tbuckley/cabot-search huggingface dataset:
Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration
Authors: Marvin Reich, Matthew J. Simon, Beate Polke, Iñaki Paris, Georg Werner, Christian Schrader, Lena Spieth, Sonnet S. Davis, Sophie Robinson, Gabrielly Lunkes de Melo, Lennart Schlaphoff, Katrin Buschmann, Stefan Berghoff, Todd Logan, Brigitte Nuscher, Lis de Weerd, Dieter Edbauer, Mikael Simons, Jung H. Suh, Thomas Sandmann, Mihalis S. Kariolis, Sarah L. DeVos, Joseph W. Lewcock, Dominik Paquet, Anja Capell, Gilbert Di Paolo, Christian Haass
Journal: Science Translational Medicine (2024)

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD- GRN ). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD- GRN , namely, Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD- GRN –associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)–derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD- GRN relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD- GRN and potentially other CNS disorders.
MmpR5 protein truncation and bedaquiline resistance in Mycobacterium tuberculosis isolates from South Africa: a genomic analysis
Authors: Leah W Roberts, Kerri M Malone, Martin Hunt, Lavania Joseph, Penelope Wintringer, Jeff Knaggs, Derrick Crook, Maha R Farhat, Zamin Iqbal, Shaheed V Omar
Journal: The Lancet Microbe (2024)

BackgroundThe antibiotic bedaquiline is a key component of new WHO regimens for drug-resistant tuberculosis; however, predicting bedaquiline resistance from bacterial genotypes remains challenging. We aimed to understand the genetic mechanisms of bedaquiline resistance by analysing Mycobacterium tuberculosis isolates from South Africa.MethodsFor this genomic analysis, we conducted whole-genome sequencing of Mycobacterium tuberculosis samples collected at two referral laboratories in Cape Town and Johannesburg, covering regions of South Africa with a high prevalence of tuberculosis. We used the tool ARIBA to measure the status of predefined genes that are associated with bedaquiline resistance. To produce a broad genetic landscape of M tuberculosis in South Africa, we extended our analysis to include all publicly available isolates from the European Nucleotide Archive, including isolates obtained by the CRyPTIC consortium, for which minimum inhibitory concentrations of bedaquiline were available.FindingsBetween Jan 10, 2019, and July, 22, 2020, we sequenced 505 M tuberculosis isolates from 461 patients. Of the 64 isolates with mutations within the mmpR5 regulatory gene, we found 53 (83%) had independent acquisition of 31 different mutations, with a particular enrichment of truncated MmpR5 in bedaquiline-resistant isolates resulting from either frameshift mutations or the introduction of an insertion element. Truncation occurred across three M tuberculosis lineages, and were present in 66% of bedaquiline-resistant isolates. Although the distributions overlapped, the median minimum inhibitory concentration of bedaquiline was 0·25 mg/L (IQR 0·12–0·25) in mmpR5-disrupted isolates, compared with 0·06 mg/L (0·03–0·06) in wild-type M tuberculosis.InterpretationReduction in the susceptibility of M tuberculosis to bedaquiline has evolved repeatedly across the phylogeny. In our data, we see no evidence that this reduction has led to the spread of a successful strain in South Africa. Binary phenotyping based on the bedaquiline breakpoint might be inappropriate to monitor resistance to this drug. We recommend the use of minimum inhibitory concentrations in addition to MmpR5 truncation screening to identify moderate increases in resistance to bedaquiline.FundingUS Centers for Disease Control and Prevention.
Comparative analysis of Bcl-2 family protein overexpression in CAR T cells alone and in combination with BH3 mimetics
Authors: Felix Korell, Michael L. Olson, Diego Salas-Benito, Mark B. Leick, Rebecca C. Larson, Amanda Bouffard, Harrison Silva, Alessandro Gasparetto, Trisha R. Berger, Michael C. Kann, Markus Mergen, Tamina Kienka, Marc Wehrli, Nicholas J. Haradhvala, Stefanie R. Bailey, Anthony Letai, Marcela V. Maus
Journal: Science Translational Medicine (2024)

