TCRvß-CART therapy mediates high-precision targeting of malignant T-cell clones.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated with poor prognosis due to ineffective treatment options and high rates of relapse. The success of chimeric antigen receptor T-cell (CART) therapy for certain hematologic malignancies makes it an attractive treatment option for PTCLs. However, shared expression of potential target antigens by both malignant and healthy T cells poses a challenge. Current prospective CART approaches cause a high degree of on-target, off-tumor activity, resulting in fratricide during CART expansion, depletion of healthy T cells in vivo, and immune compromise in the patient. To limit off-tumor targeting, we sought to develop a CART platform specific for a given T-cell receptor vß (TCRvß) family that would endow CAR-modified T cells with the ability to mediate lysis of the clonal malignant population while preserving the majority of healthy T cells. Here, CAR constructs specific for multiple TCRvß family members were designed and validated. Our results demonstrate that TCRvß-family-specific CARTs (TCRvß-CARTs) recognize and kill TCRvß-expressing target cells. This includes specific self-depletion of the targeted cell subpopulation in the CART product and lysis of cell lines engineered to express a target TCRvß family. Furthermore, TCRvß-CARTs eliminated the dominant malignant TCRvß clone in 2 patient samples. Finally, in immunodeficient mice, TCRvß-CARTs eradicated malignant cells in a TCRvß-dependent manner. Importantly, the nontargeted TCRvß families were spared in all cases. Thus, TCRvß-CART therapy provides a potential option for high-precision treatment of PTCL with limited healthy T-cell depletion.

PTEN Loss and BRCA1 Promoter Hypermethylation Negatively Predict for Immunogenicity in BRCA-Deficient Ovarian Cancer.

PURPOSE: Ovarian cancers can exhibit a prominent immune infiltrate, but clinical trials have not demonstrated substantive response rates to immune checkpoint blockade monotherapy. We aimed to understand genomic features associated with immunogenicity in BRCA1/2 mutation-associated cancers. MATERIALS AND METHODS: Using the Cancer Genome Atlas whole-exome sequencing, methylation, and expression data, we analyzed 66 ovarian cancers with either germline or somatic loss of BRCA1/2 and whole-exome sequencing, immunohistochemistry, and CyTOF in 20 ovarian cancers with germline BRCA1/2 pathogenic variants from Penn. RESULTS: We found two groups of BRCA1/2 ovarian cancers differing in their immunogenicity: (1) 37 tumors significantly enriched for PTEN loss (11, 30%) and BRCA1 promoter-hypermethylated (10, 27%; P = .0016) and (2) PTEN wild-type (28 of 29 tumors) cancers, with the latter group having longer overall survival (OS; P = .0186, median OS not reached v median OS = 66.1 months). BRCA1/2-mutant PTEN loss and BRCA1 promoter-hypermethylated cancers were characterized by the decreased composition of lymphocytes estimated by gene expression (P = .0030), cytolytic index (P = .034), and cytokine expression but higher homologous recombination deficiency scores (P = .00013). Large-scale state transitions were the primary discriminating feature (P = .001); neither mutational burden nor neoantigen burden could explain differences in immunogenicity. In Penn tumors, PTEN loss and high homologous recombination deficiency cancers exhibited fewer CD3+ (P = .05), CD8+ (P = .012), and FOXP3+ (P = .0087) T cells; decreased PRF1 expression (P = .041); and lower immune costimulatory and inhibitory molecule expression. CONCLUSION: Our study suggests that within ovarian cancers with genetic loss of BRCA1/2 are two subsets exhibiting differential immunogenicity, with lower levels associated with PTEN loss and BRCA hypermethylation. These genomic features of BRCA1/2-associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic.

Testing Wallace's intuition: water type, reproductive isolation and divergence in an Amazonian fish.

Alfred Russel Wallace proposed classifying Amazon rivers based on their colour and clarity: white, black and clear water. Wallace also proposed that black waters could mediate diversification and yield distinct fish species. Here, we bring evidence of speciation mediated by water type in the sailfin tetra (Crenuchus spilurus), a fish whose range encompasses rivers of very distinct hydrochemical conditions. Distribution of the two main lineages concords with Wallace's water types: one restricted to the acidic and nutrient-poor waters of the Negro River (herein Rio Negro lineage) and a second widespread throughout the remaining of the species' distribution (herein Amazonas lineage). These lineages occur over a very broad geographical range, suggesting that despite occurring in regions separated by thousands of kilometres, individuals of the distinct lineages fail to occupy each other's habitats, hundreds of metres apart and not separated by physical barrier. Reproductive isolation was assessed in isolated pairs exposed to black-water conditions. All pairs with at least one individual of the lineage not native to black waters showed significantly lower spawning success, suggesting that the water type affected the fitness and contributed to reproductive isolation. Our results endorse Wallace's intuition and highlight the importance of ecological factors in shaping diversity of the Amazon fish fauna.

To Ask or Not to Ask? Opinions of Pediatric Medical Inpatients about Suicide Risk Screening in the Hospital.

OBJECTIVE: To describe opinions about suicide risk screening in a pediatric medical inpatient sample. STUDY DESIGN: As part of a larger instrument validation study, 200 pediatric medical inpatients (ages 10-21 years) were screened for suicide risk. Participants completed demographic self-report forms and were asked their opinions about suicide risk screening. Patient responses were recorded verbatim by trained research social workers. Qualitative data was analyzed using thematic analysis. RESULTS: The majority of adolescents who participated had not been previously asked about suicide (N = 101; 62.3%) and were supportive of suicide risk screening (81.0%). Five salient themes emerged from the qualitative analysis of patient opinions: prevention, elevated risk, emotional benefits, provider responsibility, and lack of harm in asking. CONCLUSIONS: The majority of youth screened for suicide risk on medical inpatient units were supportive of suicide risk screening. Opinion data have the potential to inform screening practices and assure clinicians that suicide risk screening will be acceptable to pediatric patients and their parents. Given the lack of screening in these patients' past experiences, the medical setting is a unique opportunity to capture youth at risk for suicide.

Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity.

The durable remission of B-cell leukemia and lymphoma following chimeric antigen receptor (CAR) T-cell therapy has brought this new form of adoptive immunotherapy to center stage with the expectation that CAR T-cell therapy may provide similar efficacy in other hematologic and solid cancers. Herein, we review recent advances in the areas of CAR design that improve CAR T-cell proliferation, engraftment, and efficacy, as well as clinical application strategies that are designed to improve clinical efficacy while reducing the risk of toxicity and broaden patient access to this promising form of cancer immunotherapy.

Stable isotope evidence for trophic overlap of sympatric Mexican Lake Chapala silversides (Teleostei: Atherinopsidae: Chirostoma spp)

We explore the trophic role that a diverse sympatric group of fishes in the genus Chirostoma play in a large, shallow lake in central Mexico, Lake Chapala. We use δ13C and δ15N stable isotope - based food web analyses to explore how they relate to other components of the Lake Chapala ecosystem. We find five Chirostoma species in top trophic levels of the Chapala food web compared to other fishes, relying on a combination of zooplankton, fish and benthic resources as energy sources. Food web metric analyses showed generally overlapping trophic niches for members of Chirostoma, especially in terms of δ13C. However, C. jordani had lower mean δ15N isotopic values than C. promelas. As a group, "pescados blancos" (C. sphyraena and C. promelas) also had higher δ15N signatures than "charales" (C. consocium, C. jordani and C. labarcae) reflecting greater piscivory, but these differences were not strong for all food web metrics used. Trophic overlap among species of Chirostoma in Lake Chapala raises questions about the forces that might have led to a morphologically diverse but functionally similar and monophyletic group of species.(AU)

Exploramos el papel trófico de un diverso grupo de peces (género Chirostoma) que habita en simpatría en el Lago Chapala, México central. Utilizamos isótopos estables de δ13C y δ15N para explorar la relación que guardan éstos peces con otros componentes del ecosistema. Encontramos a Chirostoma en niveles altos de la red trófica de Chapala, dependiendo energéticamente de zooplankton, peces y recursos del bentos. Análisis de parámetros de la red trófica demostraron traslape de nicho trófico para cinco miembros de Chirostoma, especialmente con relación a δ13C. Sin embargo, C. jordani tuvo un menor valor promedio de δ15N que C. promelas. Al ser analizados como grupo, los "pescados blancos" (C. sphyraena, C. promelas) tuvieron niveles promedio de δ15N mayores que los "charales" (C. consocium, C. jordani, C. labarcae), indicando mayor ictiofagia, pero las diferencias no fueron significativas para todos los parámetros de red trófica utilizados. El traslape trófico entre las especies de Chirostoma en Chapala da origen a cuestionamientos acerca de las fuerzas que pueden haber intervenido en el surgimiento de un morfológicamente diverso pero funcionalmente similar grupo monofilético de peces.(AU)

Stable isotope evidence for trophic overlap of sympatric Mexican Lake Chapala silversides (Teleostei: Atherinopsidae: Chirostoma spp)

We explore the trophic role that a diverse sympatric group of fishes in the genus Chirostoma play in a large, shallow lake in central Mexico, Lake Chapala. We use δ13C and δ15N stable isotope - based food web analyses to explore how they relate to other components of the Lake Chapala ecosystem. We find five Chirostoma species in top trophic levels of the Chapala food web compared to other fishes, relying on a combination of zooplankton, fish and benthic resources as energy sources. Food web metric analyses showed generally overlapping trophic niches for members of Chirostoma, especially in terms of δ13C. However, C. jordani had lower mean δ15N isotopic values than C. promelas. As a group, "pescados blancos" (C. sphyraena and C. promelas) also had higher δ15N signatures than "charales" (C. consocium, C. jordani and C. labarcae) reflecting greater piscivory, but these differences were not strong for all food web metrics used. Trophic overlap among species of Chirostoma in Lake Chapala raises questions about the forces that might have led to a morphologically diverse but functionally similar and monophyletic group of species.

Exploramos el papel trófico de un diverso grupo de peces (género Chirostoma) que habita en simpatría en el Lago Chapala, México central. Utilizamos isótopos estables de δ13C y δ15N para explorar la relación que guardan éstos peces con otros componentes del ecosistema. Encontramos a Chirostoma en niveles altos de la red trófica de Chapala, dependiendo energéticamente de zooplankton, peces y recursos del bentos. Análisis de parámetros de la red trófica demostraron traslape de nicho trófico para cinco miembros de Chirostoma, especialmente con relación a δ13C. Sin embargo, C. jordani tuvo un menor valor promedio de δ15N que C. promelas. Al ser analizados como grupo, los "pescados blancos" (C. sphyraena, C. promelas) tuvieron niveles promedio de δ15N mayores que los "charales" (C. consocium, C. jordani, C. labarcae), indicando mayor ictiofagia, pero las diferencias no fueron significativas para todos los parámetros de red trófica utilizados. El traslape trófico entre las especies de Chirostoma en Chapala da origen a cuestionamientos acerca de las fuerzas que pueden haber intervenido en el surgimiento de un morfológicamente diverso pero funcionalmente similar grupo monofilético de peces.