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| Open AccessRETRACTED ARTICLE: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer
Polymerase (POL) θ inhibitors display synthetic lethality in tumours with homologous recombination repair deficiency. Here, the authors demonstrate that POLθ inhibition with novobiocin activates the cGAS/STING pathway in BRCA-deficient cancers.
- Jeffrey Patterson-Fortin
- , Heta Jadhav
- & Geoffrey I. Shapiro
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Article
| Open AccessCircadian clock molecule REV-ERBα regulates lung fibrotic progression through collagen stabilization
The molecular clock REV-ERBα regulates lung injury during fibrosis, but the role of REV-ERBα in fibrogenesis remains unknown. Here, the authors show that REV-ERBα interacts with the lysyl oxidase-collagen axis during fibrogenesis and demonstrate the therapeutic potential of Rev-erbα agonist against lung fibrosis.
- Qixin Wang
- , Isaac Kirubakaran Sundar
- & Irfan Rahman
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Article
| Open AccessASGARD is A Single-cell Guided Pipeline to Aid Repurposing of Drugs
The full potential of single-cell RNA-sequencing applied to precision medicine has yet to be reached. Here, we propose a drug recommendation system ASGARD, which predicts drugs by considering cell clusters to address the intercellular heterogeneity within each patient.
- Bing He
- , Yao Xiao
- & Lana X. Garmire
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Article
| Open AccessDirected self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes
Cell therapy for diabetes requires the combination of bioengineering and new sources of beta cells. Here, the authors report a self-assembly platform based on neonatal pig islets, human endothelial cells and native organ extracellular matrix, which improves ex vivo islet maturation and in vivo function in a mouse model of diabetes.
- Antonio Citro
- , Alessia Neroni
- & Lorenzo Piemonti
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Perspective
| Open AccessMedical microrobots in reproductive medicine from the bench to the clinic
Microrobotics is an emerging technology with wide implications for medical fields, such as assisted reproduction. Here the authors show how the key challenges regarding materials, processes and engineering as well as ethical and regulatory implications can be addressed towards a clinical adoption.
- Richard Nauber
- , Sandhya R. Goudu
- & Mariana Medina-Sánchez
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Perspective
| Open AccessFuture therapies for cystic fibrosis
The cystic fibrosis landscape has changed dramatically over the last few decades, with improvements in patient quality of life, prognosis and predicted survival. In part, this is related to the availability of novel CFTR modulator drugs, although prior advances in symptom-directed therapies and diagnosis had already led to substantial improvements. However, the authors, part of a national CF focused group, recognize that more needs to be done and outline their considerations on research priorities in this perspective.
- Lucy Allen
- , Lorna Allen
- & Jane C. Davies
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Article
| Open AccessSmall-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model
Idiopathic pulmonary fibrosis is a disease caused by persistent micro-injuries to the lung ultimately resulting in death. Here, the authors describe the use of a small molecule OGG1 inhibitor, TH5487, as a potent and potentially clinically relevant treatment for IPF.
- L. Tanner
- , A. B. Single
- & A. Egesten
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Article
| Open AccessDeletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy
The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.
- Marcel P. Trefny
- , Nicole Kirchhammer
- & Alfred Zippelius
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Article
| Open AccessDeciphering genetic causes for sex differences in human health through drug metabolism and transporter genes
Little is known about the causes of sex differences in disease prevalence and treatment outcomes. Here, the authors study the interaction between drug metabolism enzymes and transporters genes and sex in complex human traits to uncover sex differences in the genetic regulation of gene expression, serum biomarkers, and metabolism of drugs.
- Yingbo Huang
- , Yuting Shan
- & R. Stephanie Huang
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Article
| Open AccessEarly response evaluation by single cell signaling profiling in acute myeloid leukemia
The molecular mechanisms underlying response to chemotherapy in Acute myeloid leukemia (AML) remain to be explored. Here, the authors perform 36-dimensional mass cytometry in 32 AML patients during intensive chemotherapy and suggest functional signalling analysis for prognosis prediction early after treatment in AML.
