[Research Articles] Analysis of spatial osteochondral heterogeneity in advanced knee osteoarthritis exposes influence of joint alignment
We report strong correlations of osteochondral parameters within individual topographical patterns, highlighting their fundamental and location-dependent interactions in OA. We further identify site-specific effects of varus malalignment on the lesser loaded compartment and, conversely, an unresponsive overloaded compartment. Last, we trace compensatory mechanisms to the overloaded subarticular spongiosa in patients with additional high body weight. We therefore propose to consider and to determine axial alignment in clinical trials when selecting the location to assess structural changes in OA. Together, these findings br...
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Haberkamp, S., Olah, T., Orth, P., Cucchiarini, M., Madry, H. Tags: Research Articles Source Type: research

[Editors' Choice] The trouble with tissue factor
A bleeding disorder due to genetic deficiency in tissue factor has been identified. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Morris, G. P. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Building a better way to mend a broken heart
A novel hybrid pulsatile ventricular assist device uses an endothelialized pump surface to achieve biocompatibility. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Keller, S. P. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Therapeutic microbubbles make tumor cells pop
Combining ultrasound release and molecular targeting selectively delivered extremely toxic and hydrophobic drugs to tumor cells. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Baca, J. T. Tags: Editors ' Choice Source Type: research

[Editorial] Were on our own
The failure of U.S. government scientists in the Trump administration to follow the science around COVID-19 has left the medical community to fend for itself. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Thorp, H. H. Tags: Editorial Source Type: research

[Research Articles] A stepped-wedge randomized trial and qualitative survey of HIV pre-exposure prophylaxis uptake in the Eswatini population
Clinical trials have shown that antiretroviral drugs used as pre-exposure prophylaxis (PrEP) are highly effective for preventing HIV acquisition. PrEP efforts, including in sub-Saharan Africa, have almost exclusively focused on certain priority groups, particularly female sex workers, men having sex with men, pregnant women, serodiscordant couples, and young women. As part of a PrEP demonstration project involving the general population at six primary health care facilities in Eswatini (formerly Swaziland), we conducted a randomized trial of a health care facility–based PrEP promotion package designed to increase PrE...
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Geldsetzer, P., Bärnighausen, K., Hettema, A., McMahon, S. A., Dalal, S., Chase, R. P., Oldenburg, C. E., Kohler, S., Chen, S., Dlamini, P., Mavuso, M., Hughey, A. B., Matse, S., Bärnighausen, T. Tags: Research Articles Source Type: research

[Research Articles] Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma
Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 ...
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Hansson, K., Radke, K., Aaltonen, K., Saarela, J., Manas, A., Sjölund, J., Smith, E. M., Pietras, K., Pahlman, S., Wennerberg, K., Gisselsson, D., Bexell, D. Tags: Research Articles Source Type: research

[Research Articles] Transplanted microvessels improve pluripotent stem cell-derived cardiomyocyte engraftment and cardiac function after infarction in rats
Human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) offer an unprecedented opportunity to remuscularize infarcted human hearts. However, studies have shown that most hiPSC-CMs do not survive after transplantation into the ischemic myocardial environment, limiting their regenerative potential and clinical application. We established a method to improve hiPSC-CM survival by cotransplanting ready-made microvessels obtained from adipose tissue. Ready-made microvessels promoted a sixfold increase in hiPSC-CM survival and superior functional recovery when compared to hiPSC-CMs transplanted alone or cotra...
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Sun, X., Wu, J., Qiang, B., Romagnuolo, R., Gagliardi, M., Keller, G., Laflamme, M. A., Li, R.-k., Nunes, S. S. Tags: Research Articles Source Type: research

[Research Articles] Muse cell spheroids have therapeutic effect on corneal scarring wound in mice and tree shrews
Stem cell therapy holds promises for treating corneal scarring. Here, we use multilineage-differentiating stress-enduring (Muse) cells to study their differentiation and therapeutic potential for treating corneal injury. Muse cells were isolated from lipoaspirate, which presented biphenotype properties of both pluripotent stem cells and some mesenchymal stem cells. Muse cells expanded by about 100-fold from the initial seeding cell number to Muse spheroids with the maintenance of the Muse cell phenotype and high cell viability at 33 days by static spheroid culture. We revealed that Muse spheroids were activated by the dyna...
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Guo, Y., Xue, Y., Wang, P., Cui, Z., Cao, J., Liu, S., Yu, Q., Zeng, Q., Zhu, D., Xie, M., Zhang, J., Li, Z., Liu, H., Zhong, J., Chen, J. Tags: Research Articles Source Type: research