Approximately 50% of patients with hematologic malignancies relapse after chimeric antigen receptor (CAR) T cell treatment; mechanisms of failure include loss of CAR T persistence and tumor resistance to apoptosis. We hypothesized that both of these challenges could potentially be overcome by overexpressing one or more of the Bcl-2 family proteins in CAR T cells to reduce their susceptibility to apoptosis, both alone and in the presence of BH3 mimetics, which can be used to activate apoptotic machinery in malignant cells. We comprehensively investigated overexpression of different Bcl-2 family proteins in CAR T cells with different signaling domains as well as in different tumor types. We found that Bcl-xL and Bcl-2 overexpression in CAR T cells bearing a 4-1BB costimulatory domain resulted in increased expansion and antitumor activity, reduced exhaustion, and decreased apoptotic priming. In addition, CAR T cells expressing either Bcl-xL or a venetoclax-resistant Bcl-2 variant led to enhanced antitumor efficacy and survival in murine xenograft models of lymphoma and leukemia in the presence or absence of the BH3 mimetic venetoclax, a clinically approved BH3 mimetic. In this setting, Bcl-xL overexpression had stronger effects than overexpression of Bcl-2 or the Bcl-2(G101V) variant. These findings suggest that CAR T cells could be optimally engineered by overexpressing Bcl-xL to enhance their persistence while opening a therapeutic window for combination with BH3 mimetics to prime tumors for apoptosis.
Personal light exposure patterns and incidence of type 2 diabetes: analysis of 13 million hours of light sensor data and 670,000 person-years of prospective observation
Authors: Daniel P Windred, Angus C Burns, Martin K Rutter, Chris Ho Ching Yeung, Jacqueline M Lane, Qian Xiao, Richa Saxena, Sean W Cain, Andrew J K Phillips
Journal: The Lancet Regional Health - Europe (2024)
Click Chemistry‐Mediated Polymannose Surface‐Engineering of Natural Killer Cells for Immunotherapy of Triple‐Negative Breast Cancer
Authors: Xiaomeng Niu, He Yang, Jiangping Guo, Lihua Yao, Yichen Wang, Wenzhuo Yu, Zhuang Liu, Hong Chen
Journal: Advanced Healthcare Materials (2024)

Abstract Natural killer (NK) cells, serve as the frontline defense of the immune system, and are capable of surveilling and eliminating tumor cells. Their significance in tumor immunotherapy has garnered considerable attention in recent years. However, the absence of specific receptor–ligand interactions between NK cells and tumor cells hampers their selectivity, thereby limiting the therapeutic effectiveness of NK cell‐based tumor immunotherapy. Herein, this work constructs polymannose‐engineered NK (pM‐NK) cells via metabolic glycoengineering and copper‐free click chemistry. Polymannose containing dibenzocyclooctyne terminal groups (pM‐DBCO) is synthesized and covalently modified on the surface of azido‐labeled NK cells. Compared to the untreated NK cells, the interactions between pM‐NK cells and MDA‐MB‐231 cells, a breast tumor cell line with overexpression of mannose receptors (MRs), are significantly increased, and lead to significantly enhanced killing efficacy. Consequently, intravenous administration of pM‐NK cells will effectively inhibit the tumor growth and will prolong the survival of mice bearing MDA‐MB‐231 tumors. Thus, this work presents a novel strategy for tumor‐targeting NK cell‐based tumor immunotherapy.
Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration
Authors: Jian Liu, David A. Copland, Alison J. Clare, Mathias Gorski, Burt T. Richards, Louis Scott, Sofia Theodoropoulou, Ursula Greferath, Katherine Cox, Gongyu Shi, Oliver H. Bell, Kepeng Ou, Jenna Le Brun Powell, Jiahui Wu, Luis Martinez Robles, Yingxin Li, Lindsay B. Nicholson, Peter J. Coffey, Erica L. Fletcher, Robyn Guymer, Monte J. Radeke, Iris M. Heid, Gregory S. Hageman, Ying Kai Chan, Andrew D. Dick
Journal: Science Translational Medicine (2024)

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor-associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of
GLIDE Score
Authors: Muhammed Gerçek, Akhil Narang, M. Isabel Körber, Kai P. Friedrichs, Jyothy J. Puthumana, Maria Ivannikova, Mohamed Al-Kazaz, Paul Cremer, Abigail S. Baldridge, Zhiying Meng, Peter Luedike, James D. Thomas, Tanja K. Rudolph, Tobias Geisler, Tienush Rassaf, Roman Pfister, Volker Rudolph, Charles J. Davidson
Journal: JACC. Cardiovascular imaging (2024)

Tricuspid valve transcatheter edge-to-edge repair (T-TEER) is the most widely used transcatheter therapy to treat patients with tricuspid regurgitation (TR). The aim of this study was to develop a simple anatomical score to predict procedural outcomes of T-TEER. All patients (n = 168) who underwent T-TEER between January 2017 and November 2022 at 2 centers were included in the derivation cohort. Additionally, 126 patients from 2 separate institutions served as a validation cohort. T-TEER was performed using 2 commercially available technologies. Core laboratory assessment of procedural transesophageal echocardiograms was used to determine septolateral and anteroposterior coaptation gap, leaflet morphology, septal leaflet length and retraction, chordal structure density, tethering height, en face TR jet morphology and TR jet location, image quality, and the presence of intracardiac leads. A scoring system was derived using univariable and multivariable logistic regression. Endpoints assessed were immediate postprocedural TR reduction ≥2 grades and TR grade moderate or less. The median age was 82 years (Q1-Q3: 78-84 years); 48% of patients were women; and patients presented with severe (55%), massive (36%), and torrential (8%) TR. Five variables (septolateral coaptation gap, chordal structure density, en face TR jet morphology, TR jet location, and image quality) were identified as best predicting procedural outcome and were incorporated in the GLIDE (Gap, Location, Image quality, density, en-face TR morphology) score (range 0-5). TR reduction ≥2 grades and TR grade moderate or less were observed in >90% of patients with GLIDE scores of 0 and 1 and in only 5.6% and 16.7% of those with GLIDE scores ≥4. The GLIDE score was then externally validated in a separate cohort (area under the curve: 0.77; 95% CI: 0.69-0.86). TR reduction significantly correlated with functional improvement assessed by NYHA functional class and 6-minute walk distance at 3 months. The GLIDE score is a simple, 5-component score that is readily obtained during patient imaging and can predict successful T-TEER.
Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse
Authors: Yan Mao, Zhen Jin, Jing Yang, Dengqiu Xu, Lei Zhao, Abdukahar Kiram, Yujing Yin, Danxia Zhou, Zongchao Sun, Liwei Xiao, Zheng Zhou, Likun Yang, Tingting Fu, Zhisheng Xu, Yuhuan Jia, Xinyi Chen, Feng-Nan Niu, Xihua Li, Zezhang Zhu, Zhenji Gan
Journal: Science Translational Medicine (2024)

Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction–related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 ( Igf2 ) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.
T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas through H3K9me3 Modifications
Authors: Lucy S. Britto, Deepali Balasubramani, Sona Desai, Phunterion Phillips, Neev Trehan, Ethel Cesarman, Jean L. Koff, Ankur Singh
Journal: Advanced Healthcare Materials (2024)

Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a subtype associated with poor survival outcomes. Despite identifying therapeutic targets through molecular characterization, targeted therapies have limited success. New strategies using immune-competent tissue models are needed to understand how DLBCL cells evade treatment. Here, synthetic hydrogel-based lymphoma organoids are used to demonstrate how signals in the lymphoid tumor microenvironment (Ly-TME) can alter B cell receptor (BCR) signaling and specific histone modifications, tri-methylation of histone 3 at lysine 9 (H3K9me3), dampening the effects of BCR pathway inhibition. Using imaging modalities, T cells increase DNA methyltransferase 3A expression and cytoskeleton formation in proximal ABC-DLBCL cells, regulated by H3K9me3. Expansion microscopy on lymphoma organoids reveals T cells increase the size and quantity of segregated H3K9me3 clusters in ABC-DLBCL cells. Findings suggest the re-organization of higher-order chromatin structures that may contribute to evasion or resistance to therapy via the emergence of novel transcriptional states. Treating ABC-DLBCL cells with a G9α histone methyltransferase inhibitor reverses T cell-mediated modulation of H3K9me3 and overcomes T cell-mediated attenuation of treatment response to BCR pathway inhibition. This study emphasizes the Ly-TME's role in altering DLBCL fate and suggests targeting aberrant signaling and microenvironmental cross-talk that can benefit high-risk patients.
Future patterns in burden and incidence of squamous cell carcinoma of the anus in the United States, 2001-2035
Authors: Ashvita Garg, Haluk Damgacioglu, Keith Sigel, Alan G Nyitray, Gary M Clifford, Thomas Curran, Gweneth Lazenby, Eric G Meissner, Katherine Sterba, Kalyani Sonawane, Ashish A Deshmukh
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Squamous cell carcinoma of the anus (SCCA) incidence has been rising in the United States, particularly among older adults (≥65 years). We estimated the impact of this rise on future burden (through 2035) using age-period-cohort modeling. The SCCA burden (cases/year) is expected to rise, reaching approximately 2700 among men and approximately 7000 among women in 2031-2035 (burden during 2016-2020 among men and women was approximately 2150 and approximately 4600), with most cases 65 years of age or older (61% in men and 70% in women in 2031-2035; from 40% and 46% in 2016-2020). SCCA incidence (per 100 000) is projected to rise among older men aged 65-74, 75-84, and 85 years or older (5.0, 4.9, and 4.3 in 2031-2035 vs 3.7, 3.8, and 3.4 in 2016-2020, respectively) and women (11.2, 12.6, and 8.0 in 2031-2035 vs 8.2, 6.8, and 5.2 in 2016-2020, respectively). The projected rise in SCCA burden among older adults is troubling and highlights the importance of improving early detection and clinical care.
Teprotumumab for the treatment of Thyroid eye disease
Authors: Shoaib Ugradar, Emil Malkhasyan, Raymond S Douglas
Journal: Endocrine Reviews (2024)

Abstract Thyroid eye disease (TED) is the most common extra thyroidal manifestation of Graves’ disease (GD). It may also present in those who are hypothyroid or euthyroid. The characteristic clinical manifestations of TED, chemosis, lid swelling, proptosis, and diplopia, are driven by a combination of inflammation and extracellular matrix modification. It has recently emerged that 1 of the major drivers of this molecular signature is the overexpression of the IGF-1 receptor [IGF-1R]) on key effector cells in TED pathogenesis. The overexpression of the IGF-1R is coupled with a dysregulation of the IGF-1R axis, which links other pathways that modulate inflammation, such as fibrosis and extracellular matrix organization, in patients with TED. This overexpression is also found to persist from the acute stage into the chronic phase. Teprotumumab, a fully human IgG1 monoclonal antibody that inhibits the IGF-1R, recently gained approval in the United States for the treatment of TED. In phase 2 and phase 3 clinical studies, teprotumumab showed efficacy in reducing inflammation, proptosis, diplopia, and burden on quality of life in patients who were treated. Postintroduction studies have confirmed the results of the phase 2 and phase 3 studies. Since 2020, more than 5800 patients have been treated with teprotumumab, and it appears to be well tolerated. The American Thyroid Association and the European Thyroid Association have recommended it as first-line therapy for patients with moderate to severe TED who display features of proptosis and diplopia.
Basal cell carcinoma incidence trends - can we stop the surge?
Authors: Zoe C Venables, Marlies Wakkee
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript Basal cell carcinoma incidence trends - can we stop the surge? Get access Zoe C Venables, Zoe C Venables Norfolk and Norwich University Hospital, Norwich, UKNorwich Medical School, Norwich, UK Correspondence: Zoe Venebles, Email:zoe.venables@nnuh.nhs.uk https://orcid.org/0000-0002-9929-2693 Search for other works by this author on: Oxford Academic Google Scholar Marlies Wakkee Marlies Wakkee Department of Dermatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands https://orcid.org/0000-0001-8578-901X Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae239, https://doi.org/10.1093/bjd/ljae239 Published: 05 June 2024 Article history Received: 03 June 2024 Accepted: 04 June 2024 Published: 05 June 2024
Cascade catalysis nanozyme for interfacial functionalization in combating implant infections associated with diabetes via sonodynamic therapy and adaptive immune activation
Authors: Kun Xu, Yanan Zou, Chuanchuan Lin, Liangshuai Zhang, Meijun Tan, Meng Li, Jing Wu, Xuan Li, Ye He, Peng Liu, Ke Li, Kaiyong Cai
Journal: Biomaterials (2024)
Management of Immune Thrombotic Thrombocytopenic Purpura without Therapeutic Plasma Exchange
Authors: Lucas Kühne, Paul Knöbl, Kathrin Eller, Johannes Thaler, Wolfgang R Sperr, Karoline V. Gleixner, Thomas Osterholt, Jessica Katharina Kaufeld, Jan Menne, Veronika Buxhofer-Ausch, Anja Susanne Mühlfeld, Evelyn Seelow, Adrian Schreiber, Polina Todorova, Sadrija Cukoski, Wolfram Johannes Jabs, Fedai Özcan, Anja Gäckler, Kristina Schönfelder, Felix S. Seibert, Timm H. Westhoff, Vedat Schwenger, Dennis A. Eichenauer, Linus Völker, Paul Brinkkötter
Journal: Blood (2024)
Dose/Exposure Relationship of Exercise and Distant Recurrence in Primary Breast Cancer
Authors: Davide Soldato, Stefan Michiels, Julie Havas, Antonio Di Meglio, Martina Pagliuca, Maria Alice Franzoi, Barbara Pistilli, Neil M. Iyengar, Paul Cottu, Florence Lerebours, Charles Coutant, Aurélie Bertaut, Oliver Tredan, Laurence Vanlemmens, Christelle Jouannaud, Iona Hrab, Sibille Everhard, Anne-Laure Martin, Fabrice André, Ines Vaz-Luis, Lee W. Jones
Journal: Journal of Clinical Oncology (2024)

