HA-1-targeted T cell receptor (TCR) T cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective anti-leukemic effect post-HCT. We conducted a phase I clinical trial employing a novel TCR-T product targeting the minor H antigen HA-1 to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T post-HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8-co-receptor were successfully manufactured from HA-1 disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to nine HCT recipients who had developed disease recurrence post-HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, four patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with one ongoing at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial is registered at clinicaltrials.gov as NCT03326921.

Improving the knowledge management of marine megafauna strandings.

Although the marine megafauna often strands on beaches around the world, such as sea turtles and whales, stranding data are poorly managed and incorporated into management and conservation strategies. Here we use a knowledge value chain framework to call attention for the urgent need to improve our data architecture and knowledge management on marine megafauna strandings. We use Brazil, a continental megadiverse federative republic, as study model. After describing the main components and identifying the strengths and weaknesses of the current Brazilian data architecture, we propose 10 practical measures for its improvement involving researchers, companies, non-governmental organizations, legislators, policy makers, public agents, citizen scientists, and local communities. Although Brazil has notable strengths such as comprehensive environmental legislation, hundreds of scientists and dozens of prestigious research institutions, stranding data is not translated into technical-scientific knowledge; technical-scientific knowledge is not transformed into effective public regulations; deficient regulations lead to bad decisions and limited actions, which in turn result in ineffective management and conservation strategies. In light of the UN Decade of Ocean Science for Sustainable Development (2021-2030), we propose (1) expanding standardized beach monitoring projects to the entire Brazilian coast; (2) creating a governmental database with FAIR principles; (3) encouraging the development of broad citizen science initiatives; (4) funding scientists and research institutions; (5) boosting outreach activities among researchers to popularize the scientific knowledge; (6) raising awareness among legislators and policy makers on the problem of strandings; (7) updating the existing legal provisions on the environmental licensing of activities developed at sea; (8) hiring new environmental analysts and inspectors and improving the infrastructure of executing environmental agencies; (9) strengthening existing conservation networks with multiple stakeholders; and (10) making the results of the management and conservation strategies broadly accessible to society. These recommendations may also apply to other coastal countries around the world.

Exploring the relationship between environmental drivers and the manifestation of fibropapillomatosis in green turtles (Chelonia mydas) in eastern Brazil.

Fibropapillomatosis (FP) is a disease characterized by epithelial tumors that can impede life-sustaining activities of sea turtles, especially green turtles (Chelonia mydas). FP is caused by a herpesvirus, but environmental factors are also thought to play a role in triggering FP tumor growth. In this study, we evaluate the epidemiology of FP tumors in green turtles along the coast of Espírito Santo, Brazil, a region where juvenile green turtles are known to aggregate with high FP prevalence. A dataset comprising 2024 beach-cast green turtles recorded through daily beach surveys on 400 km of coastline from 2018 to 2021 (inclusive) was evaluated. FP tumors were recorded in 40.9% of the individuals in this dataset, and presence of FP tumors was predicted by individual variables (presence of marine leeches, stranding code, curved carapace length, body mass-size residual) and characteristics of the stranding site (distance to nearest metallurgical plant, mean sea surface salinity (SSS), annual range of sea surface temperature (SST)). Additionally, a second dataset comprising detailed information about the size and anatomical distribution of tumors in 271 green turtles with FP from the same region was evaluated. Hierarchical clustering analysis revealed these turtles could be classified in three groups according to the anatomical distribution of their tumors, and in turn the group to which each turtle was assigned could be predicted by the study period (2010-2014 vs. 2018-2022) and by characteristics of the stranding/capture site (green turtle stranding density, mean sea surface chlorophyll-a concentration, mean SSS, mean SST, annual range of SST). These results corroborate that individual and environmental factors play a significant role driving FP epidemiology. Furthermore, the results suggest that rather than behaving as a single entity, FP may be seen as a mosaic of distinct anatomical patterns that are not necessarily driven by the same environmental factors.

Plastic pollution on the world's coral reefs.

