A novel mechanism for TNFR-associated factor 6-dependent CD40 signaling

Members of the TNFR family play critical roles in the regulation of the immune system. One member of the family critical for efficient activation of T-dependent humoral immune responses is CD40, a cell surface protein expressed by B cells and other APC. The cytoplasmic domain of CD40 interacts with several members of the TNFR-associated factor (TRAF) family, which link CD40 to intracellular signaling pathways. TRAF2 and 6 appear to play particularly important roles in CD40 signaling. Previous studies suggest that the two molecules have certain overlapping roles in signaling, but that unique roles for each molecule also exist. To better define the roles of TRAF2 and TRAF6 in CD40 signaling, we used somatic cell gene targeting to generate TRAF-deficient mouse B cell lines. A20.2J cells deficient in TRAF6 exhibit marked defects in CD40-mediated JNK activation and the up-regulation of CD80. Our previous experiments with TRAF2-deficient B cell lines suggest that TRAF6 and TRAF2 may have redundant roles in CD40-mediated NF-kappaB activation. Consistent with this hypothesis, we found CD40-mediated activation of NF-kappaB intact in TRAF6-deficient cells and defective in cells lacking both TRAF2 and TRAF6. Interestingly, we found that TRAF6 mutants defective in CD40 binding were able to restore CD40-mediated JNK activation and CD80 up-regulation in TRAF6-deficient cells, indicating that TRAF6 may be able to contribute to certain CD40 signals without directly binding CD40.     

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA''s mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt''s lymphoma cell lines. Phagocytosis contributed to DARA''s anti-tumor activity in vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model. Finally, DARA was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression. In summary, we demonstrate that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of DARA in multiple myeloma and potentially other hematological tumors.     

A Guide to the Study and Identification of Fossil Testate Amoebae in Quaternary Lake Sediments

Fossil shells of testate amoebae, commonly found in Quaternary sediments, provide another key for the interpretation of the recent history of lakes. Outline drawings and details of shell composition provide the micropalaeontologist with a practical guide to the taxonomy of these organisms.     

Mangrove Restoration: Do We Know Enough?

Mangrove restoration projects have been attempted, with mixed results, throughout the world. In this paper, I first examine goals of existing mangrove restoration projects and determine whether these goals are clear and adequate, and whether or not they account for the full range of biological diversity and ecological processes of mangrove ecosystems. Many restored mangrove forests resemble forest plantations rather than truly integrated ecosystems, but mangrove plantations can be a first step toward mangrove rehabilitation. Mangrove restoration projects that involve associated aquaculture or mariculture operations tend to be more likely to approximate the biological diversity and ecological processes of undisturbed mangrove ecosystems than are projects that focus only on the trees. These integrated restoration projects also provide a higher economic return than do silvicultural projects alone. Second, I briefly assess whether existing ecological data are sufficient to undergird successful restoration of mangal and define criteria for determining whether or not a mangrove ecosystem has been restored successfully. These criteria include characteristics of vegetation (forest) structure, levels of primary production, composition of associated animal communities, and hydrology. Finally, I suggest ways to improve mangrove restoration projects and identify key research needs required to support these efforts. Ecological theories derived from other wetland and upland systems rarely have been applied to either “basic” or “applied” mangrove forest studies, to the detriment of restoration projects, whereas lessons from restoration of the relatively species‐poor mangrove ecosystems could be beneficially applied to restoration projects in other contexts. An international database of mangrove restoration projects would reduce the likelihood that unsuccessful restoration projects would be repeated elsewhere. Clear criteria for evaluating success, greater accessibility of information by managers in the developing world, intensified international cooperation, and application of relevant ecological theories will improve the success rate of mangrove restoration projects.     

Origins of mangrove ecosystems and the mangrove biodiversity anomaly

1. Mangrove species richness declines dramatically from a maximum in the Indo-West Pacific (IWP) to a minimum in the Caribbean and Western Atlantic. Explaining this ‘anomalous’ biogeographic pattern has been a focus of discussion for most of this century. 2. Two hypotheses have been put forward to explain the mangrove biodiversity anomaly. The ‘centre-of-origin hypothesis’ asserts that all mangrove taxa originated in the IWP and subsequently dispersed to other parts of the world. The ‘vicariance hypothesis’ asserts that mangrove taxa evolved around the Tethys Sea during the Late Cretaceous, and regional species diversity resulted from in situ diversification after continental drift. 3. Five lines of evidence are used to test between these two hypotheses. First, we review the mangrove fossil record. Second, we compare modern and fossil distributions of mangroves and eight genera of gastropods that show high fidelity to the mangrove environment. Third, we describe species-area relationships of mangroves and associated gastropods with respect to area of available habitat. Fourth, we analyse patterns of nestedness of individual plant and gastropod communities in mangrove forests. Fifth, we analyse patterns of nestedness of individual plant and gastropod species. 4. All five lines of evidence support the vicariance hypothesis. The first occurrences in the fossil record of most mangrove genera and many genera of gastropods associated with mangrove forests appear around the Tethys Sea from the Late Cretaceous through the Early Tertiary. Globally, species richness in any given mangrove forest is tightly correlated with available area. Patterns of nestedness at the community and species-level both point towards three independent regions of diversification of mangrove ecosystems: South-east Asia, the Caribbean and Eastern Pacific, and the Indian Ocean region.     

