Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma

Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. While immunotherapies have shown a remarkable success in melanoma treatment, patients develop resistance by mechanisms that include the establishment of an immune suppressive tumor microenvironment. Thus, understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that macrophages (MOs) and dendritic cells (DCs) are suppressed in metastatic melanoma and that the Ig-CDR-based peptide C36L1 is able to restore MOs and DCs' antitumorigenic and immunogenic functions and to inhibit metastatic growth in lungs. Specifically, C36L1 treatment is able to repolarize M2-like immunosuppressive MOs into M1-like antitumorigenic MOs, and increase the number of immunogenic DCs, and activated cytotoxic T cells, while reducing the number of regulatory T cells and monocytic myeloid-derived suppressor cells in metastatic lungs. Mechanistically, we find that C36L1 directly binds to the MIF receptor CD74 which is expressed on MOs and DCs, disturbing CD74 structural dynamics and inhibiting MIF signaling on these cells. Interfering with MIF-CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells. Our findings suggest that interfering with MIF-CD74 immunosuppressive signaling in MOs and DCs, using peptide-based immunotherapy can restore the antitumor immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the antitumor immune response in metastatic melanoma

Classical theta constants vs. lattice theta series, and super string partition functions

Recently, various possible expressions for the vacuum-to-vacuum superstring amplitudes has been proposed at genus $g=3,4,5$. To compare the different proposals, here we will present a careful analysis of the comparison between the two main technical tools adopted to realize the proposals: the classical theta constants and the lattice theta series. We compute the relevant Fourier coefficients in order to relate the two spaces. We will prove the equivalence up to genus 4. In genus five we will show that the solutions are equivalent modulo the Schottky form and coincide if we impose the vanishing of the cosmological constant.Comment: 21 page

Benzofuroxan derivatives N-Br and N-I induce intrinsic apoptosis in melanoma cells by regulating AKT/BIM signaling and display anti metastatic activity in vivo

Abstract\ud \ud Background\ud Malignant melanoma is an aggressive type of skin cancer, and despite recent advances in treatment, the survival rate of the metastatic form remains low. Nifuroxazide analogues are drugs based on the substitution of the nitrofuran group by benzofuroxan, in view of the pharmacophore similarity of the nitro group, improving bioavailability, with higher intrinsic activity and less toxicity. Benzofuroxan activity involves the intracellular production of free-radical species. In the present work, we evaluated the antitumor effects of different benzofuroxan derivatives in a murine melanoma model.\ud \ud \ud Methods\ud B16F10-Nex2 melanoma cells were used to investigate the antitumor effects of Benzofuroxan derivatives in vitro and in a syngeneic melanoma model in C57Bl/6 mice. Cytotoxicity, morphological changes and reactive oxygen species (ROS) were assessed by a diphenyltetrasolium reagent, optical and fluorescence microscopy, respectively. Annexin-V binding and mitochondrial integrity were analyzed by flow cytometry. Western blotting and colorimetry identified cell signaling proteins.\ud \ud \ud Results\ud Benzofuroxan N-Br and N-I derivatives were active against murine and human tumor cell lines, exerting significant protection against metastatic melanoma in a syngeneic model. N-Br and N-I induce apoptosis in melanoma cells, evidenced by specific morphological changes, DNA condensation and degradation, and phosphatidylserine translocation in the plasma membrane. The intrinsic mitochondrial pathway in B16F10-Nex2 cells is suggested owing to reduced outer membrane potential in mitochondria, followed by caspase −9, −3 activation and cleavage of PARP. The cytotoxicity of N-Br and N-I in B16F10-Nex2 cells is mediated by the generation of ROS, inhibited by pre-incubation of the cells with N-acetylcysteine (NAC). The induction of ROS by N-Br and N-I resulted in the inhibition of AKT activation, an important molecule related to tumor cell survival, followed by upregulation of BIM.\ud \ud \ud Conclusion\ud We conclude that N-Br and N-I are promising agents aiming at cancer treatment. They may be useful in melanoma therapy as inducers of intrinsic apoptosis and by exerting significant antitumor activity against metastatic melanoma, as presently shown in syngeneic mice.The present work was supported by Fundação de Amparo a Pesquisa do\ud Estado de São Paulo (FAPESP) and the Conselho Nacional de Desenvolvimento\ud Científico e Tecnológico (CNPq)