Coral reefs are losing the capacity to sustain their biological functions1. In addition to other well-known stressors, such as climatic change and overfishing1, plastic pollution is an emerging threat to coral reefs, spreading throughout reef food webs2, and increasing disease transmission and structural damage to reef organisms3. Although recognized as a global concern4, the distribution and quantity of plastics trapped in the world's coral reefs remains uncertain3. Here we survey 84 shallow and deep coral ecosystems at 25 locations across the Pacific, Atlantic and Indian ocean basins for anthropogenic macrodebris (pollution by human-generated objects larger than 5 centimetres, including plastics), performing 1,231 transects. Our results show anthropogenic debris in 77 out of the 84 reefs surveyed, including in some of Earth's most remote and near-pristine reefs, such as in uninhabited central Pacific atolls. Macroplastics represent 88% of the anthropogenic debris, and, like other debris types, peak in deeper reefs (mesophotic zones at 30-150 metres depth), with fishing activities as the main source of plastics in most areas. These findings contrast with the global pattern observed in other nearshore marine ecosystems, where macroplastic densities decrease with depth and are dominated by consumer items5. As the world moves towards a global treaty to tackle plastic pollution6, understanding its distribution and drivers provides key information to help to design the strategies needed to address this ubiquitous threat.

Plastic ingestion as an evolutionary trap: Toward a holistic understanding.

Human activities are changing our environment. Along with climate change and a widespread loss of biodiversity, plastic pollution now plays a predominant role in altering ecosystems globally. Here, we review the occurrence of plastic ingestion by wildlife through evolutionary and ecological lenses and address the fundamental question of why living organisms ingest plastic. We unify evolutionary, ecological, and cognitive approaches under the evolutionary trap theory and identify three main factors that may drive plastic ingestion: (i) the availability of plastics in the environment, (ii) an individual's acceptance threshold, and (iii) the overlap of cues given by natural foods and plastics.

CBFB-MYH11 fusion neoantigen enables T cell recognition and killing of acute myeloid leukemia.

Proteins created from recurrent fusion genes like CBFB-MYH11 are prevalent in acute myeloid leukemia (AML), often necessary for leukemogenesis, persistent throughout the disease course, and highly leukemia specific, making them attractive neoantigen targets for immunotherapy. A nonameric peptide derived from a prevalent CBFB-MYH11 fusion protein was found to be immunogenic in HLA-B*40:01+ donors. High-avidity CD8+ T cell clones isolated from healthy donors killed CBFB-MYH11+ HLA-B*40:01+ AML cell lines and primary human AML samples in vitro. CBFB-MYH11-specific T cells also controlled CBFB-MYH11+ HLA-B*40:01+ AML in vivo in a patient-derived murine xenograft model. High-avidity CBFB-MYH11 epitope-specific T cell receptors (TCRs) transduced into CD8+ T cells conferred antileukemic activity in vitro. Our data indicate that the CBFB-MYH11 fusion neoantigen is naturally presented on AML blasts and enables T cell recognition and killing of AML. We provide proof of principle for immunologically targeting AML-initiating fusions and demonstrate that targeting neoantigens has clinical relevance even in low-mutational frequency cancers like fusion-driven AML. This work also represents a first critical step toward the development of TCR T cell immunotherapy targeting fusion gene-driven AML.

Exploring plastic-induced satiety in foraging green turtles.

In the last decade many studies have described the ingestion of plastic in marine animals. While most studies were dedicated to understanding the pre-ingestion processes involving decision-making foraging choices based on visual and olfactory cues of animals, our knowledge in the post-ingestion consequences remains limited. Here we proposed a theoretical complementary view of post-ingestion consequences, attempting to connect plastic ingestion with plastic-induced satiety. We analyzed data of plastic ingestion and dietary information of 223 immature green turtles (Chelonia mydas) from tropical Brazilian reefs in order to understand the impacts of plastic ingestion on foraging behavior. Generalized linear mixing models and permutational analysis of variance suggested that plastic accumulations in esophagus, stomach and intestine differed in their impact on green turtle's food intake. At the initial stages of plastic ingestion, where the plastic still in the stomach, an increase in food intake was observed. The accumulation of plastic in the gastrointestinal tract can reduce food intake likely leading to plastic-induced satiety. Our results also suggest that higher amounts of plastics in the gastrointestinal tract may led to underweight and emaciated turtles. We hope that adopting and refining our proposed framework will help to clarify the post-ingestion consequences of plastic ingestion in wildlife.

Anthropogenic litter on Brazilian beaches: Baseline, trends and recommendations for future approaches.