Projected estimates of cancer in Canada in 2022

Background:Regular cancer surveillance is crucial for understanding where progress is being made and where more must be done. We sought to provide an overview of the expected burden of cancer in Canada in 2022.Methods:We obtained data on new cancer incidence from the National Cancer Incidence Reporting System (1984–1991) and Canadian Cancer Registry (1992–2018). Mortality data (1984–2019) were obtained from the Canadian Vital Statistics — Death Database. We projected cancer incidence and mortality counts and rates to 2022 for 22 cancer types by sex and province or territory. Rates were age standardized to the 2011 Canadian standard population.Results:An estimated 233 900 new cancer cases and 85 100 cancer deaths are expected in Canada in 2022. We expect the most commonly diagnosed cancers to be lung overall (30 000), breast in females (28 600) and prostate in males (24 600). We also expect lung cancer to be the leading cause of cancer death, accounting for 24.3% of all cancer deaths, followed by colorectal (11.0%), pancreatic (6.7%) and breast cancers (6.5%). Incidence and mortality rates are generally expected to be higher in the eastern provinces of Canada than the western provinces.Interpretation:Although overall cancer rates are declining, the number of cases and deaths continues to climb, owing to population growth and the aging population. The projected high burden of lung cancer indicates a need for increased tobacco control and improvements in early detection and treatment. Success in breast and colorectal cancer screening and treatment likely account for the continued decline in their burden. The limited progress in early detection and new treatments for pancreatic cancer explains why it is expected to be the third leading cause of cancer death in Canada.

The impact of cancer on the Canadian population and health care systems is substantial. Cancer is the leading cause of death in Canada^1,2 and previous estimates have shown that 43% of all people in Canada are expected to receive a cancer diagnosis in their lifetime.³ With an aging and growing population, the number of new cancer cases and deaths in Canada is also increasing.⁴ In addition to its impact on health, cancer is costly. The economic burden of cancer care in Canada rose from $2.9 billion in 2005 to $7.5 billion in 2012, annually.⁵Given the considerable health and economic impact of cancer in Canada, comprehensive and reliable surveillance information is necessary for identifying where progress has been made and where more attention and resources are needed. To meet these needs, the Canadian Cancer Statistics Advisory Committee, in collaboration with the Canadian Cancer Society, Statistics Canada and the Public Health Agency of Canada, produces the latest surveillance statistics on cancer in Canada.Cancer data often lag the current date by several years, owing to the time associated with collecting, verifying and analyzing the data. Short-term cancer incidence and mortality rates can be projected by extrapolating past trends to estimate future trends, using statistical models. These short-term projections provide a more up-to-date estimate of the cancer landscape in Canada. Incidence and mortality counts, along with age-standardized rates, provide a picture of the impact of cancer in Canada, which is essential for resource planning, research and informing cancer-control programs.Canadian Cancer Statistics 2021³ provided detailed estimates of cancer incidence, mortality and survival in Canada by age, sex, geographic region and over time for 22 cancer types.³ Here, we provide updated estimates of the counts and age-standardized rates of new cancer cases (incidence) and cancer deaths (mortality) expected in 2022 by sex and province and territory, for all ages combined.     

A computer aided thermodynamic approach for predicting the formation of Z-DNA in naturally occurring sequences.

The ease with which a particular DNA segment adopts the left-handed Z-conformation depends largely on the sequence and on the degree of negative supercoiling to which it is subjected. We describe a computer program (Z-hunt) that is designed to search long sequences of naturally occurring DNA and retrieve those nucleotide combinations of up to 24 bp in length which show a strong propensity for Z-DNA formation. Incorporated into Z-hunt is a statistical mechanical model based on empirically determined energetic parameters for the B to Z transition accumulated to date. The Z-forming potential of a sequence is assessed by ranking its behavior as a function of negative superhelicity relative to the behavior of similar sized randomly generated nucleotide sequences assembled from over 80,000 combinations. The program makes it possible to compare directly the Z-forming potential of sequences with different base compositions and different sequence lengths. Using Z-hunt, we have analyzed the DNA sequences of the bacteriophage phi X174, plasmid pBR322, the animal virus SV40 and the replicative form of the eukaryotic adenovirus-2. The results are compared with those previously obtained by others from experiments designed to locate Z-DNA forming regions in these sequences using probes which show specificity for the left-handed DNA conformation.