Postdiagnosis exercise is associated with lower breast cancer (BC) mortality but its link with risk of recurrence is less clear. We investigated the impact and dose-response relationship of exercise and recurrence in patients with primary BC.
Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner
Authors: Yong Wang, Guo Li, Bingni Chen, George Shakir, Mario Volz, Emiel P C van der Vorst, Sanne L Maas, Martina Geiger, Carolin Jethwa, Alexander Bartelt, Zhaolong Li, Justus Wettich, Nadja Sachs, Lars Maegdefessel, Maliheh Nazari Jahantigh, Michael Hristov, Michael Lacy, Beat Lutz, Christian Weber, Stephan Herzig, Raquel Guillamat Prats, Sabine Steffens
Journal: Cardiovascular Research (2024)

Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signalling in atherosclerosis.
Improved Survival in Contemporary Community-Based Patients With Metastatic Clear-Cell Renal Cell Carcinoma Undergoing Active Treatment
Authors: Reha-Baris Incesu, Simone Morra, Lukas Scheipner, Andrea Baudo, Letizia Maria Ippolita Jannello, Mario de Angelis, Carolin Siech, Anis Assad, Zhe Tian, Fred Saad, Shahrokh F. Shariat, Felix K.H. Chun, Alberto Briganti, Ottavio de Cobelli, Luca Carmignani, Sascha Ahyai, Nicola Longo, Derya Tilki, Markus Graefen, Pierre I. Karakiewicz
Journal: Journal of the National Comprehensive Cancer Network (2024)

We hypothesized that the evolving treatment paradigms recommended based on phase III trials may have translated into improved overall survival (OS) in contemporary community-based patients with clear-cell metastatic renal cell carcinoma (ccmRCC) undergoing active treatment.
Case 17-2024: A 45-Year-Old Woman with Metastatic Breast Cancer
Authors: Neelima Vidula, Karen Rodriguez, Alexandra K Wong, Baris Boyraz
Journal: New England Journal of Medicine (2024)

A 45-year-old woman was evaluated in the oncology clinic of the hospital because of metastatic triple-negative breast cancer that had progressed despite chemotherapy. Management decisions were made.