Emerging roles for tumor stroma in antigen presentation and anti-cancer immunity.

Advances in immunotherapy in the last decade have revolutionized treatment paradigms across multiple cancer diagnoses. However, only a minority of patients derive durable benefit and progress with traditional approaches, such as cancer vaccines, remains unsatisfactory. A key to overcoming these barriers resides with a deeper understanding of tumor antigen presentation and the complex and dynamic heterogeneity of tumor-infiltrating antigen-presenting cells (APCs). Reminiscent of the 'second touch' hypothesis proposed by Klaus Ley for CD4+ T cell differentiation, the acquisition of full effector potential by lymph node- primed CD8+ T cells requires a second round of co-stimulation at the site where the antigen originated, i.e. the tumor bed. The tumor stroma holds a prime role in this process by hosting specialized APC niches, apparently distinct from tertiary lymphoid structures, that support second antigenic touch encounters and CD8+ T cell effector proliferation and differentiation. We propose that APC within second-touch niches become licensed for co-stimulation through stromal-derived instructive signals emulating embryonic or wound-healing provisional matrix remodeling. These immunostimulatory roles of stroma contrast with its widely accepted view as a physical and functional 'immune barrier'. Stromal control of antigen presentation makes evolutionary sense as the host stroma-tumor interface constitutes the prime line of homeostatic 'defense' against the emerging tumor. In this review, we outline how stroma-derived signals and cells regulate tumor antigen presentation and T-cell effector differentiation in the tumor bed. The re-definition of tumor stroma as immune rheostat rather than as inflexible immune barrier harbors significant untapped therapeutic opportunity.

[Nutritional status of women with gestational diabetes and characteristics of newborn]. / Estado nutricional de mujeres con diabetes gestacional y caracteristicas del recién nacido.

The objective was to determine the relationship between the mother's nutritional status and the newborn's gestational characteristics. A sample of 149 women with gestational diabetes was controlled in the High Risk Obstetric Unit of the Medical Specialties Public Health Center before delivery in the maternity ward of the Hospital Clinico Herminda Martín de Chillán, Chile in 2010. Data were obtained from the perinatal clinical history and the newborn's chart. The variables recorded for the mother were nutritional status, type of delivery, number of pregnancies, and metabolic control. Data for the newborn were weight, length, head circumference, and gestational diagnosis. These data were analyzed by ANOVA, Chi-square test, and Multiple Correspondence. Women with a normal nutritional status were multiparous with natural childbirth; the newborn had an adequate gestational age and normal head circumference. On the other hand, maternal obesity was related to a Cesarean; the newborn was large for gestational age and had a larger head circumference. Overweight women were primiparous and the newborn was small for gestational age with a smaller head circumference (p < 0.01). It was concluded that obesity in women with gestational diabetes explains variables such as type of delivery, number of gestations, and the newborn's diagnosis.

Polymorphic variant Asp239Tyr of human DNA glycosylase NTHL1 is inactive for removal of a variety of oxidatively-induced DNA base lesions from genomic DNA.

Base excision repair is the major pathway for the repair of oxidatively-induced DNA damage, with DNA glycosylases removing modified bases in the first step. Human NTHL1 is specific for excision of several pyrimidine- and purine-derived lesions from DNA, with loss of function NTHL1 showing a predisposition to carcinogenesis. A rare single nucleotide polymorphism of the Nthl1 gene leading to the substitution of Asp239 with Tyr within the active site, occurs within global populations. In this work, we overexpressed and purified the variant NTHL1-Asp239Tyr (NTHL1-D239Y) and determined the substrate specificity of this variant relative to wild-type NTHL1 using gas chromatography-tandem mass spectrometry with isotope-dilution, and oxidatively-damaged genomic DNA containing multiple pyrimidine- and purine-derived lesions. Wild-type NTHL1 excised seven DNA base lesions with different efficiencies, whereas NTHL1-D239Y exhibited no glycosylase activity for any of these lesions. We also measured the activities of human glycosylases OGG1 and NEIL1, and E. coli glycosylases Nth and Fpg under identical experimental conditions. Different substrate specificities among these DNA glycosylases were observed. When mixed with NTHL1-D239Y, the activity of NTHL1 was not reduced, indicating no substrate binding competition. These results and the inactivity of the variant D239Y toward the major oxidatively-induced DNA lesions points to the importance of the understanding of this variant's role in carcinogenesis and the potential of individual susceptibility to cancer in individuals carrying this variant.

Cognitive flexibility and aging in coyotes (Canis latrans).