- Benedicte Sjo Tislevoll
- , Monica Hellesøy
- & Bjørn Tore Gjertsen
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Article
| Open AccessRapid, label-free histopathological diagnosis of liver cancer based on Raman spectroscopy and deep learning
Biopsy is recommended for definitive diagnosis of liver carcinoma, however, this process requires staining and expert pathologists to confirm diagnosis. Here, the authors employ a portable Raman spectroscopy system combined with deep learning to detect carcinoma from normal tissue in real time.
- Liping Huang
- , Hongwei Sun
- & Yi Wang
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Article
| Open AccessModulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.
- Houfu Leng
- , Hanlin Zhang
- & Nicole J. Horwood
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Article
| Open AccessOptimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer’s disease
Deep brain stimulation has been investigated as a potential treatment for cognitive impairments in Alzheimer’s disease. Here the authors carry out post hoc analysis of multi-center cohorts to investigate the anatomical and functional correlates of effective deep brain stimulation, and find that stimulating circuit of Papez, fornix and bed nucleus of the stria terminalis, and a multi-region functional network, were associated with clinical improvement.
- Ana Sofía Ríos
- , Simón Oxenford
- & Andreas Horn
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Article
| Open AccessA Multifaceted benchmarking of synthetic electronic health record generation models
Synthetic health data have the potential to mitigate privacy concerns when sharing data to support biomedical research and the development of innovative healthcare applications. In this work, the authors introduce a use case oriented benchmarking framework to evaluate data synthesis models through a set of utility and privacy metrics.
- Chao Yan
- , Yao Yan
- & Bradley A. Malin
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Article
| Open AccessA metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes
Hyperactivation of the toll-like receptors (TLRs) have been implicated as risk factors for more severe forms of disease in COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here the authors report that MBOAT7 is reduced in macrophages of patients with MAFLD and COVID-19, and acts as a negative regulator of TLR signalling.
- Jawaher Alharthi
- , Ali Bayoumi
- & Mohammed Eslam
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Article
| Open AccessTargeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease
Repair processes in kidney are impaired in severe disease. Here, the authors show that in kidney failure, genetic or pharmacologic inhibition of IL11 releases the brake on regeneration, reverses tissue damage and restores kidney function.
- Anissa A. Widjaja
- , Sivakumar Viswanathan
- & Stuart A. Cook
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Article
| Open AccessQuadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma
The use of chimeric antigen receptor modified immune cell therapeutics has improved the treatment of a range of tumours. Here the authors explore a dual-target iPSC-derived NK cell product as a potential therapeutic for the treatment of multiple myeloma.
- Frank Cichocki
- , Ryan Bjordahl
- & Jeffrey S. Miller
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Article
| Open AccessLow-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes
Low-dose interleukin-2 is showing promise in the treatment of several autoimmune inflammatory diseases. Here authors map the trajectory of cellular and transcriptional changes in type 1 diabetes patients receiving an interval dosing interleukin-2 regimen, which shows an anti-inflammatory gene expression signature shared by all immune cell types analysed, persisting for at least a month after ending treatment.
- Jia-Yuan Zhang
- , Fiona Hamey
- & Ricardo C. Ferreira
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Article
| Open AccessDefective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity
The interferon response has been shown to be linked to severity of SARS-CoV-2 infection and is an essential component of the immune response to COVID-19. Here the authors stratify patients according to COVID-19 severity and asses the interferon response showing defective responses in severe infection and highlight the importance of assay variables and confounding factors that impact the detection of interferon.
- Nikaïa Smith
- , Céline Possémé
- & Darragh Duffy
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Article
| Open AccessCancer cell survival depends on collagen uptake into tumor-associated stroma
Collagen can be a metabolic source to fuel cancer growth. Here the authors show that cell surface protein TEM8 mediates the binding and uptake of collagen in stromal cells and these cells processed the collagen to glutamine, providing an alternative energy source for tumour cells to grow.
