[Research Articles] Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies
Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced me...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Tlemsani, C., Takahashi, N., Pongor, L., Rajapakse, V. N., Tyagi, M., Wen, X., Fasaye, G.-A., Schmidt, K. T., Desai, P., Kim, C., Rajan, A., Swift, S., Sciuto, L., Vilimas, R., Webb, S., Nichols, S., Figg, W. D., Pommier, Y., Calzone, K., Steinberg, S. M. Tags: Research Articles Source Type: research
[Research Articles] A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity
Although chimeric antigen receptor (CAR)–modified T cells have shown great success in the treatment of B cell malignancies, this approach has limited efficacy in patients with solid tumors. Various modifications in CAR structure have been explored to improve this efficacy, including the incorporation of two costimulatory domains. Because costimulatory signals are transduced together with T cell receptor signals during T cell activation, we engineered a type of CAR-T cells with a costimulatory signal that was activated independently from the tumor antigen to recapitulate physiological stimulation. We screened 12 costi...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Zhang, H., Li, F., Cao, J., Wang, X., Cheng, H., Qi, K., Wang, G., Xu, K., Zheng, J., Fu, Y.-X., Yang, X. Tags: Research Articles Source Type: research
[Research Articles] Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein receptor binding domain in patients with COVID-19 and healthy individuals
Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were composed of immunoglobulin heavy variable 3-53 (IGHV3-53) or IGHV3-66 and immunoglobulin heavy joining 6 (IGHJ6) genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching a...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Kim, S. I., Noh, J., Kim, S., Choi, Y., Yoo, D. K., Lee, Y., Lee, H., Jung, J., Kang, C. K., Song, K.-H., Choe, P. G., Kim, H. B., Kim, E. S., Kim, N.-J., Seong, M.-W., Park, W. B., Oh, M.-d., Kwon, S., Chung, J. Tags: Research Articles Source Type: research
[Research Articles] Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA
Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resul...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Kong, L., Valdivia, D. O., Simon, C. M., Hassinan, C. W., Delestree, N., Ramos, D. M., Park, J. H., Pilato, C. M., Xu, X., Crowder, M., Grzyb, C. C., King, Z. A., Petrillo, M., Swoboda, K. J., Davis, C., Lutz, C. M., Stephan, A. H., Zhao, X., Weetall, M., Tags: Research Articles Source Type: research
[Reviews] Engineering biopharmaceutical formulations to improve diabetes management
Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately mimicking endogenous glycemic control. Moreover, the controlled delivery of complementary hormones (such as amylin or glucagon) is complicated by instability of the pharmacologic agents and complexity of maintaining multiple infusions. In this review, we highlight the advantages and limitations of recent advances in drug formulation that improve protein stability and pharmacokinetics, prolong drug delivery, or enable alternative dosage forms for the manage...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Maikawa, C. L., dAquino, A. I., Lal, R. A., Buckingham, B. A., Appel, E. A. Tags: Reviews Source Type: research
[Editors' Choice] Visualizing antibody production in a human lymph node in a dish
Development of a human lymphoid organoid system enables in vitro modeling of immune responses and antibody formation. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Morris, G. P. Tags: Editors ' Choice Source Type: research
[Editors' Choice] Better together: Alveolar macrophage and memory T cell cosignaling in ex vivo human lungs
Ex vivo lung perfusion enables assessment of the resident adaptive immune system and provides insight into the lung response to pathogen exposure. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Keller, S. P. Tags: Editors ' Choice Source Type: research
[Editors' Choice] Folding DNA to foil the clotting cascade
Origami-inspired DNA aptamer arrays prevent blood clotting in hemodialysis circuits. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Baca, J. T. Tags: Editors ' Choice Source Type: research
[Research Articles] Toward robust mammography-based models for breast cancer risk
Improved breast cancer risk models enable targeted screening strategies that achieve earlier detection and less screening harm than existing guidelines. To bring deep learning risk models to clinical practice, we need to further refine their accuracy, validate them across diverse populations, and demonstrate their potential to improve clinical workflows. We developed Mirai, a mammography-based deep learning model designed to predict risk at multiple timepoints, leverage potentially missing risk factor information, and produce predictions that are consistent across mammography machines. Mirai was trained on a large dataset ...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Yala, A., Mikhael, P. G., Strand, F., Lin, G., Smith, K., Wan, Y.-L., Lamb, L., Hughes, K., Lehman, C., Barzilay, R. Tags: Research Articles Source Type: research
[Research Articles] Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma
Medulloblastoma (MB) consists of four core molecular subgroups with distinct clinical features and prognoses. Treatment consists of surgery, followed by radiotherapy and cytotoxic chemotherapy. Despite this intensive approach, outcome remains dismal for patients with certain subtypes of MB, namely, MYC-amplified Group 3 and TP53-mutated SHH. Using high-throughput assays, six human MB cell lines were screened against a library of 3208 unique compounds. We identified 45 effective compounds from the screen and found that cell cycle checkpoint kinase (CHK1/2) inhibition synergistically enhanced the cytotoxic activity of clinic...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Endersby, R., Whitehouse, J., Pribnow, A., Kuchibhotla, M., Hii, H., Carline, B., Gande, S., Stripay, J., Ancliffe, M., Howlett, M., Schoep, T., George, C., Andradas, C., Dyer, P., Schluck, M., Patterson, B., Tacheva-Gigorova, S. K., Cooper, M. N., Robins Tags: Research Articles Source Type: research
[Research Articles] Diet-induced obesity promotes infection by impairment of the innate antimicrobial defense function of dermal adipocyte progenitors
Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor–β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors an...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Zhang, L.-j., Guerrero-Juarez, C. F., Chen, S. X., Zhang, X., Yin, M., Li, F., Wu, S., Chen, J., Li, M., Liu, Y., Jiang, S. I. B., Hata, T., Plikus, M. V., Gallo, R. L. Tags: Research Articles Source Type: research
[Editors' Choice] Unconventional interleukin-1{beta} release suppresses antitumor immunity
Inflammasome-independent release of IL-1β in the tumor microenvironment recruits T cell–suppressive neutrophils that support cancer progression. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Van den Bossche, J. Tags: Editors ' Choice Source Type: research
[Editors' Choice] The benefits of memory growing granular
Brain imaging approaches show that the essential machinery for memory formation continues to develop into late childhood. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Stevens, J. S. Tags: Editors ' Choice Source Type: research
[Editors' Choice] Could COVID-19 eliminate the alarm clock?
Social restriction due to COVID-19 relieves social jet lag. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Hurley, J. M. Tags: Editors ' Choice Source Type: research
[Research Articles] IgA dominates the early neutralizing antibody response to SARS-CoV-2
Humoral immune responses are typically characterized by primary IgM antibody responses followed by secondary antibody responses associated with immune memory and composed of IgG, IgA, and IgE. Here, we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of SARS-CoV-2–specific neutralizing antibodies in the serum, saliva, and bronchoalveolar fluid of 159 patients with COVID-19. Early SARS-CoV-2–specific humoral responses were dominated by IgA antibodies. Peripheral expansion of IgA plasmablasts with mucosal homing potential was detected shortly aft...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Sterlin, D., Mathian, A., Miyara, M., Mohr, A., Anna, F., Claër, L., Quentric, P., Fadlallah, J., Devilliers, H., Ghillani, P., Gunn, C., Hockett, R., Mudumba, S., Guihot, A., Luyt, C.-E., Mayaux, J., Beurton, A., Fourati, S., Bruel, T., Schwartz, Tags: Research Articles Source Type: research
