Preclinical evaluation of chimeric antigen receptor T cells targeting the carcinoembryonic antigen as a potential immunotherapy for gallbladder cancer.

Gallbladder cancer (GBC) is commonly diagnosed at late stages when conventional treatments achieve only modest clinical benefit. Therefore, effective treatments for advanced GBC are needed. In this context, the administration of T cells genetically engineered with chimeric antigen receptors (CAR) has shown remarkable results in hematological cancers and is being extensively studied for solid tumors. Interestingly, GBC tumors express canonical tumor-associated antigens, including the carcinoembryonic antigen (CEA). However, the potential of CEA as a relevant antigen in GBC to be targeted by CAR-T cell-based immunotherapy has not been addressed. Here we show that CEA was expressed in 88% of GBC tumors, with higher levels associated with advanced disease stages. CAR-T cells specifically recognized plate-bound CEA as evidenced by up-regulation of 4-1BB, CD69 and PD-1, and production of effector cytokines IFN-γ and TNF-α. In addition, CD8+ CAR-T cells up-regulated the cytotoxic molecules granzyme B and perforin. Interestingly, CAR-T cell activation occurred even in the presence of PD-L1. Consistent with these results, CAR-T cells efficiently recognized GBC cell lines expressing CEA and PD-L1, but not a CEA-negative cell line. Furthermore, CAR-T cells exhibited in vitro cytotoxicity and reduced in vivo tumor growth of GB-d1 cells. In summary, we demonstrate that CEA represents a relevant antigen for GBC that can be targeted by CAR-T cells at the preclinical level. This study warrants further development of the adoptive transfer of CEA-specific CAR-T cells as a potential immunotherapy for GBC.

Transcriptional and Functional Analysis of CD1c+ Human Dendritic Cells Identifies a CD163+ Subset Priming CD8+CD103+ T Cells.

Dendritic cells (DCs) are antigen-presenting cells controlling T cell activation. In humans, the diversity, ontogeny, and functional capabilities of DC subsets are not fully understood. Here, we identified circulating CD88-CD1c+CD163+ DCs (called DC3s) as immediate precursors of inflammatory CD88-CD14+CD1c+CD163+FcεRI+ DCs. DC3s develop via a specific pathway activated by GM-CSF, independent of cDC-restricted (CDP) and monocyte-restricted (cMoP) progenitors. Like classical DCs but unlike monocytes, DC3s drove activation of naive T cells. In vitro, DC3s displayed a distinctive ability to prime CD8+ T cells expressing a tissue homing signature and the epithelial homing alpha-E integrin (CD103) through transforming growth factor ß (TGF-ß) signaling. In vivo, DC3s infiltrated luminal breast cancer primary tumors, and DC3 infiltration correlated positively with CD8+CD103+CD69+ tissue-resident memory T cells. Together, these findings define DC3s as a lineage of inflammatory DCs endowed with a strong potential to regulate tumor immunity.

Osteomielitis de cadera: caso clínico pediátrico reportado en Hospital General Enrique Garcés / Hip osteomyelitis: a reported pediatric clinic case at Enrique Garcés General Hospital

La osteomielitis de cadera es una infección poco frecuente en la edad pediátrica, que suele afectar el ilion, el isquion, el pubis y el acetábulo. Su diagnóstico es complejo y se retrasa debido a la localización profunda del foco infeccioso por lo que amerita la realización de una resonancia magnética para su diagnóstico certero. Este artículo presenta el caso clínico de un paciente de 5 años con dolor en la cadera derecha posterior a un traumatismo. El paciente fue diagnosticado de osteomielitis pélvica en el Hospital General Enrique Garcés donde recibió tratamiento antibiótico intravenoso por 30 días, con resultados satisfactorios. En conclusión, si bien la osteomielitis pélvica es una infección inusual en pediatría, es una enfermedad importante por las complicaciones que puede ocasionar si no se trata a tiempo por lo que es necesario comenzar el tratamiento de inmediato, para lograr resultados clínicos satisfactorios.

Osteomyelitis of the hip is a rare infection in children, which usually affects the ilium, ischium, pubis and acetabulum. Its diagnosis is complex and it is delayed due to the deep location of the infection, which requires a magnetic resonance imaging for its accurate diagnosis. This article presents the clinical case of a 5-year-old patient with pain in the right hip after trauma. The patient was diagnosed with pelvic osteomyelitis at the Enrique Garcés General Hospital where he received intravenous antibiotic treatment for 30 days, with satisfactory results. In conclusion, although pelvic osteomyelitis is an unusual infection in pediatrics, it is an important disease due to the complications it can cause if it is not treated in time, so it is necessary to begin treatment immediately, in order to achieve satisfactory clinical results.

Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma.

Memory CD8+ T cell responses have the potential to mediate long-lasting protection against cancers. Resident memory CD8+ T (Trm) cells stably reside in non-lymphoid tissues and mediate superior innate and adaptive immunity against pathogens. Emerging evidence indicates that Trm cells develop in human solid cancers and play a key role in controlling tumor growth. However, the specific contribution of Trm cells to anti-tumor immunity is incompletely understood. Moreover, clinically applicable vaccination strategies that efficiently establish Trm cell responses remain largely unexplored and are expected to strongly protect against tumors. Here we demonstrated that a single intradermal administration of gene- or protein-based vaccines efficiently induces specific Trm cell responses against models of tumor-specific and self-antigens, which accumulated in vaccinated and distant non-vaccinated skin. Vaccination-induced Trm cells were largely resistant to in vivo intravascular staining and antibody-dependent depletion. Intradermal, but not intraperitoneal vaccination, generated memory precursors expressing skin-homing molecules in circulation and Trm cells in skin. Interestingly, vaccination-induced Trm cell responses strongly suppressed the growth of B16F10 melanoma, independently of circulating memory CD8+ T cells, and were able to infiltrate tumors. This work highlights the therapeutic potential of vaccination-induced Trm cell responses to achieve potent protection against skin malignancies.

Grado de dolor al pinchar la fistula arteriovenosa con agujas congeladas comparando con agujas a temperatura ambiente / Level of pain in the arteriovenous fistula comparing frozen needles with room temperature needles

El dolor es una sensación subjetiva de malestar o sufrimiento que se origina como resultado de estimulaciones nocivas que indican daño tisular o enfermedad de cualquier tipo. Ocupa un lugar preeminente entre todas las experiencias sensoriales por medio de las cuales el hombre es consciente de que padece una enfermedad o está sufriendo una agresión externa, provocada por otra persona, sobre alguna parte de su cuerpo al realizar un tratamiento médico, produciendo dolor agudo. El objetivo principal del trabajo es comparar el grado de dolor al que es sometido el paciente cuando se punciona su fístula arteriovenosa (FA-VI) con agujas a distinta temperatura. El número de pacientes fueron 25. Las variables estudiadas: edad, sexo y tipo de acceso vascular no han sido estadísticamente significativas, por el contrario, en la comparación entre agujas a - 8°C y agujas a temperatura ambiente, si existe diferencia significativa en la intensidad del dolor que siente el paciente (AU)