Molecular, Biological and Structural Features of VL CDR-1 Rb44 Peptide, Which Targets the Microtubule Network in Melanoma Cells

Microtubules are important drug targets in tumor cells, owing to their role in supporting and determining the cell shape, organelle movement and cell division. The complementarity-determining regions (CDRs) of immunoglobulins have been reported to be a source of anti-tumor peptide sequences, independently of the original antibody specificity for a given antigen. We found that, the anti-Lewis B mAb light-chain CDR1 synthetic peptide Rb44, interacted with microtubules and induced depolymerization, with subsequent degradation of actin filaments, leading to depolarization of mitochondrial membrane-potential, increase of ROS, cell cycle arrest at G2/M, cleavage of caspase-9, caspase-3 and PARP, upregulation of Bax and downregulation of Bcl-2, altogether resulting in intrinsic apoptosis of melanoma cells. The in vitro inhibition of angiogenesis was also an Rb44 effect. Peritumoral injection of Rb44L1 delayed growth of subcutaneously grafted melanoma cells in a syngeneic mouse model. L1-CDRs from immunoglobulins and their interactions with tubulin-dimers were explored to interpret effects on microtubule stability. The opening motion of tubulin monomers allowed for efficient L1-CDR docking, impairment of dimer formation and microtubule dissociation. We conclude that Rb44 VL-CDR1 is a novel peptide that acts on melanoma microtubule network causing cell apoptosis in vitro and melanoma growth inhibition in vivo

Blockade of MIF-CD74 signalling on macrophages and dendritic cells restores the anti-tumour immune response against metastatic melanoma.

Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. While immunotherapies have shown a remarkable success in melanoma treatment, patients develop resistance by mechanisms that include the establishment of an immune suppressive tumor microenvironment. Thus, understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that macrophages (MOs) and dendritic cells (DCs) are suppressed in metastatic melanoma and that the Ig-CDR-based peptide C36L1 is able to restore MOs and DCs’ antitumorigenic and immunogenic functions and to inhibit metastatic growth in lungs. Specifically, C36L1 treatment is able to repolarize M2-like immunosuppressive MOs into M1-like antitumorigenic MOs, and increase the number of immunogenic DCs, and activated cytotoxic T cells, while reducing the number of regulatory T cells and monocytic myeloid-derived suppressor cells in metastatic lungs. Mechanistically, we find that C36L1 directly binds to the MIF receptor CD74 which is expressed on MOs and DCs, disturbing CD74 structural dynamics and inhibiting MIF signaling on these cells. Interfering with MIF–CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells. Our findings suggest that interfering with MIF–CD74 immunosuppressive signaling in MOs and DCs, using peptide-based immunotherapy can restore the antitumor immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the antitumor immune response in metastatic melanoma

Twelve-crystal prototype of Li2_2MoO4_4 scintillating bolometers for CUPID and CROSS experiments

An array of twelve 0.28 kg lithium molybdate (LMO) low-temperature bolometers equipped with 16 bolometric Ge light detectors, aiming at optimization of detector structure for CROSS and CUPID double-beta decay experiments, was constructed and tested in a low-background pulse-tube-based cryostat at the Canfranc underground laboratory in Spain. Performance of the scintillating bolometers was studied depending on the size of phonon NTD-Ge sensors glued to both LMO and Ge absorbers, shape of the Ge light detectors (circular vs. square, from two suppliers), in different light collection conditions (with and without reflector, with aluminum coated LMO crystal surface). The scintillating bolometer array was operated over 8 months in the low-background conditions that allowed to probe a very low, $\mu$Bq/kg, level of the LMO crystals radioactive contamination by $^{228}$Th and $^{226}$Ra.Comment: Prepared for submission to JINST; 23 pages, 9 figures, and 4 table