[Research Articles] PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma
Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA...
Source: Science Translational Medicine - September 23, 2020 Category: Biomedical Science Authors: Jiang, T.-Y., Pan, Y.-F., Wan, Z.-H., Lin, Y.-K., Zhu, B., Yuan, Z.-g., Ma, Y.-H., Shi, Y.-Y., Zeng, T.-M., Dong, L.-W., Tan, Y.-X., Wang, H.-Y. Tags: Research Articles Source Type: research

[Research Articles] Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to the graft-versus-leukemia effect
Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell–intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic, and epigenetic analyses of CLL cells from 10 patients r...
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Bachireddy, P., Ennis, C., Nguyen, V. N., Gohil, S. H., Clement, K., Shukla, S. A., Forman, J., Barkas, N., Freeman, S., Bavli, N., Elagina, L., Leshchiner, I., Mohammad, A. W., Mathewson, N. D., Keskin, D. B., Rassenti, L. Z., Kipps, T. J., Brown, J. R., Tags: Research Articles Source Type: research

[Research Articles] B cell acute lymphoblastic leukemia cells mediate RANK-RANKL-dependent bone destruction
Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL–driven bone destruction, we examined the p53–/–; Rag2–/–; Prkdcscid/scid triple mutant (TM) mice and p53–/–; Prkdcscid/scid double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals...
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Rajakumar, S. A., Papp, E., Lee, K. K., Grandal, I., Merico, D., Liu, C. C., Allo, B., Zhang, L., Grynpas, M. D., Minden, M. D., Hitzler, J. K., Guidos, C. J., Danska, J. S. Tags: Research Articles Source Type: research

[Research Articles] Interleukin-2 signals converge in a lymphoid-dendritic cell pathway that promotes anticancer immunity
Tumor-infiltrating dendritic cells (DCs) correlate with effective anticancer immunity and improved responsiveness to anti–PD-1 checkpoint immunotherapy. However, the drivers of DC expansion and intratumoral accumulation are ill-defined. We found that interleukin-2 (IL-2) stimulated DC formation through innate and adaptive lymphoid cells in mice and humans, and this increase in DCs improved anticancer immunity. Administration of IL-2 to humans within a clinical trial and of IL-2 receptor (IL-2R)–biased IL-2 to mice resulted in pronounced expansion of type 1 DCs, including migratory and cross-presenting subsets, ...
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Raeber, M. E., Rosalia, R. A., Schmid, D., Karakus, U., Boyman, O. Tags: Research Articles Source Type: research

[Research Articles] ROR2 blockade as a therapy for osteoarthritis
Osteoarthritis is characterized by the loss of the articular cartilage, bone remodeling, pain, and disability. No pharmacological intervention can currently halt progression of osteoarthritis. Here, we show that blocking receptor tyrosine kinase–like orphan receptor 2 (ROR2) improves cartilage integrity and pain in osteoarthritis models by inhibiting yes-associated protein (YAP) signaling. ROR2 was up-regulated in the cartilage in response to inflammatory cytokines and mechanical stress. The main ligand for ROR2, WNT5A, and the targets YAP and connective tissue growth factor were up-regulated in osteoarthritis in hum...
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Thorup, A.-S., Strachan, D., Caxaria, S., Poulet, B., Thomas, B. L., Eldridge, S. E., Nalesso, G., Whiteford, J. R., Pitzalis, C., Aigner, T., Corder, R., Bertrand, J., DellAccio, F. Tags: Research Articles Source Type: research

[Research Articles] Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes
Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naìˆve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in disco...
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Garcia-Calzon, S., Perfilyev, A., Martinell, M., Ustinova, M., Kalamajski, S., Franks, P. W., Bacos, K., Elbere, I., Pihlajamäki, J., Volkov, P., Vaag, A., Groop, L., Maziarz, M., Klovins, J., Ahlqvist, E., Ling, C. Tags: Research Articles Source Type: research

