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The effects of low-dose IL-2 on Treg adoptive cell therapy in patients with Type 1 diabetes.

JCI Insight 2021 Jul 29. Epub 2021 Jul 29.

Diabetes Center, UCSF, San Francisco, United States of America.

Background: A previous Phase I study showed that the infusion of autologous Treg cells expanded ex-vivo into recent onset Type 1 Diabetes (T1D) patients had an excellent safety profile, however, the majority of the infused Tregs could no longer be detected in the peripheral blood three months post-infusion (NCT01210664-Treg-T1D Trial). Interleukin-2 (IL-2) has been shown to enhance human Treg cell survival and expansion at low doses in vivo. Therefore, we conducted a Phase 1 study (NCT02772679-TILT trial) combining polyclonal Treg and low-dose IL-2 and assessed the impact over time on Tregs populations and other immune cells. Read More

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Loss of the mitochondrial phosphate carrier SLC25A3 induces remodeling of the cardiac mitochondrial protein acylome.

Am J Physiol Cell Physiol 2021 07 28. Epub 2021 Jul 28.

Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, GA, United States.

Mitochondria are recognized as signaling organelles because, under stress, mitochondria can trigger various signaling pathways to coordinate the cell's response. The specific pathway(s) engaged by mitochondria in response to mitochondrial energy defects in vivo and in high-energy tissues like the heart are not fully understood. Here, we investigated cardiac pathways activated in response to mitochondrial energy dysfunction by studying mice with cardiomyocyte-specific loss of the mitochondrial phosphate carrier (SLC25A3), an established model that develops cardiomyopathy as a result of defective mitochondrial ATP synthesis. Read More

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Virus Induced Lymphocytes (VIL) as a novel viral antigen-specific T cell therapy for COVID-19 and potential future pandemics.

Sci Rep 2021 07 27;11(1):15295. Epub 2021 Jul 27.

Intima Bioscience, Inc., New York, NY, USA.

The a priori T cell repertoire and immune response against SARS-CoV-2 viral antigens may explain the varying clinical course and prognosis of patients having a mild COVID-19 infection as opposed to those developing more fulminant multisystem organ failure and associated mortality. Using a novel SARS-Cov-2-specific artificial antigen presenting cell (aAPC), coupled with a rapid expansion protocol (REP) as practiced in tumor infiltrating lymphocytes (TIL) therapy, we generate an immune catalytic quantity of Virus Induced Lymphocytes (VIL). Using T cell receptor (TCR)-specific aAPCs carrying co-stimulatory molecules and major histocompatibility complex (MHC) class-I immunodominant SARS-CoV-2 peptide-pentamer complexes, we expand virus-specific VIL derived from peripheral blood mononuclear cells (PBMC) of convalescent COVID-19 patients up to 1000-fold. Read More

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Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through 'reverse phenotyping'.

Nat Commun 2021 07 26;12(1):4515. Epub 2021 Jul 26.

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), Munich, Germany.

The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. Read More

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Indices of Defective Autophagy in Whole Muscle and Lysosome Enriched Fractions From Aged D2-mdx Mice.

Front Physiol 2021 9;12:691245. Epub 2021 Jul 9.

Department of Animal Science, Iowa State University, Ames, IA, United States.

Duchenne muscular dystrophy (DMD) is a fatal, progressive muscle disease caused by the absence of functional dystrophin protein. Previous studies in mdx mice, a common DMD model, identified impaired autophagy with lysosomal insufficiency and impaired autophagosomal degradation as consequences of dystrophin deficiency. Thus, we hypothesized that lysosomal abundance would be decreased and degradation of autophagosomes would be impaired in muscles of D2-mdx mice. Read More

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Ectopic Overexpression of PPARγ2 in the Heart Determines Differences in Hypertrophic Cardiomyopathy After Treatment With Different Thiazolidinediones in a Mouse Model of Diabetes.

Front Pharmacol 2021 7;12:683156. Epub 2021 Jul 7.

Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

The clinical controversy of rosiglitazone as a hypoglycemic agent is potentially associated with heart failure, mainly due to its potent activation of peroxisome proliferator-activated receptor γ (PPARγ). PPARγ partial agonists showed superior pharmacological profiles to rosiglitazone. This study compared differences in cardiac morphology and function of the PPARγ partial agonist CMHX008 with rosiglitazone. Read More

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A rechargeable anti-thrombotic coating for blood-contacting devices.

Biomaterials 2021 Jul 9;276:121011. Epub 2021 Jul 9.

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Wyss Institute of Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA. Electronic address:

Despite the potential of anti-thrombogenic coatings, including heparinized surfaces, to improve the performance of blood-contacting devices, the inevitable deterioration of bioactivity remains an important factor in device failure and related thrombotic complications. As a consequence, the ability to restore the bioactivity of a surface coating after implantation of a blood-contacting device provides a potentially important strategy to enhance its clinical performance. Here, we report the regeneration of a multicomponent anti-thrombogenic coating through use of an evolved sortase A to mediate reversible transpeptidation. Read More

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Generation of Tumor-activated T cells using electroporation.

Bioelectrochemistry 2021 Jul 13;142:107886. Epub 2021 Jul 13.

Department of Biomedical Engineering and Mechanics, Virginia Tech, 325 Stanger Street, Blacksburg, VA 24061, USA; Department of Mechanical Engineering, Virginia Tech, Goodwin Hall, 635 Prices Fork Road, Blacksburg, VA 24061, USA; Institute for Critical Technology and Applied Sciences, Virginia Tech, Kelly Hall, Blacksburg, VA 24061, USA. Electronic address:

Expansion of cytotoxic T lymphocytes (CTLs) is a crucial step in almost all cancer immunotherapeutic methods. Current techniques for expansion of tumor-reactive CTLs present major limitations. This study introduces a novel method to effectively produce and expand tumor-activated CTLs using high-voltage pulsed electric fields. Read More

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RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation.

Int J Mol Sci 2021 Jul 14;22(14). Epub 2021 Jul 14.

Department of Microbiology and Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea.

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Read More

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The Intrinsic Nutrient Sensing Adipokinetic Hormone Producing Cells Function in Modulation of Metabolism, Activity, and Stress.

Int J Mol Sci 2021 Jul 13;22(14). Epub 2021 Jul 13.

Department of Biology, Wake Forest University, Winston-Salem, NC 27109, USA.

All organisms confront the challenges of maintaining metabolic homeostasis in light of both variabilities in nutrient supplies and energetic costs of different physiologies and behaviors. While all cells are nutrient sensitive, only relative few cells within Metazoans are nutrient sensing cells. Nutrient sensing cells organize systemic behavioral and physiological responses to changing metabolic states. Read More

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Phosphorylated WNK kinase networks in recoded bacteria recapitulate physiological function.

Cell Rep 2021 Jul;36(3):109416

Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06520, USA; Systems Biology Institute, