Iterative Evolution of Sympatric Seacow (Dugongidae, Sirenia) Assemblages during the Past ∼26 Million Years

Extant sirenians show allopatric distributions throughout most of their range. However, their fossil record shows evidence of multispecies communities throughout most of the past ∼26 million years, in different oceanic basins. Morphological differences among co-occurring sirenian taxa suggest that resource partitioning played a role in structuring these communities. We examined body size and ecomorphological differences (e.g., rostral deflection and tusk morphology) among sirenian assemblages from the late Oligocene of Florida, early Miocene of India and early Pliocene of Mexico; each with three species of the family Dugongidae. Although overlapping in several ecomorphological traits, each assemblage showed at least one dominant trait in which coexisting species differed. Fossil sirenian occurrences occasionally are monotypic, but the assemblages analyzed herein show iterative evolution of multispecies communities, a phenomenon unparalleled in extant sirenian ecology. As primary consumers of seagrasses, these communities likely had a strong impact on past seagrass ecology and diversity, although the sparse fossil record of seagrasses limits direct comparisons. Nonetheless, our results provide robust support for previous suggestions that some sirenians in these extinct assemblages served as keystone species, controlling the dominance of climax seagrass species, permitting more taxonomically diverse seagrass beds (and sirenian communities) than many of those observed today

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL

Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 (NCT02935257) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4-84.4) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL

Seagrass and submerged aquatic vegetation (VAS) habitats off the Coast of Brazil: state of knowledge, conservation and main threats

Seagrass meadows are among the most threatened ecosystems on earth, raising concerns about the equilibrium of coastal ecosystems and the sustainability of local fisheries. The present review evaluated the current status of the research on seagrasses and submerged aquatic vegetation (SAV) habitats off the coast of Brazil in terms of plant responses to environmental conditions, changes in distribution and abundance, and the possible role of climate change and variability. Despite an increase in the number of studies, the communication of the results is still relatively limited and is mainly addressed to a national or regional public; thus, South American seagrasses are rarely included or cited in global reviews and models. The scarcity of large-scale and long-term studies allowing the detection of changes in the structure, abundance and composition of seagrass habitats and associated species still hinders the investigation of such communities with respect to the potential effects of climate change. Seagrass meadows and SAV occur all along the Brazilian coast, with species distribution and abundance being strongly influenced by regional oceanography, coastal water masses, river runoff and coastal geomorphology. Based on these geomorphological, hydrological and ecological features, we characterised the distribution of seagrass habitats and abundances within the major coastal compartments. The current conservation status of Brazilian seagrasses and SAV is critical. The unsustainable exploitation and occupation of coastal areas and the multifold anthropogenic footprints left during the last 100 years led to the loss and degradation of shoreline habitats potentially suitable for seagrass occupation. Knowledge of the prevailing patterns and processes governing seagrass structure and functioning along the Brazilian coast is necessary for the global discussion on climate change. Our review is a first and much-needed step toward a more integrated and inclusive approach to understanding the diversity of coastal plant formations along the Southwestern Atlantic coast as well as a regional alert the projected or predicted effects of global changes on the goods and services provided by regional seagrasses and SAV

O comércio internacional de peles silvestres na Amazônia brasileira no século XX

Durante o século XX, o comércio internacional de peles foi responsável pelo abate de milhões de mamíferos e répteis na Amazônia. Negociadas no regime de comércio fluvial e aviamento, as peles seguiam dos portos e seringais, localizados no interior, para as casas aviadoras e exportadoras de Manaus e Belém, de onde eram exportadas principalmente para os Estados Unidos, a Europa e o sul brasileiro. Neste artigo, analisamos documentos fiscais inéditos liberados pelo extinto império econômico do aviamento - a empresa J. G. Araujo -, bem como periódicos da Associação Comercial do Amazonas e os registros portuários da Manáos Harbour Ltd. O comércio internacional de peles silvestres intensificou-se imediatamente após a crise da borracha (1912) e atingiu seu auge entre 1935 e 1946, com o pico durante a Segunda Guerra Mundial. O segundo pico ocorreu na década de 1960, principal e ironicamente logo após a publicação da Lei de Proteção à Fauna (1967). Ao longo do período que antecedeu a aprovação da Convenção sobre o Comércio Internacional de Espécies Ameaçadas (CITES), em 1973-1975, não houve depreciação significativa no preço ou na demanda internacional por peles silvestres, sugerindo um esforço de caça constante e intenso por quase meio século

The life and scientific work of William R. Evitt (1923-2009)

Occasionally (and fortunately), circumstances and timing combine to allow an individual, almost singlehandedly, to generate a paradigm shift in his or her chosen field of inquiry. William R. (‘Bill’) Evitt (1923-2009) was such a person. During his career as a palaeontologist, Bill Evitt made lasting and profound contributions to the study of both dinoflagellates and trilobites. He had a distinguished, long and varied career, researching first trilobites and techniques in palaeontology before moving on to marine palynomorphs. Bill is undoubtedly best known for his work on dinoflagellates, especially their resting cysts. He worked at three major US universities and spent a highly significant period in the oil industry. Bill's early profound interest in the natural sciences was actively encouraged both by his parents and at school. His alma mater was Johns Hopkins University where, commencing in 1940, he studied chemistry and geology as an undergraduate. He quickly developed a strong vocation in the earth sciences, and became fascinated by the fossiliferous Lower Palaeozoic strata of the northwestern United States. Bill commenced a PhD project on silicified Middle Ordovician trilobites from Virginia in 1943. His doctoral research was interrupted by military service during World War II; Bill served as an aerial photograph interpreter in China in 1944 and 1945, and received the Bronze Star for his excellent work. Upon demobilisation from the US Army Air Force, he resumed work on his PhD and was given significant teaching duties at Johns Hopkins, which he thoroughly enjoyed. He accepted his first professional position, as an instructor in sedimentary geology, at the University of Rochester in late 1948. Here Bill supervised his first two graduate students, and shared a great cameraderie with a highly motivated student body which largely comprised World War II veterans. At Rochester, Bill continued his trilobite research, and was the editor of the Journal of Paleontology between 1953 and 1956. Seeking a new challenge, he joined the Carter Oil Company in Tulsa, Oklahoma, during 1956. This brought about an irrevocable realignment of his research interests from trilobites to marine palynology. He undertook basic research on aquatic palynomorphs in a very well-resourced laboratory under the direction of one of his most influential mentors, William S. ‘Bill’ Hoffmeister. Bill Evitt visited the influential European palynologists Georges Deflandre and Alfred Eisenack during late 1959 and, while in Tulsa, first developed several groundbreaking hypotheses. He soon realised that the distinctive morphology of certain fossil dinoflagellates, notably the archaeopyle, meant that they represent the resting cyst stage of the life cycle. The archaeopyle clearly allows the excystment of the cell contents, and comprises one or more plate areas. Bill also concluded that spine-bearing palynomorphs, then called hystrichospheres, could be divided into two groups. The largely Palaeozoic spine-bearing palynomorphs are of uncertain biological affinity, and these were termed acritarchs. Moreover, he determined that unequivocal dinoflagellate cysts are all Mesozoic or younger, and that the fossil record of dinoflagellates is highly selective. Bill was always an academic at heart and he joined Stanford University in 1962, where he remained until retiring in 1988. Bill enjoyed getting back into teaching after his six years in industry. During his 26-year tenure at Stanford, Bill continued to revolutionise our understanding of dinoflagellate cysts. He produced many highly influential papers and two major textbooks. The highlights include defining the acritarchs and comprehensively documenting the archaeopyle, together with highly detailed work on the morphology of Nannoceratopsis and Palaeoperidinium pyrophorum using the scanning electron microscope. Bill supervised 11 graduate students while at Stanford University. He organised the Penrose Conference on Modern and Fossil Dinoflagellates in 1978, which was so successful that similar meetings have been held about every four years since that inaugural symposium. Bill also taught many short courses on dinoflagellate cysts aimed at the professional community. Unlike many eminent geologists, Bill actually retired from actively working in the earth sciences. His full retirement was in 1988; after this he worked on only a small number of dinoflagellate cyst projects, including an extensive paper on the genus Palaeoperidinium

A new dugongine sirenian from the early Miocene of India

We redescribe the holotype skull of "Metaxytherium" kachchhense Bajpai, Singh, and Singh, 1987, and erect for it the new genus Bharatisiren. This skull is the best-preserved specimen of a fossil sirenian so far reported from the Indian Ocean region, and is also the first fossil from that region that is unequivocally referable to the subfamily Dugonginae. Bharatisiren kachchhensis (new combination) is related cladistically to other members of the subfamily as follows: (Crenatosiren (Dugong (Bharatisiren (other dugongines)))). The Dugonginae probably arose in the Caribbean-western Atlantic region, and underwent an adaptive radiation and pantropical dispersal in the late Oligocene and early Miocene