[Editors' Choice] Memory at the margins: Antipsychotic enhances the binding of fear memory with its context
A nontraditional antipsychotic medication enhances healthy memory function in a mouse model of fear conditioning. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Stevens, J. S. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Can eating help treat malaria?
The identification of metabolic control of the Plasmodium life cycle may open novel avenues for malaria treatment. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Hurley, J. M. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Metabolic control of NLRP3 inflammasome by itaconation
The Krebs cycle–derived immunometabolite itaconate constrains NLRP3 inflammasome activation and IL-1β release. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Van den Bossche, J. Tags: Editors ' Choice Source Type: research

[Research Articles] Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine
Cell therapy treatment of myocardial infarction (MI) is mediated, in part, by exosomes secreted from transplanted cells. Thus, we compared the efficacy of treatment with a mixture of cardiomyocytes (CMs; 10 million), endothelial cells (ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells (hiPSCs), or with exosomes extracted from the three cell types, in pigs after MI. Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs (MI + Cell group); with homogenized fragments from the sa...
Source: Science Translational Medicine - September 16, 2020 Category: Biomedical Science Authors: Gao, L., Wang, L., Wei, Y., Krishnamurthy, P., Walcott, G. P., Menasche, P., Zhang, J. Tags: Research Articles Source Type: research

[Research Articles] Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair
Dysbiosis of the skin microbiota is increasingly implicated as a contributor to the pathogenesis of atopic dermatitis (AD). We previously reported first-in-human safety and clinical activity results from topical application of the commensal skin bacterium Roseomonas mucosa for the treatment of AD in 10 adults and 5 children older than 9 years of age. Here, we examined the potential mechanism of action of R. mucosa treatment and its impact on children with AD less than 7 years of age, the most common age group for children with AD. In 15 children with AD, R. mucosa treatment was associated with amelioration of disease sever...
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Myles, I. A., Castillo, C. R., Barbian, K. D., Kanakabandi, K., Virtaneva, K., Fitzmeyer, E., Paneru, M., Otaizo-Carrasquero, F., Myers, T. G., Markowitz, T. E., Moore, I. N., Liu, X., Ferrer, M., Sakamachi, Y., Garantziotis, S., Swamydas, M., Lionakis, M Tags: Research Articles Source Type: research

[Research Articles] Characterization of ANGPT2 mutations associated with primary lymphedema
Primary lymphedema is caused by developmental and functional defects of the lymphatic vascular system that result in accumulation of protein-rich fluid in tissues, resulting in edema. The 28 currently known genes causing primary lymphedema can explain
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Leppänen, V.-M., Brouillard, P., Korhonen, E. A., Sipilä, T., Jha, S. K., Revencu, N., Labarque, V., Fastre, E., Schlögel, M., Ravoet, M., Singer, A., Luzzatto, C., Angelone, D., Crichiutti, G., DElia, A., Kuurne, J., Elamaa, H., K Tags: Research Articles Source Type: research

[Research Articles] Ultrasensitive molecular imaging of intestinal mucosal inflammation using leukocyte-mimicking particles targeted to MAdCAM-1 in mice
Mucosal tissues play critical roles in health and disease as the primary barrier between the external world and the inner body, lining the digestive, respiratory, urinary, mammary, and reproductive tracts. Clinical evaluation of mucosal tissues is currently performed using endoscopy, such as ileocolonoscopy for the intestinal mucosa, which causes substantial patient discomfort and can lead to organ damage. Here, we developed a contrast agent for molecular magnetic resonance imaging (MRI) that is targeted to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), an adhesion molecule overexpressed by inflamed mucosa...
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Fournier, A. P., Martinez de Lizarrondo, S., Rateau, A., Gerard-Brisou, A., Waldner, M. J., Neurath, M. F., Vivien, D., Docagne, F., Gauberti, M. Tags: Research Articles Source Type: research

[Research Articles] A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinsons disease
Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we id...
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Boussaad, I., Obermaier, C. D., Hanss, Z., Bobbili, D. R., Bolognin, S., Glaab, E., Wołynska, K., Weisschuh, N., De Conti, L., May, C., Giesert, F., Grossmann, D., Lambert, A., Kirchen, S., Biryukov, M., Burbulla, L. F., Massart, F., Bohler, J., Cr Tags: Research Articles Source Type: research