- Kuo-Sheng Hsu
- , James M. Dunleavey
- & Brad St. Croix
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Article
| Open AccessThe endocannabinoid anandamide is an airway relaxant in health and disease
Obstructive lung diseases are a frequent cause of morbidity worldwide. Here, the authors identify the endocannabinoid anandamide (AEA) as an airway relaxant under physiological and pathophysiological conditions that can be locally applied to the lung as an aerosol in mice.
- Annika Simon
- , Thomas von Einem
- & Daniela Wenzel
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Article
| Open AccessEvaluation of cutaneous immune response in a controlled human in vivo model of mosquito bites
Vector-borne pathogens are known to elicit immune response upon mosquito biting the host which is critically linked to the establishment of infection and pathogenesis of disease, yet the impact of the mosquito bite itself is not immunologically well-appreciated. Here the authors characterize the immune response to the mosquito vector Aedes aegypti in a controlled human in vivo challenge model and show the induction of a range of immune pathways and cell types.
- David Guerrero
- , Hoa Thi My Vo
- & Jessica E. Manning
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Article
| Open AccessInterferon-λ treatment accelerates SARS-CoV-2 clearance despite age-related delays in the induction of T cell immunity
The interferon response is a critical component response to SARS-CoV-2 infection and prior studies have established a role for the administration of PEGylated interferon-lambda1 and its impact on viral clearance. Here the authors show that PEGylated interferon-lambda1 accelerates the clearance of SARS-CoV-2 despite the negative impact of age on the host T cell response.
- Deanna M. Santer
- , Daniel Li
- & Adam J. Gehring
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Article
| Open AccessDisulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism
Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, the authors show that disulfiram (DSF) reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis and ameliorate NASH in mice, and validate DSF regulation of the gut-liver axis in healthy men in a self-controlled clinical trial.
- Yuanyuan Lei
- , Li Tang
- & Bo Tang
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Article
| Open AccessThe Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction
Surgery is an important part of treatment for gastric adenocarcinoma, however, the consensus on perioperative care is less clear. Here, the authors report the results of a phase II clinical trial investigating neoadjuvant camrelizumab with concurrent chemoradiotherapy, followed by surgery for the treatment of advanced gastric adenocarcinoma.
- Zhaoqing Tang
- , Yan Wang
- & Yihong Sun
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Article
| Open AccessDeep learning-based image analysis predicts PD-L1 status from H&E-stained histopathology images in breast cancer
Programmed death ligand-1 (PD-L1) has been recently adopted for breast cancer as a predictive biomarker for immunotherapies. Here, the authors show that PD-L1 expression can be predicted from H&E-stained images using deep learning.
- Gil Shamai
- , Amir Livne
- & Ron Kimmel
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Article
| Open AccessGeneralizable spelling using a speech neuroprosthesis in an individual with severe limb and vocal paralysis
Previous work has described a neuroprosthesis to directly decode full words in real time during attempts to speak. Here the authors demonstrate that a patient with anarthria can control this neuroprosthesis to spell out intended messages in real time using attempts to silently speak.
- Sean L. Metzger
- , Jessie R. Liu
- & Edward F. Chang
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Article
| Open AccessDeep learning empowered volume delineation of whole-body organs-at-risk for accelerated radiotherapy
Volume delineation of organs-at risk (OARs) and target tumors is an indispensable process for creating radiotherapy treatment planning. Herein, the authors propose a lightweight deep learning framework to empower the rapid and precise volume delineation of whole-body OARs and target tumors.
- Feng Shi
- , Weigang Hu
- & Dinggang Shen
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Article
| Open AccessAdministration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8+ T cell immunity
Broadly neutralising anti-HIV-1 antibody (bNAb) administration in nonhuman primates has been shown to stimulate adaptive T cell-specific immunity, with infection prevention observed. In this work, the authors longitudinally analyse HIV-1 specific cellular immunity in HIV-1- infected individuals starting ART with or without adjunctive bNAb treatment.
- Miriam Rosás-Umbert
- , Jesper D. Gunst
- & Ole S. Søgaard
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Article
| Open AccessIntramyocardial hemorrhage drives fatty degeneration of infarcted myocardium
It is unclear why hemorrhagic myocardial infarctions (hMI) are destined for adverse outcomes. Here, the authors show that hMI drives fatty degeneration of infarct territories and contributes to adverse remodeling of the heart, which can be mitigated via timely depletion of iron within the hMI zone.
- Ivan Cokic
- , Shing Fai Chan
- & Rohan Dharmakumar
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Article
| Open AccessMolecular characterization of renal cell carcinoma tumors from a phase III anti-angiogenic adjuvant therapy trial
Based on the S-TRAC results, sunitinib is approved as adjuvant treatment for adult patients at high risk of recurrent RCC following nephrectomy. Here, the authors report the results of an integrated multi-omics tumor analysis of 171 patients from the trial and identify specific molecular subtypes as well as potential new targets.
- Robert J. Motzer
- , Jean-François Martini
- & Alain Ravaud
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Review Article
| Open Access3D-printed microrobots from design to translation
Microbots have attracted attention due to an ability to reach places and perform tasks which are not possible with conventional techniques in a wide range of applications. Here, the authors review the recent work in the field on the fabrication, application and actuation of 3D printed microbots offering a view of the direction of future microbot research.
- Sajjad Rahmani Dabbagh
- , Misagh Rezapour Sarabi
- & Savas Tasoglu
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Article
| Open AccessExploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics
Immunoglobulin light chain amyloidosis is a lethal hematologic disorder driven by clonal plasma cells producing abnormal light chains that damage healthy tissues. Fraser et al. show that BH3 mimetics, which inhibit pro-survival proteins BCL-2 or MCL-1, can effectively eliminate diseased cells.
- Cameron S. Fraser
- , Johan K. E. Spetz
- & Kristopher A. Sarosiek
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Article
| Open AccessBacteriophage-antibiotic combination therapy against extensively drug-resistant Pseudomonas aeruginosa infection to allow liver transplantation in a toddler
In this study, authors use combinatory bacteriophage-antibiotic therapy, as treatment for extensively drug-resistant Pseudomonas aeruginosa infection in a toddler post liver transplantation. They report on the clinical and microbiological improvement, and present their investigation on how bacterial phage resistance did not result in therapeutic failure.
- Brieuc Van Nieuwenhuyse
- , Dimitri Van der Linden
- & Jean-Paul Pirnay
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Article
| Open AccessInterferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity
Murine models of obesity suggest that decreases in the adipose tissue regulatory T cell compartment may contribute to insulin resistance, but how this corresponds in the human clinical context is less well understood. Here the authors propose a role for interferon gamma in shrinking the adipose tissue regulatory T cell compartment seen in human obesity and assess the alterations seen during induction of dietary changes.
- David Bradley
- , Alan J. Smith
- & Willa A. Hsueh
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Article
| Open AccessDiabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder
Patients with diabetes have an increased susceptibility to infections. Here the authors show that high glucose impairs innate immunity through reduced levels of the antimicrobial peptide psoriasin and impaired epithelial barrier function, resulting in an increased risk of urinary tract infection.
- Soumitra Mohanty
- , Witchuda Kamolvit
- & Annelie Brauner
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Article
| Open AccessSerum neutralization activity declines but memory B cells persist after cure of chronic hepatitis C
Long-term dynamics of the humoral response to HCV in cured individuals aren’t well understood. Here, Nishio et al. show that virus-neutralizing antibody levels decrease in potency and breadth after cure of chronic hepatitis C, while HCV-specific memory B cells persist.
- Akira Nishio
- , Sharika Hasan
- & Barbara Rehermann
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Article
| Open AccessIn vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response
Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
- Aditi Sahu
- , Kivanc Kose
- & Milind Rajadhyaksha
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Article
| Open AccessReversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression
Persistent diabetic complications despite controlled blood glucose levels, known as hyperglycemic memory, remain a poorly understood phenomenon in diabetic kidney disease. Here the authors identify senescence-associated gene p21 as a regulator of hyperglycemic memory, the suppression of which improves hyperglycemic memory and renal function.