Beaches are fundamental habitats that regulate the functioning of several coastal processes and key areas contributing to national and local budgets. In this study we provide the first large-scale systematic survey of anthropogenic litter on Brazilian beaches, covering a total of 35 degrees of latitude, recording the litter type, its use and size. Plastic comprised the most abundant litter type, followed by cigarette butts and paper. Small pieces (<5 cm) were dominant among litter size-classes and food-related use was associated to most litter recorded types. Generalized additive models showed that proximity to estuarine run-offs was the main driver to beach litter accumulation, reinforcing river drainages as the primary route of litter coastal pollution. Also, the Clean-Coast Index evidenced there was not a pattern of beach litter pollution among regions, which denotes that actions regarding marine pollution must be taken by all state governances of the country.

Marine debris in Trindade Island, a remote island of the South Atlantic.

Marine debris is widespread in oceans worldwide, including the most remote locations. Here, for the first time, we report macro-debris accumulation on beaches of Trindade Island, a remote island 1160 km from mainland Brazil. High debris density was recorded on windward, east-coast beaches, which are exposed to wind-driven currents. Small-sized plastic fragments were the most abundant debris. Polyethylene (67%), polypropylene (30%) and polyamide (3%) were the most prevalent polymeric materials identified by ATR-FTIR. Identified debris show that interaction with Trindade fauna, mainly with seabirds and endangered terrestrial crabs, exists and already has some impact. This study provides baseline information on Trindade macro-debris demonstrating that the island, located on the edge of the South Atlantic Gyre, acts as a sink for gyre debris, exposing the island fauna to the threats related to plastic contamination.

Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse.

Leukemia relapse remains the major cause of allogeneic hematopoietic stem cell transplantation (HCT) failure, and the prognosis for patients with post-HCT relapse is poor. There is compelling evidence that potent selective antileukemic effects can be delivered by donor T cells specific for particular minor histocompatibility (H) antigens. Thus, T-cell receptors (TCRs) isolated from minor H antigen-specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage post-HCT leukemic relapse. Recognizing that several elements may be crucial to the efficacy and safety of engineered T-cell immunotherapy, we developed a therapeutic transgene with 4 components: (1) a TCR specific for the hematopoietic-restricted, leukemia-associated minor H antigen, HA-1; (2) a CD8 coreceptor to promote function of the class I-restricted TCR in CD4+ T cells; (3) an inducible caspase 9 safety switch to enable elimination of the HA-1 TCR T cells in case of toxicity; and (4) a CD34-CD20 epitope to facilitate selection of the engineered cell product and tracking of transferred HA-1 TCR T cells. The T-cell product includes HA-1 TCR CD4+ T cells to augment the persistence and function of the HA-1 TCR CD8+ T cells and includes only memory T cells; naive T cells are excluded to limit the potential for alloreactivity mediated by native TCR coexpressed by HA-1 TCR T cells. We describe the development of this unique immunotherapy and demonstrate functional responses to primary leukemia by CD4+ and CD8+ T cells transduced with a lentiviral vector incorporating the HA-1 TCR transgene construct.

The anti-predator role of within-nest emergence synchrony in sea turtle hatchlings.

Group formation is a common behaviour among prey species. In egg-laying animals, despite the various factors that promote intra-clutch variation leading to asynchronous hatching and emergence from nests, synchronous hatching and emergence occurs in many taxa. This synchrony may be adaptive by reducing predation risk, but few data are available in any natural system, even for iconic examples of the anti-predator function of group formation. Here, we show for the first time that increased group size (number of hatchlings emerging together from a nest) reduces green turtle (Chelonia mydas) hatchling predation. This effect was only observed earlier in the night when predation pressure was greatest, indicated by the greatest predator abundance and a small proportion of predators preoccupied with consuming captured prey. Further analysis revealed that the effect of time of day was due to the number of hatchlings already killed in an evening; this, along with the apparent lack of other anti-predatory mechanisms for grouping, suggests that synchronous emergence from a nest appears to swamp predators, resulting in an attack abatement effect. Using a system with relatively pristine conditions for turtle hatchlings and their predators provides a more realistic environmental context within which intra-nest synchronous emergence has evolved.

Origin of marine debris is related to disposable packs of ultra-processed food.

Marine debris is currently distributed worldwide, and the discard and contamination pose hazards to human and wildlife health. One of the gaps in debris science is tracking the source of debris to better evaluate and avoid the pathway of debris from the source to marine environment. For this, we evaluated three beaches of different urbanization levels and environmental influences; a low urbanized beach, a highly urbanized beach and a non-urbanized estuary-associated beach, in order to determine the sources and original use of debris. Plastic was the major material found on beaches, and the urbanized beach recorded the highest debris densities. Marine debris was primarily from land-based sources, and the debris recorded in all beaches was mainly assigned as food-related items. Our results highlight the major presence of disposable and short-lived products comprising the majority of debris that enters the ocean and draw attention to the unsustainable lifestyle of current society.

Marine debris ingestion and Thayer's law - The importance of plastic color.

In recent years marine plastic pollution has gained considerable attention as a significant threat to marine animals. Despite the abundant literature related to marine debris ingestion, only a few studies attempted to understand the factors involved in debris ingestion. Plastic ingestion is commonly attributed to visual similarities of plastic fragments to animal's prey items, such as plastic bags and jellyfish. However, this simple explanation is not always coherent with the variety of debris items ingested and with the species' main prey items. We assess differences in the conspicuousness of plastic debris related to their color using Thayer's law to infer the likelihood that visual foragers detect plastic fragments. We hypothesize that marine animals that perceive floating plastic from below should preferentially ingest dark plastic fragments, whereas animals that perceive floating plastic from above should select for paler plastic fragments.

Ataxia, ophthalmoplegia and laryngeal stridor related to glutamic acid decarboxylase antibodies / Ataxia, oftalmoplegia e estridor laríngeo relacionados a anticorpos antidescarboxilase do ácido glutâmico

Glutamic acid decarboxylase (GAD) is the enzyme responsible for the conversion of glutamate to gamma-aminobutyric acid (GABA) in the central nervous system. The presence of anti-GAD antibody in cerebrospinal fluid and high levels in blood have been described in some neurological disorders, such as stiff person syndrome and cerebellar ataxia. It is postulated that African descent with anti-GAD may exhibit more severe neurological impairment. We report a case of a young adult African descent with cerebellar syndrome associ-ated with ophthalmoplegia and laryngeal stridor. We found in the literature relationship of ophthalmoplegia plus ataxia with anti-GAD, but no reports of these symptoms with laryngeal stridor, apparently being the first reported case.

Descarboxilase do ácido glutâmico (GAD) é a enzima responsável pela conversão do glutamato em ácido gama-aminobutírico (GABA) no sistema nervoso central. A presença do anticorpo anti-GAD no líquido cefalorraquidiano e em altos níveis no sangue tem sido descrita em alguns distúrbios neurológicos, tais como a síndrome da pessoa rígida e ataxia cerebelar. Postula-se que pacientes afrodescendentes podem apresentar comprometimento neurológico mais severo. Relatamos o caso de um adulto jovem afrodescendente com síndrome cerebelar associada a oftalmoplegia e estridor laríngeo. Encontramos na literatura relação entre a oftalmoplegia com ataxia e anti-GAD, mas nenhum relato desses sintomas com estridor laríngeo, sendo aparentemente o primeiro caso reportado.

In contrast to other species, α-Galactosylceramide (α-GalCer) is not an immunostimulatory NKT cell agonist in horses.

α-GalCer is a potent immunomodulatory molecule that is presented to NKT cells via the CD1 antigen-presenting system. We hypothesized that when used as an adjuvant α-GalCer would induce protective immune responses against Rhodococcus equi, an important pathogen of young horses. Here we demonstrate that the equine CD1d molecule shares most features found in CD1d from other species and has a suitable lipid-binding groove for presenting glycolipids to NKT cells. However, equine CTL stimulated with α-GalCer failed to kill cells infected with R. equi, and α-GalCer did not increase killing by CTL co-stimulated with R. equi antigen. Likewise, α-GalCer did not induce the lymphoproliferation of equine PBMC or increase the proliferation of R. equi-stimulated cells. Intradermal injection of α-GalCer in horses did not increase the recruitment of lymphocytes or cytokine production. Furthermore, α-GalCer-loaded CD1d tetramers, which have been shown to be broadly cross-reactive, did not bind equine lymphocytes. Altogether, our results demonstrate that in contrast to previously described species, horses are unable to respond to α-GalCer. This raises questions about the capabilities and function of NKT cells and other lipid-specific T lymphocytes in horses.

The equine CD1 gene family is the largest and most diverse yet identified.

The CD1 family is a group of non-polymorphic MHC class I-like molecules that present lipid-based antigens to T cells. Previous work in our laboratory demonstrated that cytotoxic T lymphocytes from immune adult horses recognize lipids from the cell wall of an important equine pathogen, Rhodococcus equi. These findings suggest an important role for the equine CD1 antigen presentation system in protective immune responses to microbial pathogens in the horse. In this study, we characterized and mapped the equine CD1 gene cluster. The equine genome was found to contain 13 complete CD1 genes; seven genes were classified as homologues of human CD1a, two CD1b, one CD1c, one CD1d, and two CD1e, making it the largest CD1 family to date. All but one of the eqCD1 molecules were expressed in all antigen-presenting cells investigated. The major amino acid differences between equine CD1 isoforms are located in the predicted antigen binding site, suggesting that a variety of lipid antigens can be presented. R. equi survives and replicates within professional phagocytes by arresting phagosome maturation between the early endosome and late phagosome. Based on the absence of a tyrosine sorting motif in all eqCD1a, CD1a molecules are predicted to co-localize with R. equi in the early endosome. Here, they could acquire lipid antigen and present it to T lymphocytes. The extraordinarily large number of CD1 molecules in the horse may reflect their crucial role in immunity to R. equi.

Análise crítica com TCFC da altura e espessura em sítios maxilares edêntulos potenciais para implantes dentários, usando-se a técnica all-on-four: estudo piloto / A critical CBCT analysis of height and thickness in edentulous maxillary potential implant sites regarding the all-on-four technique: pilot study

A técnica da cirurgia guiada sem retalho representa um grande avanço tecnológico, e é considerada uma realidade na Osseointegração. Sendo assim, a sua execução deve seguir alguns cuidados para o sucesso no tratamento proposto, no que tange alguns aspectos essenciais, a exemplo da disponibilidade óssea mínima para correta instalação dos implantes. Portanto, foi realizado um estudo tomográfico com amostra de 20 maxilas totalmente edêntulas para avaliar a viabilidade da instalação virtual de implantes no software Dental Slice, de acordo com a disponibilidade óssea, seguindo o protocolo all-on-four, além de mensurar nos cortes tomográficos a altura e a espessura dos sítios de instalação dos implantes. Os resultados encontrados de acordo com a análise estatística foram: 5% das maxilas estudadas apresentaram disponibilidade suficiente para a inserção completa dos quatro implantes no osso remanescente; 95% das maxilas apresentaram áreas de fenestrações ou ausência completa de possibilidade de inserção. Nos 80 sítios de instalação de implantes mensurados foram encontradas médias de 8,58 mm (p=0,66) e de 3,52 mm (p=0,85) de altura e de espessura óssea, respectivamente. Os autores concluem que apenas 5% das 20 maxilas estudadas foram consideradas viáveis para a inserção completa de implantes seguindo o protocolo all-on-four...

Guided flapless surgery has proved to be a major breakthrough in the practice of Implantodontics, but certain precautions should be taken in the execution of this technique, particularly with respect to the minimum availability of bone required for the successful implant placement. With this in mind, a tomographic study of 20 completely edentulous maxillae was carried out using Dental Slice software, to measure the bone height and thickness of potential implant insertion sites and evaluate the viability of installing implants following an ‘All-on-four’ protocol. A total of 80 sites were evaluated and a mean height of 8.58mm (p= 0.66) and a mean thickness of 3.52 mm (p= 0.85) were recorded. Statistical analysis of the results showed that only 5% of the maxillae studied had suffi cient remaining bone for the complete insertion of four implants, while 95% either presented areas of fenestration or were completely inadequate for implant placement. It was concluded that complete implant insertion following an ‘All-on-four’ protocol was viable in only 5% of studied cases...

Coastal habitat degradation and green sea turtle diets in Southeastern Brazil.

To show the influence of coastal habitat degradation on the availability of food for green turtles (Chelonia mydas), we assessed the dietary preferences and macroalgae community at a feeding area in a highly urbanized region. The area showed low species richness and was classified as degraded. We examined stomach contents of 15 dead stranded turtles (CCL=44.0cm (SD 6.7cm)). The diet was composed primarily of green algae Ulva spp. (83.6%). In contrast, the macroalgae community was dominated by the green alga Caulerpa mexicana. We found a selection for red algae, seagrass and Ulva spp., and avoidance for C. mexicana and brown alga Dictyopteris delicatula. The low diversity of available food items, possibly a result of environmental degradation, likely contributed to the low dietary diversity. The nutritional implications of this restricted diet are unclear.