[Research Articles] Restoring the natural tropism of AAV2 vectors for human liver
Recent clinical successes in gene therapy applications have intensified interest in using adeno-associated viruses (AAVs) as vectors for therapeutic gene delivery. Although prototypical AAV2 shows robust in vitro transduction of human hepatocyte–derived cell lines, it has not translated into an effective vector for liver-directed gene therapy in vivo. This is consistent with observations made in Fah–/–/Rag2–/–/Il2rg–/– (FRG) mice with humanized livers, showing that AAV2 functions poorly in this xenograft model. Here, we derived naturally hepatotropic AAV capsid sequences from prima...
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Cabanes-Creus, M., Hallwirth, C. V., Westhaus, A., Ng, B. H., Liao, S. H. Y., Zhu, E., Navarro, R. G., Baltazar, G., Drouyer, M., Scott, S., Logan, G. J., Santilli, G., Bennett, A., Ginn, S. L., McCaughan, G., Thrasher, A. J., Agbandje-McKenna, M., Alexan Tags: Research Articles Source Type: research

[Research Articles] Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade
Immune checkpoint blockade (ICB) therapies are now established as first-line treatments for multiple cancers, but many patients do not derive long-term benefit from ICB. Here, we report that increased amounts of histone 3 lysine 4 demethylase KDM5A in tumors markedly improved response to the treatment with the programmed cell death protein 1 (PD-1) antibody in mouse cancer models. In a screen for molecules that increased KDM5A abundance, we identified one (D18) that increased the efficacy of various ICB agents in three murine cancer models when used as a combination therapy. D18 potentiated ICB efficacy through two orthogo...
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Wang, L., Gao, Y., Zhang, G., Li, D., Wang, Z., Zhang, J., Hermida, L. C., He, L., Wang, Z., Si, J., Geng, S., Ai, R., Ning, F., Cheng, C., Deng, H., Dimitrov, D. S., Sun, Y., Huang, Y., Wang, D., Hu, X., Wei, Z., Wang, W., Liao, X. Tags: Research Articles Source Type: research

[Editors' Choice] Targeting leukemia-specific mutations
T cells can recognize neoantigens derived from protein products of characteristic genetic fusions and thereby specifically target leukemia cells. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Kanakry, C. G. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Leaky pipes: Tau and apoE implicated in blood-brain barrier dysfunction in Alzheimer disease
Concentrations of tight junction proteins correlate with tau and apolipoprotein E in Alzheimer disease brain tissue independent of cerebral amyloid angiopathy. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Davis, A. A. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Interfering too soon: Type I interferons can dampen antiviral immunity
Short-term blockade of type I interferons at the time of viral infection or vaccine administration enhances immunological memory. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 9, 2020 Category: Biomedical Science Authors: Billi, A. C. Tags: Editors ' Choice Source Type: research

[Research Articles] Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis
We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface. Agrin attracted joint resident progenitor cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signaling downstream of β-catenin, induced expression of the chondrogenic stem cell marker GDF5 and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, an agrin-containi...
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: Eldridge, S. E., Barawi, A., Wang, H., Roelofs, A. J., Kaneva, M., Guan, Z., Lydon, H., Thomas, B. L., Thorup, A.-S., Fernandez, B. F., Caxaria, S., Strachan, D., Ali, A., Shanmuganathan, K., Pitzalis, C., Whiteford, J. R., Henson, F., McCaskie, A. W., De Tags: Research Articles Source Type: research

[Research Articles] SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control
Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)–cAMP-dependent protein kinase (PKA)–cAMP response element–binding protein (CREB) signaling in the liv...
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: Montgomery, M. K., Bayliss, J., Devereux, C., Bezawork-Geleta, A., Roberts, D., Huang, C., Schittenhelm, R. B., Ryan, A., Townley, S. L., Selth, L. A., Biden, T. J., Steinberg, G. R., Samocha-Bonet, D., Meex, R. C. R., Watt, M. J. Tags: Research Articles Source Type: research