- Moh’d Mohanad Al-Dabet
- , Khurrum Shahzad
- & Berend Isermann
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Article
| Open AccessThe CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma
Metastatic pancreatic ductal adenocarcinoma (mPDAC) has limited therapeutic options and is associated with a poor prognosis. Here the authors report the results of a randomized phase II trial showing that combining checkpoint inhibitors (durvalumab and tremelimumab) with chemotherapy (gemcitabine and nab-paclitaxel) does not improve survival compared to chemotherapy alone in patients with mPDAC.
- Daniel J. Renouf
- , Jonathan M. Loree
- & Chris J O’Callaghan
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Article
| Open AccessPredicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.
- Yang Chen
- , Keren Jia
- & Lin Shen
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Article
| Open AccessA TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin
BDNS and TrkB are involved in bone fracture healing by inhibiting AEP. Here the authors show that a TrkB agonist prodrug can inhibit AEP and promote bone formation in osteoporotic mice.
- Jing Xiong
- , Jianming Liao
- & Keqiang Ye
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Article
| Open AccessComparative immunogenicity and reactogenicity of heterologous ChAdOx1-nCoV-19-priming and BNT162b2 or mRNA-1273-boosting with homologous COVID-19 vaccine regimens
Multiple formulations and technologies for vaccinating against SARS-CoV-2 exist but how the use of these in homologous or heterologous format impacts immunogenicity is far from clear. Here the authors compare a range of heterologous and homologous SARS-CoV-2 vaccination strategies and assess the induced humoral and cellular immune response.
- Verena Klemis
- , Tina Schmidt
- & Martina Sester
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Article
| Open AccessConnecting omics signatures and revealing biological mechanisms with iLINCS
There are only a few platforms that integrate multiple omics data types, bioinformatics tools, and interfaces for integrative analyses and visualization that do not require programming skills. Here the authors present an integrative web-based platform for analysis of omics data and signatures of cellular perturbations.
- Marcin Pilarczyk
- , Mehdi Fazel-Najafabadi
- & Mario Medvedovic
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Article
| Open AccessHomotypic and heterotypic immune responses to Omicron variant in immunocompromised patients in diverse clinical settings
Immunocompromised individuals are predisposed to severe SARS-CoV-2 infection, with transplant recipients typically displaying impaired immune response to pathogens, due to typical life-long immunosuppressive treatment. In this work, the authors evaluate the immune response to Omicron subvariants BA.1 and BA.2 in organ transplant recipients across a diverse clinical spectrum.
- Victor H. Ferreira
- , Javier T. Solera
- & Atul Humar
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Article
| Open AccessComprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity
The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.
- Lino Möhrmann
- , Maximilian Werner
- & Hanno Glimm
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Article
| Open AccessEvaluation of transplacental transfer of mRNA vaccine products and functional antibodies during pregnancy and infancy
Pregnant individuals are at higher risk of SARS-CoV-2-related morbidity and mortality, yet more studies are needed to evaluate safety and efficacy of vaccination during pregnancy, and also the level of protection provided to the newborn. Here, the authors evaluate transplacental transfer of mRNA vaccine products and functional SARS-CoV-2 antibodies during pregnancy and early infancy.
- Mary Prahl
- , Yarden Golan
- & Stephanie L. Gaw
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Article
| Open AccessA multimodal iPSC platform for cystic fibrosis drug testing
Hundreds of mutations in the gene CFTR lead to cystic fibrosis and represent a challenge to developing therapeutics. Here, authors demonstrate the ability of airway cells derived from human iPSCs to model genotype-specific CFTR function as well as pharmacologic rescue of disease causing mutations.
- Andrew Berical
- , Rhianna E. Lee
- & Finn J. Hawkins
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Article
| Open AccessReduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation
Lung transplantation is hindered by the scarcity of organs and by mortality following primary graft dysfunction. Here, the authors show that cytokine absorption can be used in donor lungs during ex vivo lung perfusion and post-transplant, and leads to restored lung function and reduced primary graft dysfunction in animal models.
- Haider Ghaidan
- , Martin Stenlo
- & Sandra Lindstedt