We analyzed their molecular aberrations, calculated their Tumor Mutational Burden and described their immune landscape by immunohistochemistry and a dedicated RNAseq panel. We defined novel subgroups of NSCLC tumors with specific immune, molecular and clinical features, showing an association between their molecular genotype and immune phenotype. Based on these data, subgroups were proposed as pro-immunogenic, pro-tumorigenic or mixed. Adenocarcinomas clustered in 4 groups. The pro-tumorigenic group had a significant higher proportion of alterations in ARID1A, FGF10, ROS1, TP53. One pro-immunogenic group had a significant higher proportion of MET alterations and lower proportion of EGFR alterations. An immune mixed group significantly accrued never smokers and had no alterations in FGF10. Squamous cell carcinomas clustered in 4 groups. The pro-tumorigenic group had a significant higher proportion of alterations in CCND1, FGF3, FGF10, FGF19, NOTCH1, PIK3CA, PIK3CB, TFRC. A pro-immunogenic group had a significant higher infiltration of T CD4+, T CD8+ and B cells and a higher overall survival. Another pro-immunogenic group had a significant absence of MYCN and NF1 alterations. Taken together we identified a set of candidate predictive biomarkers of response to immunotherapy in NSCLC. Genes overexpressed in pro-immunogenic tumors are related to adaptive immune response stimulation (CD28, FCRLA, JCHAIN, LY9, MS4A1, SLAMF7, TNFRSF9, TNFRSF17), antigen presentation (CD1C, CD1D, HLA-A), apoptosis (FAS), immune chemotaxis (CCL20, CCR4, CCR6), and immune regulation (CD53, PDCD1, SH2D1A, ZAP70). On the other hand, genes upregulated in pro-tumorigenic tumors are involved in angiogenesis (VEGFA), cell cycle regulation (BUB1, CCNB2, FOXM1, MAD2L1, TOP2A), cell growth/survival (IGF1R), DNA replication/repair (KIAA0101) and iron metabolism (HMBS, TFRC). These findings are being validated by Digital Spatial Profiling in a cohort of patients with advanced stage NSCLC that were treated with checkpoint blockers. If confirmed, these results could remarkably improve patient selection and the benefit upon immunotherapy. Citation Format: Javier Ramos-Paradas, David Gomez-Sanchez, Aranzazu Rosado, Alvaro Conrado Ucero, Nuria Carrizo, Ana Belen Enguita, Maria Teresa Muñoz, Esther Conde, Luis Paz-Ares, Eva Maria Garrido-Martin. Comprehensive analysis of non-small cell lung cancer identifies molecular genotype-immunophenotype associations and candidate biomarkers predictive of response to immunotherapy [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 1245.
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Sanfeliu, Esther, Fara Brasó-Maristany, Maria Vittoria Dieci, Mercedes Marín-Aguilera, Blanca González-Farré, Gaia Griguolo, Tomas Pascual, et al. "Abstract P4-02-30: Association between tumor infiltrating lymphocytes (TILs) and the HER2DX assay in early-stage of HER2-positive (HER2+) breast cancer." Cancer Research 83, no. 5_Supplement (March 1, 2023): P4–02–30—P4–02–30. http://dx.doi.org/10.1158/1538-7445.sabcs22-p4-02-30.