A first test of CUPID prototypal light detectors with NTD-Ge sensors in a pulse-tube cryostat

CUPID is a next-generation bolometric experiment aiming at searching for neutrinoless double-beta decay with ~250 kg of isotopic mass of $^{100}$Mo. It will operate at $\sim$10 mK in a cryostat currently hosting a similar-scale bolometric array for the CUORE experiment at the Gran Sasso National Laboratory (Italy). CUPID will be based on large-volume scintillating bolometers consisting of $^{100}$Mo-enriched Li$_2$MoO$_4$ crystals, facing thin Ge-wafer-based bolometric light detectors. In the CUPID design, the detector structure is novel and needs to be validated. In particular, the CUORE cryostat presents a high level of mechanical vibrations due to the use of pulse tubes and the effect of vibrations on the detector performance must be investigated. In this paper we report the first test of the CUPID-design bolometric light detectors with NTD-Ge sensors in a dilution refrigerator equipped with a pulse tube in an above-ground lab. Light detectors are characterized in terms of sensitivity, energy resolution, pulse time constants, and noise power spectrum. Despite the challenging noisy environment due to pulse-tube-induced vibrations, we demonstrate that all the four tested light detectors comply with the CUPID goal in terms of intrinsic energy resolution of 100 eV RMS baseline noise. Indeed, we have measured 70--90 eV RMS for the four devices, which show an excellent reproducibility. We have also obtained outstanding energy resolutions at the 356 keV line from a $^{133}$Ba source with one light detector achieving 0.71(5) keV FWHM, which is -- to our knowledge -- the best ever obtained when compared to $\gamma$ detectors of any technology in this energy range.Comment: Prepared for submission to JINST; 16 pages, 7 figures, and 1 tabl

Perspectives on global leadership and the Covid-19 crisis

As the world struggled to come to grips with the Covid-19 pandemic, over twenty scholars, practitioners, and global leaders wrote brief essays for this curated chapter on the role of global leadership in this extreme example of a global crisis. Their thoughts span helpful theoretical breakthroughs to essential, pragmatic adaptations by companies

I. Encuentro de la Red de Asentamientos Populares : aportes teórico-metodológicos para la reflexión sobre políticas públicas de acceso al hábitat