[Research Articles] A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components
Acquired resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) remains a clinical challenge. Especially challenging are cases in which resistance emerges through EGFR-independent mechanisms, such as through pathways that promote epithelial-to-mesenchymal transition (EMT). Through an integrated transcriptomic, proteomic, and drug screening approach, we identified activation of the yes-associated protein (YAP) and forkhead box protein M1 (FOXM1) axis as a driver of EMT-associated EGFR TKI resistance. EGFR inhibitor resistance was associated with broad multidrug resistance that extended ac...
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: Nilsson, M. B., Sun, H., Robichaux, J., Pfeifer, M., McDermott, U., Travers, J., Diao, L., Xi, Y., Tong, P., Shen, L., Hofstad, M., Kawakami, M., Le, X., Liu, X., Fan, Y., Poteete, A., Hu, L., Negrao, M. V., Tran, H., Dmitrovsky, E., Peng, D., Gibbons, D. Tags: Research Articles Source Type: research

[Editors' Choice] Shedding light on heart failure
Optogenetic stimulation of vagal preganglionic neurons preserved left ventricular ejection fraction in an experimental heart failure model. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: Roche, E. T. Tags: Editors ' Choice Source Type: research

[Editors' Choice] PARP inhibitors unleash the antitumor immune response
Combination of a PARP inhibitor with immune checkpoint blockade showed promising antitumor activity without additional toxicity. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: Ileana-Dumbrava, E. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Organoids control glucose
Human islet-like organoids improve glucose control in immunocompetent mice. (Source: Science Translational Medicine)
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: György, B. Tags: Editors ' Choice Source Type: research

[Research Articles] C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy
TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G4C2 repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G4C2 repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 i...
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: Cook, C. N., Wu, Y., Odeh, H. M., Gendron, T. F., Jansen-West, K., del Rosso, G., Yue, M., Jiang, P., Gomes, E., Tong, J., Daughrity, L. M., Avendano, N. M., Castanedes-Casey, M., Shao, W., Oskarsson, B., Tomassy, G. S., McCampbell, A., Rigo, F., Dickson, Tags: Research Articles Source Type: research

[Research Articles] A comparison of four serological assays for detecting anti-SARS-CoV-2 antibodies in human serum samples from different populations
It is of paramount importance to evaluate the prevalence of both asymptomatic and symptomatic cases of SARS-CoV-2 infection and their differing antibody response profiles. Here, we performed a pilot study of four serological assays to assess the amounts of anti–SARS-CoV-2 antibodies in serum samples obtained from 491 healthy individuals before the SARS-CoV-2 pandemic, 51 individuals hospitalized with COVID-19, 209 suspected cases of COVID-19 with mild symptoms, and 200 healthy blood donors. We used two ELISA assays that recognized the full-length nucleoprotein (N) or trimeric spike (S) protein ectodomain of SARS-CoV-...
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: Grzelak, L., Temmam, S., Planchais, C., Demeret, C., Tondeur, L., Huon, C., Guivel-Benhassine, F., Staropoli, I., Chazal, M., Dufloo, J., Planas, D., Buchrieser, J., Rajah, M. M., Robinot, R., Porrot, F., Albert, M., Chen, K.-Y., Crescenzo-Chaigne, B., Do Tags: Research Articles Source Type: research

[Research Articles] Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors
Chimeric antigen receptor (CAR)–engineered T cell therapy for solid tumors is limited by the lack of both tumor-restricted and homogeneously expressed tumor antigens. Therefore, we engineered an oncolytic virus to express a nonsignaling, truncated CD19 (CD19t) protein for tumor-selective delivery, enabling targeting by CD19-CAR T cells. Infecting tumor cells with an oncolytic vaccinia virus coding for CD19t (OV19t) produced de novo CD19 at the cell surface before virus-mediated tumor lysis. Cocultured CD19-CAR T cells secreted cytokines and exhibited potent cytolytic activity against infected tumors. Using several mo...
Source: Science Translational Medicine - September 2, 2020 Category: Biomedical Science Authors: Park, A. K., Fong, Y., Kim, S.-I., Yang, J., Murad, J. P., Lu, J., Jeang, B., Chang, W.-C., Chen, N. G., Thomas, S. H., Forman, S. J., Priceman, S. J. Tags: Research Articles Source Type: research

[Research Articles] CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice
Brown and brown-like beige/brite adipocytes dissipate energy and have been proposed as therapeutic targets to combat metabolic disorders. However, the therapeutic effects of cell-based therapy in humans remain unclear. Here, we created human brown-like (HUMBLE) cells by engineering human white preadipocytes using CRISPR-Cas9–SAM–gRNA to activate endogenous uncoupling protein 1 expression. Obese mice that received HUMBLE cell transplants showed a sustained improvement in glucose tolerance and insulin sensitivity, as well as increased energy expenditure. Mechanistically, increased arginine/nitric oxide (NO) metab...
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Wang, C.-H., Lundh, M., Fu, A., Kriszt, R., Huang, T. L., Lynes, M. D., Leiria, L. O., Shamsi, F., Darcy, J., Greenwood, B. P., Narain, N. R., Tolstikov, V., Smith, K. L., Emanuelli, B., Chang, Y.-T., Hagen, S., Danial, N. N., Kiebish, M. A., Tseng, Y.-H. Tags: Research Articles Source Type: research

[Research Articles] Bioadhesive hydrogels demonstrating pH-independent and ultrafast gelation promote gastric ulcer healing in pigs
Hydrogels are soft materials used in an array of biomedical applications. However, the in situ formation of hydrogels at target sites, particularly in dynamic in vivo environments, usually requires a prolonged gelation time and results in poor adhesion. These limitations cause considerable loss of both hydrogel mass and encapsulated therapeutic cargoes, thereby compromising treatment outcomes. Here, we report the development of a hydrogel based on thiourea-catechol reaction to enhance the bioadhesion. Compared with classical bioadhesive hydrogels, our hydrogels show enhanced mechanical properties, exceedingly short curing ...
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Xu, X., Xia, X., Zhang, K., Rai, A., Li, Z., Zhao, P., Wei, K., Zou, L., Yang, B., Wong, W.-K., Chiu, P. W.-Y., Bian, L. Tags: Research Articles Source Type: research

[Research Articles] Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome
Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in the SCN1A gene, resulting in haploinsufficiency of the voltage-gated sodium channel α subunit NaV1.1. Here, we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human cell lines, as well as in mo...
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Han, Z., Chen, C., Christiansen, A., Ji, S., Lin, Q., Anumonwo, C., Liu, C., Leiser, S. C., Meena, , Aznarez, I., Liau, G., Isom, L. L. Tags: Research Articles Source Type: research

[Editors' Choice] Novel stem cell niche to preserve vision
Neural derived cells in the optic nerve express multiple stem cell markers and can differentiate into multiple neural lineages. (Source: Science Translational Medicine)
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Xinyi, S. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Sirt2: A master regulator of T cell metabolism?
Sirt2 controls metabolic fitness and antitumor function of T cells. (Source: Science Translational Medicine)
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Shi, L. Z. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Breaking up forces stem cells to come together
Microfracture surgery followed by local delivery of therapy induces stem cells to rebuild cartilage in osteoarthritis. (Source: Science Translational Medicine)
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Aguilar, C. A. Tags: Editors ' Choice Source Type: research

[Research Articles] A second X chromosome contributes to resilience in a mouse model of Alzheimers disease
A major sex difference in Alzheimer’s disease (AD) is that men with the disease die earlier than do women. In aging and preclinical AD, men also show more cognitive deficits. Here, we show that the X chromosome affects AD-related vulnerability in mice expressing the human amyloid precursor protein (hAPP), a model of AD. XY-hAPP mice genetically modified to develop testicles or ovaries showed worse mortality and deficits than did XX-hAPP mice with either gonad, indicating a sex chromosome effect. To dissect whether the absence of a second X chromosome or the presence of a Y chromosome conferred a disadvantage on male ...
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Davis, E. J., Broestl, L., Abdulai-Saiku, S., Worden, K., Bonham, L. W., Minones-Moyano, E., Moreno, A. J., Wang, D., Chang, K., Williams, G., Garay, B. I., Lobach, I., Devidze, N., Kim, D., Anderson-Bergman, C., Yu, G.-Q., White, C. C., Harris, J. A., Mi Tags: Research Articles Source Type: research

[Focus] Mapping cancer genetics at single-cell resolution
CRISPR genetic interaction mapping reveals networks of genes that drive cancer phenotypes. (Source: Science Translational Medicine)
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Gilbert, L. A. Tags: Focus Source Type: research

[Research Articles] BET inhibition increases {beta}III-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine
In this study, we conducted a systematic analysis to determine the regulation of TUBB3 expression in breast cancer metastases to the brain and strategically target these metastases using vinorelbine (VRB), a drug approved by the U.S. Food and Drug Administration (FDA). We found that human epidermal growth factor receptor 2 (HER2) signaling regulates TUBB3 expression in both trastuzumab-sensitive and trastuzumab-resistant neoplastic cells. We further discovered that bromodomain and extra-terminal domain (BET) inhibition increases TUBB3 expression, rendering neoplastic cells more susceptible to apoptosis by VRB. Orthotopic x...
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Kanojia, D., Panek, W. K., Cordero, A., Fares, J., Xiao, A., Savchuk, S., Kumar, K., Xiao, T., Pituch, K. C., Miska, J., Zhang, P., Kam, K.-L., Horbinski, C., Balyasnikova, I. V., Ahmed, A. U., Lesniak, M. S. Tags: Research Articles Source Type: research

[Research Articles] Gastrointestinal synthetic epithelial linings
Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here, we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the small intestine, given its role in drug and nutrient absorption and identified catalase as an essential enzyme with the potential to catalyze polymerization and growth of synthetic biomaterial layers. We demonstrated that the polymerization of dopamine by catalase yields strong tissue adhesion. We characterized th...
Source: Science Translational Medicine - August 26, 2020 Category: Biomedical Science Authors: Li, J., Wang, T., Kirtane, A. R., Shi, Y., Jones, A., Moussa, Z., Lopes, A., Collins, J., Tamang, S. M., Hess, K., Shakur, R., Karandikar, P., Lee, J. S., Huang, H.-W., Hayward, A., Traverso, G. Tags: Research Articles Source Type: research

[Research Articles] Pathophysiological regulation of lung function by the free fatty acid receptor FFA4
Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein–coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activatio...
Source: Science Translational Medicine - August 19, 2020 Category: Biomedical Science Authors: Prihandoko, R., Kaur, D., Wiegman, C. H., Alvarez-Curto, E., Donovan, C., Chachi, L., Ulven, T., Tyas, M. R., Euston, E., Dong, Z., Alharbi, A. G. M., Kim, R. Y., Lowe, J. G., Hansbro, P. M., Chung, K. F., Brightling, C. E., Milligan, G., Tobin, A. B. Tags: Research Articles Source Type: research

[Research Articles] Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice
Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout o...
Source: Science Translational Medicine - August 19, 2020 Category: Biomedical Science Authors: Alsamman, S., Christenson, S. A., Yu, A., Ayad, N. M. E., Mooring, M. S., Segal, J. M., Hu, J. K.-H., Schaub, J. R., Ho, S. S., Rao, V., Marlow, M. M., Turner, S. M., Sedki, M., Pantano, L., Ghoshal, S., Ferreira, D. D. S., Ma, H.-Y., Duwaerts, C. C., Esp Tags: Research Articles Source Type: research

[Research Articles] Artery to vein configuration of arteriovenous fistula improves hemodynamics to increase maturation and patency
Arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, but 60% of conventional [vein-to-artery (V-A)] AVF fail to mature, and only 50% remain patent at 1 year. We previously showed improved maturation and patency in a pilot study of the radial artery deviation and reimplantation (RADAR) technique that uses an artery-to-vein (A-V) configuration. Here, we show that RADAR exhibits higher rates of maturation, as well as increased primary and secondary long-term patencies. RADAR is also protective in female patients, where it is associated with decreased reintervention rates and improved secondary patency. ...
Source: Science Translational Medicine - August 19, 2020 Category: Biomedical Science Authors: Bai, H., Sadaghianloo, N., Gorecka, J., Liu, S., Ono, S., Ramachandra, A. B., Bonnet, S., Mazure, N. M., Declemy, S., Humphrey, J. D., Dardik, A. Tags: Research Articles Source Type: research