Stool DNA testing is a new approach to colorectal cancer detection. Few data are available from the screening setting.
To compare stool DNA and fecal blood testing for detection of screen-relevant ...neoplasia (curable-stage cancer, high-grade dysplasia, or adenomas >1 cm).
Blinded, multicenter, cross-sectional study.
Communities surrounding 22 participating academic and regional health care systems in the United States.
4482 average-risk adults.
Fecal blood and DNA markers. Participants collected 3 stools, smeared fecal blood test cards and used same-day shipment to a central facility. Fecal blood cards (Hemoccult and HemoccultSensa, Beckman Coulter, Fullerton, California) were tested on 3 stools and DNA assays on 1 stool per patient. Stool DNA test 1 (SDT-1) was a precommercial 23-marker assay, and a novel test (SDT-2) targeted 3 broadly informative markers. The criterion standard was colonoscopy.
Sensitivity for screen-relevant neoplasms was 20% by SDT-1, 11% by Hemoccult (P = 0.020), 21% by HemoccultSensa (P = 0.80); sensitivity for cancer plus high-grade dysplasia did not differ among tests. Specificity was 96% by SDT-1, compared with 98% by Hemoccult (P < 0.001) and 97% by HemoccultSensa (P = 0.20). Stool DNA test 2 detected 46% of screen-relevant neoplasms, compared with 16% by Hemoccult (P < 0.001) and 24% by HemoccultSensa (P < 0.001). Stool DNA test 2 detected 46% of adenomas 1 cm or larger, compared with 10% by Hemoccult (P < 0.001) and 17% by HemoccultSensa (P < 0.001). Among colonoscopically normal patients, the positivity rate was 16% with SDT-2, compared with 4% with Hemoccult (P = 0.010) and 5% with HemoccultSensa (P = 0.030).
Stool DNA test 2 was not performed on all subsets of patients without screen-relevant neoplasms. Stools were collected without preservative, which reduced detection of some DNA markers.
Stool DNA test 1 provides no improvement over HemoccultSensa for detection of screen-relevant neoplasms. Stool DNA test 2 detects significantly more neoplasms than does Hemoccult or HemoccultSensa, but with more positive results in colonoscopically normal patients. Higher sensitivity of SDT-2 was particularly apparent for adenomas.
Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined ...by local intracellular availability of the active hormone 3,5,3'-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.
There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to ...address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.
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•Limited autism-microbiome associations from stool metagenomics of n = 247 children•Romboutsia timonensis was the only taxa associated with autism diagnosis•Autistic traits such as restricted interests are associated with less-diverse diet•Less-diverse diet, in turn, is associated with lower microbiome alpha-diversity
Large autism stool metagenomics study finds limited direct autism associations, in contrast to strong relationships with dietary traits, stool consistency, and age, suggestive of a model whereby genetic and phenotypic measures of the autism spectrum promote a less-diverse diet that reduces microbiome diversity.
Satellite-tracking of mature white sharks (Carcharodon carcharias) has revealed open-ocean movements spanning months and covering tens of thousands of kilometers. But how are the energetic demands of ...these active apex predators met as they leave coastal areas with relatively high prey abundance to swim across the open ocean through waters often characterized as biological deserts? Here we investigate mesoscale oceanographic variability encountered by two white sharks as they moved through the Gulf Stream region and Sargasso Sea in the North Atlantic Ocean. In the vicinity of the Gulf Stream, the two mature female white sharks exhibited extensive use of the interiors of clockwise-rotating anticyclonic eddies, characterized by positive (warm) temperature anomalies. One tagged white shark was also equipped with an archival tag that indicated this individual made frequent dives to nearly 1,000 m in anticyclones, where it was presumably foraging on mesopelagic prey. We propose that warm temperature anomalies in anticyclones make prey more accessible and energetically profitable to adult white sharks in the Gulf Stream region by reducing the physiological costs of thermoregulation in cold water. The results presented here provide valuable new insight into open ocean habitat use by mature, female white sharks that may be applicable to other large pelagic predators.
Somatic mutations are hypothesized to play a role in many non-neoplastic diseases. We performed whole-exome sequencing of 1,182 microbiopsies dissected from lesional and nonlesional epidermis from ...111 patients with psoriasis to search for evidence that somatic mutations in keratinocytes may influence the disease process. Lesional skin remained highly polyclonal, showing no evidence of large-scale spread of clones carrying potentially pathogenic mutations. The mutation rate of keratinocytes was similarly only modestly affected by the disease. We found evidence of positive selection in previously reported driver genes NOTCH1, NOTCH2, TP53, FAT1 and PPM1D and also identified mutations in four genes (GXYLT1, CHEK2, ZFP36L2 and EEF1A1) that we hypothesize are selected for in squamous epithelium irrespective of disease status. Finally, we describe a mutational signature of psoralens-a class of chemicals previously found in some sunscreens and which are used as part of PUVA (psoralens and ultraviolet-A) photochemotherapy treatment for psoriasis.
The Planetary Instrument for X-ray Lithochemistry (PIXL) is a micro-focus X-ray fluorescence spectrometer mounted on the robotic arm of NASA's Perseverance rover. PIXL will acquire high spatial ...resolution observations of rock and soil chemistry, rapidly analyzing the elemental chemistry of a target surface. In 10 seconds, PIXL can use its powerful 120 micrometer diameter X-ray beam to analyze a single, sand-sized grain with enough sensitivity to detect major and minor rock-forming elements, as well as many trace elements. Over a period of several hours, PIXL can autonomously scan an area of the rock surface and acquire a hyperspectral map comprised of several thousand individual measured points.
Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in ...specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched 'on' by engagement with bone-lining cells or osteoblasts, and switched 'off' by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.
Bispecific antibodies, which simultaneously target CD3 on T cells and tumor-associated antigens to recruit cytotoxic T cells to cancer cells, are a promising new approach to the treatment of ...hormone-refractory prostate cancer. Here we report a site-specific, semisynthetic method for the production of bispecific antibody-like therapeutics in which a derivative of the prostate-specific membrane antigen-binding small molecule DUPA was selectively conjugated to a mutant αCD3 Fab containing the unnatural amino acid, p-acetylphenylalanine, at a defined site. Homogeneous conjugates were generated in excellent yields and had good solubility. The efficacy of the conjugate was optimized by modifying the linker structure, relative binding orientation, and stoichiometry of the ligand. The optimized conjugate showed potent and selective in vitro activity (EC ₅₀ ∼100 pM), good serum half-life, and potent in vivo activity in prophylactic and treatment xenograft mouse models. This semisynthetic approach is likely to be applicable to the generation of additional bispecific agents using drug-like ligands selective for other cell-surface receptors.
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