Contenidos Introducción / M. Cecilia Marengo, Ana Laura Elorza, Virginia Monayar ; Eje 1. Acceso al hábitat y urbanizaciones informales; Asentamientos (in)formales en pequeñas metrópolis del Cono Sur. Estado de situación y debate actual / Ricardo Apaolaza, Elizabeth Zenteno Torres, Marco Sumiza; Un análisis comparativo sobre la expansión de asentamientos populares en las ciudades patagónicas / Santiago Bachiller, Mariana Giaretto, Pablo Marigo, Natalia Usach ; Acceso al Hábitat para los ¨sin techo¨: la lucha por la tierra en la Ciudad de Posadas-Misiones / Myriam Elena Barone, Jonas Dumas, Mariela Dachary, Celia Draganchuk; El mercado informal de suelo y vivienda en resistencia. El caso del asentamiento en "La Rubita" Resistencia, Argentina / María Andrea Benitez, María Victoria Cazorla; Brazos Unidos un realojo en construcción colectiva / Borelli, Lily, Halich, Verónica; Transformaciones en el hábitat de asentamientos informales y políticas públicas sociales. El caso de barrio nuestro hogar III / Renzo Cáceres; Discursividad mediática sobre el acceso y producción del hábitat popular en el barrio Costanera / Debora Leticia Decima; Trayectorias residenciales y usos de la ciudad como clave de lectura de la lucha por el acceso a la ciudad / María Mercedes Di Virgilio, Natalia Cosacov, Denise Brikman, Mercedes Najman; Asentamientos en el borde metropolitano. Avances de investigación, reflexiones y preguntas / Lucas Jordán Dombroski; Repensando el acceso al hábitat en ciudades medias. La problemática habitacional de Tandil / Agustina Girado; Narrativas de un asentamiento de comienzos de siglo: más allá de la épica y la mafia / María Maneiro; Informalidad y periferia urbana. Derivas de la política habitacional / M. Cecilia Marengo, Virginia Monayar, Florencia Sosa; Sobre las ¿nuevas? ocupaciones de tierras. Notas para una periodización de las tomas en San Francisco Solano, 1981-2002 / Santiago Nardin Memorias villeras en disputa sobre las intervenciones estatales de erradicación en Villa 20 (1976-1983) / Julieta Oxman; El Centro para Erradicación de Villas de Emergencia. Planificación, censo y viviendas, Rosario (1964-1983) / Anahí G. Pagnoni; Ensayo de una cartografía de asentamientos informales en la Ciudad de Córdoba / German Gustavo Rebord, Andrea Karina Stiefkens; Urbanización y prácticas estatales en asentamientos populares en Comodoro Rivadavia. El caso del “Barrio las Américas” / Letizia Vázquez; Eje 2: Derecho a la ciudad: conflictos y disputas por el territorio urbano; La ciudad contra el barrio. El caso de los Barrios del Sur en San José de Costa Rica / Pablo Acuña Quiel; Procesos autogestionarios de hábitat popular y políticas urbanas en la ciudad de Ushuaia. Tierra del Fuego. Argentina / Alicia Delia Alcaráz; Conflictos y tensiones en la ocupación del suelo en Posadas. Misiones, Argentina: procesos de diferenciación / Lucia Mariana Andrujovich, Laura Josefa Krujoski,Myriam Elena Barone; Políticas públicas, exclusión y conformación de identidades colectivas / Sandra Raquel Ávalos; La reurbanización del Playón de Chacarita como problema público. Arenas, actores y políticas públicas / Joaquín Benítez; Relocalización, organización y derecho a la ciudad. El caso de Barrio Nuevo (La Plata) / María Sofía Bernat; Resistencias y disputas político-judiciales en casos de desalojos de asentamientos en Buenos Aires / María Cristina Cravino; Análisis de las herramientas territoriales de la organización ArqCom (LP) en el periodo 2012-2018 / Andrea Di Croce Garay, Nahir Meline Cantar, Ángeles Belén Carrizo Romero, Tamara Dileo; Planificación y urbanización del Barrio 31 y 31 bis / Rosana Karina Espejo; Mercado de suelo: tensiones y ambigüedades. El caso de la zona Norte de Resistencia, Chaco, Argentina / Sebastián Galvaliz, María del Rosario Olmedo; Marta Graciela Giró; Experiencias de urbanización y ciudadanización en La Carbonilla. Una propuesta de análisis en escalas / María Belén Garibotti, Luciana Boroccioni, María Florencia Girola ¿Integración? A la trama formal. De complejidades a desafíos / Carolain Izaguirre, Marion Tejera y Carolina Leiva; ¿Urbanizar o aniquilar? Disyuntivas ontológicas en los procesos de urbanización de las sierras de Córdoba / Denise Mattioli; Conflicto y construcción de resistencias en el asentamiento Barrio Flores / Emilia Elisa Molina; Conflictos