Cognitive flexibility evolves in species that live in complex and dynamic social systems and habitats and may enable species to better cope with anthropogenic habitat modification. Aging may also impact the cognitive abilities of canids. Coyotes (Canis latrans) and domestic dogs (Canis lupus familiaris) differ markedly in their social and trophic ecology but have both been highly successful in adapting to human-modified ecosystems. Aging dogs develop a form of dementia that mirrors Alzheimer's disease in humans, but it is unknown whether similar cognitive deficits develop with age in coyotes and other wild canids. In this study, we modified a spatial serial reversal-learning test that was sensitive to cognitive aging in pet dogs to test cognitive flexibility in captive coyotes. We also performed a second experiment using a color discrimination task to test for flexible rule learning. A total of 19 of 20 coyotes demonstrated the ability to track shifts in spatial reward contingencies and learned to rapidly complete reversals by using a win-stay, lose-shift strategy. In addition, coyotes inhibited prepotent win-stay choices to acquire the color discrimination task. These findings suggest that behavioral flexibility may help coyotes to detect and respond appropriately to both rapid fluctuations and gradual changes in ecological conditions. Performance did not differ between coyotes and previously tested dogs, but similar to dogs, behavioral flexibility declined with age in adult coyotes. Thus, cognitive decline and flexibility may be conserved among canines pending additional studies on other Canis species. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells.

Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors (PARPi) have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat BRCA1 mutant cells derived from a patient with triple negative breast cancer and control cells for three weeks with veliparib, a PARPi, to determine if treatment with this drug induces increased levels of mutations and/or an inflammatory response. We show that long-term treatment with PARPi induces an inflammatory response in HCC1937 BRCA1 mutant cells. The levels of chromatin-bound PARP1 in the BRCA1 mutant cells correlate with significant upregulation of inflammatory genes and activation of the cyclic GMP-AMP synthase (cGAS)/signaling effector stimulator of interferon genes (STING pathway). In contrast, an increased mutational load is induced in BRCA1-complemented cells treated with a PARPi. Our results suggest that long-term PARP inhibitor treatment may prime both BRCA1 mutant and wild-type tumors for positive responses to immune checkpoint blockade, but by different underlying mechanisms.

NTHL1 in genomic integrity, aging and cancer.

Efficient DNA repair is essential to maintain genomic integrity. An average of 30,000 base lesions per cell are removed daily by the DNA glycosylases of the base excision repair machinery. With the advent of whole genome sequencing, many germline mutations in these DNA glycosylases have been identified and associated with various diseases, including cancer. In this graphical review, we discuss the function of the NTHL1 DNA glycosylase and how genomic mutations and altered function of this protein contributes to cancer and aging. We highlight its role in a rare tumor syndrome, NTHL1-associated polyposis (NAP), and summarize various other polymorphisms in NTHL1 that can induce early hallmarks of cancer, including genomic instability and cellular transformation.

Estado nutricional de mujeres con diabetes gestacional y características del recién nacido

El propósito fue determinar la relación entre el estado nutricional de la madre y las características de gestación del recién nacido de un grupo de embarazadas con diabetes gestacional. Se estudiaron 149 mujeres con diabetes gestacional de la Unidad de Alto Riesgo Obstétrico del Consultorio de Especialidades y Maternidad del Hospital Clínico Herminda Martin de Chillán, Chile, cuyos hijos nacieron en el año 2010. Los datos se obtuvieron de la historia clínica perinatal y la ficha del recién nacido. Las variables registradas en la madre fueron estado nutricional, vía de parto, número de gestaciones, control metabólico de la diabetes gestacional. Del niño se obtuvo el peso, circunferencia craneana y diagnóstico gestacional. Los datos fueron estudiados mediante análisis descriptivo univariado, bivariado y multivariado, ANOVA de un factor, Chi cuadrado y análisis de correspondencia múltiple. Se encontró que las mujeres con estado nutricional normal, eran multigestas, tuvieron parto vaginal, su hijo recién nacido fue adecuado para la edad gestacional, normocefálico;por otro lado, la condición de obesidad materna se relacionó con partos por cesárea, recién nacidos grandes para edad gestacional y macrocefalia; las mujeres con sobrepeso en general fueron primigestas y el recién nacido pequeño para edad gestacional con microcefalia p<0,01. Se concluyó que la obesidad en las mujeres con diabetes gestacional explica variables como la vía de parto, el número de gestaciones y el diagnóstico del recién nacido.

Nutritional status of women with gestational diabetes and characteristics of newborn. The objective was to determine the relationship between the mother’s nutritional status and the newborn’s gestational characteristics. A sample of 149 women with gestational diabetes was controlled in the High Risk Obstetric Unit of the Medical Specialties Public Health Center before delivery in the maternity ward of the Hospital Clínico Herminda Martín de Chillán, Chile in 2010. Data were obtained from the perinatal clinical history and the newborn’s chart. The variables recorded for the mother were nutritional status, type of delivery, number of pregnancies,and metabolic control. Data for the newborn were weight, length, head circumference, and gestational diagnosis.These data were analyzed by ANOVA, Chi-square test, and Multiple Correspondence. Women with a normal nutritional status were multiparous with natural childbirth; the newborn had an adequate gestational age and normal head circumference. On the other hand, maternal obesity was related to a Cesarean; the newborn was large for gestational age and had a larger head circumference. Overweight women were primiparous and the newborn was small for gestational age with a smaller head circumference (p<0,01). It was concluded that obesity in women with gestational diabetes explains variables such as type of delivery, number of gestations, and the newborn’s diagnosis.