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Abstract Background: The HER2DX assay is a genomic test in early-stage HER2-positive (HER2+) breast cancer that provides prognostic and predictive information. HER2DX is a supervised learning algorithm incorporating tumor size, nodal staging, and 4 gene expression signature scores (immune/IGG, tumor cell proliferation, luminal differentiation and the expression of the HER2 amplicon). Among them, the IGG signature is associated with both overall survival and probability of achieving a pathologic complete response (pCR). Here, we studied the association of percentage (%) of tumor infiltrating lymphocytes (TILs) with HER2DX scores, immune genes and other breast cancer-related genes. Methods: HER2DX and %TILs were evaluated in 670 formalin-fixed paraffin-embedded (FFPE) samples of HER2+ breast cancer, including in 3 clinical studies SHORTHER (n=437), PAMELA (n=86), a cohort of patients treated with anti-HER2 therapy plus chemotherapy at Hospital Clínic of Barcelona (n=147). The %TILs were quantified by histological evaluation with hematoxylin eosin staining according to International TILs Working Group guidelines. The nCounter platform determined the expression of 192 genes and HER2DX scores. Pearson correlations (Cor) and Significance Analysis of Microarrays (SAM) with a false-discovery rate (FDR) < 5% assessed the association between %TILs and the expression of individual genes or HER2DX signature scores. Results: A moderate correlation was observed between %TILs and the immune IGG signature (Cor=0.56, p< 0.001). Of note, 171 (25.52%) cases had low %TILs (< 30%) and high IGG score, while 1 (0.15%) case had high %TILs (≥30%) and low IGG score. The %TILs were significantly associated with the expression of immune genes, ERBB2, IGG signature and HER2 amplicon score, and negatively associated with the expression of luminal genes (i.e., ESR1, PRG and BCL2). An unclear relationship between TILs and proliferation genes was observed. Finally, moderate correlations were observed between %TILs and HER2DX pCR score (Cor=0.48, p< 0.001) and between %TILs and HER2DX risk score (Cor=0.33, p< 0.001). Conclusions: Important differences exist between the %TILs and the HER2DX IGG signature in early-stage HER2+ breast cancer. The %TILs should not be used to predict the HER2DX scores. Biologically, a higher %TILs indirectly capture a higher ERBB2 expression and a lower expression of luminal genes, both associated with response to anti-HER2 treatment. Citation Format: Esther Sanfeliu, Fara Brasó-Maristany, Maria Vittoria Dieci, Mercedes Marín-Aguilera, Blanca González-Farré, Gaia Griguolo, Tomas Pascual, Patricia Galván, Laura Angelats, Oleguer Castillo, Paula Blasco, Valeria Sirenko, Pedro Jares, Joan Antón Puig-Butillé, Laia Paré, Antonio Martínez, Antonio Llombart-Cussac, Javier Cortés, Ana Vivancos, Patricia Villagrasa, Joel S Parker, Charles M Perou, Aleix Prat, PierFranco Conte, Valentina Guarneri. Association between tumor infiltrating lymphocytes (TILs) and the HER2DX assay in early-stage of HER2-positive (HER2+) breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-30.
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Reiss, David J., Andrew Browne, Brian Fox, Alexander V. Ratushnyy, Maria Wang, Andrew V. Biankin, and Thomas Lila. "Abstract C085: Spatial arrangements of immune cells of the pancreatic ductal adenocarcinoma tumor microenvironment correlated with outcomes in the phase 3 APACT trial." Cancer Research 82, no. 22_Supplement (November 15, 2022): C085. http://dx.doi.org/10.1158/1538-7445.panca22-c085.
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Abstract Introduction The newly diagnosed pancreatic ductal adenocarcinoma (PDAC) population has a high unmet need for effective treatments, with median survival of < 1 year. The phase 3 APACT (Adjuvant Pancreatic Adenocarcinoma Clinical Trial) evaluated the use of adjuvant nab-paclitaxel plus gemcitabine vs. gemcitabine in 866 patients with surgically resected PDAC. We explored the tumor microenvironment (TME) of >500 baseline resected APACT tumors to identify TME features that are associated with adverse outcomes. Methods Biopsy analyses included RNA-seq, DNA-seq, and multiplexed immunohistochemistry (mIHC). We quantified, for 533 patient biopsies, via mIHC the spatial arrangement of 7 immune cell types and 2 checkpoint markers relative to tumor and nontumor regions, and pairwise colocalization relative to each other. We identified combinations of biomarkers that correlate significantly with molecular signatures, predefined patient subsets, and overall survival (OS). Hazard ratios (HR) and p-values were computed via a Cox proportional hazards regression model which included resection and lymph node status as covariates. Significantly differentially-expressed transcripts were associated with biomarkers derived from the mIHC via unpaired t-test. Results Higher densities of CD8+ T cells within tumor regions correlated with longer OS (hazard ratio HR=0.76; p=0.03), and higher overall densities of CD163+ macrophages correlated with shorter OS (HR=1.44; p=0.006). We furthermore identified a patient subset (n=72) with a combination of higher CD8+ T cell and lower CD163+ macrophage densities that had a strikingly significant decreased HR of 0.46 (p=0.009). Moreover, patients with a high degree of spatial colocalization between CD8+ T cells and dual-positive CMAF+CD163+ M2-like macrophages observed a significant increased HR of 1.51 (p=0.0006), a biomarker only surpassed by nodal status in significance of correlation with OS (HR=1.9; p=0.00015). While this cellular colocalization was computed to be independent of cell densities, we found that the association of this colocalized pair of cell types with shorter OS was most significant for patients with lower overall CD8+ T cell densities (HR=1.84; p=0.0004). We further identified differentially regulated transcripts associated with this interaction and found specific putative ligand-receptor pairs that were also associated with lower OS. Conclusion A combination of greater infiltration of CD8+ cytotoxic T cells and lower infiltration of macrophages is associated with longer OS in the APACT trial. Moreover, the spatial colocalization between CD8+ T cells and CMAF+ M2 macrophages is associated with shorter OS. These findings were observed across both treatment arms of the study. Future investigation of this apparent interaction, and associated differentially expressed transcripts, may inform management of patients with pancreatic adenocarcinoma and increase effectiveness of PDAC therapies. Citation Format: David J. Reiss, Andrew Browne, Brian Fox, Alexander V. Ratushnyy, Maria Wang, Andrew V. Biankin, Thomas Lila. Spatial arrangements of immune cells of the pancreatic ductal adenocarcinoma tumor microenvironment correlated with outcomes in the phase 3 APACT trial [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C085.
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Bilotta, Maria Teresa, Antonella Antignani, and David J. Fitzgerald. "Abstract 1653: Toward developing a humanized mouse model of the microenvironment associated with the malignant cells of Hodgkin lymphoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1653. http://dx.doi.org/10.1158/1538-7445.am2022-1653.
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Abstract The tumor microenvironment (TME) represents a highly complex compartment that includes cancer cells, non-hematopoietic stromal cells, extracellular matrix, lymphocytes, and myeloid cells. Interactions between these populations and the factors they secrete play critical roles in determining the host response to cancer. Conventional mouse xenograft models of human cancer lack a competent immune system. Indeed, the use of xenograft models often fail to translate into effective human treatments. Classical Hodgkin Lymphoma (HL) is characterized by the presence in the lymphonodes of abnormal Reed-Sternberg cells, and many cell types beyond them, in particular Treg. To reconstitute a more complete TME, human PBMCs were injected into NSG mice bearing L540 HL cells. Then over time the presence of various human CD45+ cell populations were monitored within the tumor mass, in the spleen and in circulation. The goal of our study is to gain a better understanding of the interaction of the immune cell infiltrates into the HL microenvironment, leading ultimately to improved treatment outcomes. Lymphocyte infiltration into the tumor showed a predominance of human CD3+ cells (T lymphocytes), even if in the spleen we found both human T and B cells, indicating that this model might help us design more effective treatments. To reflect the immune reconstitution of these animals and its interaction with tumor and to better understand the capacity of T lymphocytes to kill the cancer cells, we evaluated the production of human IFN- gamma. We found an increase of IFN- gamma in L540-bearing mice reconstituted with hPBMCs compared to the mice without them, indicating a certain functionality of the T cells in these tumors. Moreover, in this model, the immune reconstitution did not decrease tumor growth, rendering this model useful for the study of biotherapeutic and immunotherapeutic studies. The model might be useful to study the anticancer therapy at a preclinical level because a remodeling of the anti-tumor immune response can be evaluated. Citation Format: Maria Teresa Bilotta, Antonella Antignani, David J. Fitzgerald. Toward developing a humanized mouse model of the microenvironment associated with the malignant cells of Hodgkin lymphoma [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 1653.