territoriales y recualificación de la ribera. Los pescadores artesanales y los espacios públicos / Diego Roldán; El Bajo Belgrano: del Barrio de las Latas a la Villa 30 / Valeria Laura Snitcofsky; Líneas de fuga en un barrio de resistencia. Visualización de una lucha / Rafael Ramón Franco Spatuzza; Nuevas legalidades para la reurbanización de villas en CABA. Un desafío para los derechos / Agustín Territoriale, María Julia López; Los Vacíos Urbanos. Dinámicas Urbanas y Respuestas Innovadoras frente al Derecho a la Ciudad / Ezequiel Zeitune, Silvia A Politi, Natalia Czytajlo; Eje 3: Políticas públicas para atender la informalidad y de gestión en el hábitat popular; Tolerancia y precariedad. Advertencias de la política de regularización del Gran Resistencia al RENABAP / Miguel Ángel Barreto, Evelyn Roxana Abildgaard, María Laura Puntel; Adicciones y narcomenudeo, barreras (in) franqueables para los asentamientos informales en Tucumán, Argentina / Paula Boldrini; Políticas de relocalización de villas: ¿qué pasa después? La organización consorcial como práctica comunitaria / María Florencia Bruno, Belén Demoy, Natalia Fainburg, Romina Olejarczyk; La disputa por la participación y la noción de participación en disputa: una reflexión desde el proceso de urbanización de la Villa 31 (2015-2019) / Tomás Capalbo; Economía popular en asentamientos informales del Gran San Miguel de Tucumán / Corina María Cattáneo; La producción de territorialidades en el habitar un asentamiento: procesos de intervención estatal y disociaciones socio espaciales / Magali Chanampa; Estrategias de gestión territorial desde las políticas públicas: replicando el “modelo Medellín” con acento Cordobés / Ana Laura Elorza, Mónica Alvarado Rodríguez, Fani Balcazar, Ernesto Morillo, Mariana Gamboa; Discusiones sobre la conceptualización e identificación de asentamientos informales. Análisis de la realidad en Chubut / María Paula Ferrari, Sergio Andrés Kaminker, Roxana Yanina Velásquez; Barrios autoproducidos en ciudades intermedias. El caso de Río Grande, Tierra del Fuego AIAS / Nadia B. Finck; Luces y sombras del Programa Compra de Vivienda Usada / Elena Inés Gabriel Hernández; Programas de Inclusión Socio-Urbana: ¿Producto de última generación de la Nueva Agenda Urbana? / Fernando Murillo, Gabriel Artese, Andrés Mage; Los dispositivos de espera en las políticas habitacionales / Romina Olejarczyk; Tres debates recurrentes acerca de la vivienda para la población urbana de menores ingresos / Juan Santiago Palero; Nuevos asentamientos precarios: un desafío a la Política Habitacional y Urbana Chilena / Rubén Sepúlveda Ocampo, Felipe Núñez Orrego; Irrumpir con las recetas. Reflexiones en torno a desarrollo, políticas públicas y hábitat popular / Carla Eleonora Pedrazzani, María Inés Sesma.Esta publicación presenta los trabajos del I. Encuentro de la Red de Asentamientos Populares: aportes teórico -metodológicos para la reflexión sobre políticas públicas de acceso al hábitat, desarrollado los días 23 y 24 de mayo de 2019 en la Facultad de Arquitectura, Urbanismo y Diseño de la Universidad Nacional de Córdoba. En las últimas dos décadas, el INVIHAB (Instituto de Investigación de Vivienda y Hábitat) se ha conformado como un espacio de referencia en la investigación, transferencia y formación en temáticas relativas a las políticas de vivienda, territorio, informalidad urbana, ambiente y ciudadanía. Experiencia que ha llevado a la articulación con otros espacios académicos, organizaciones socio-territoriales, gobiernos locales, en el sentido de confluir en la comprensión, reflexión y formulación de propuestas para mitigar las desigualdades socioterritoriales. En este escenario, se viene construyendo una red de investigadores que estudian la informalidad urbana desde diversos enfoques -territoriales, físico-espaciales, sociales, urbanos, laborales, entre otros- tendientes a superar las miradas parciales y locales desde los abordajes teórico metodológicos y propiciar la comprensión del fenómeno desde una perspectiva que abarque la multiplicidad de campos y su complejidad.FIL: Marengo, María Cecilia. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina.FIL: Elorza, Ana Laura. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina.FIL: Monayar, Virginia. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentina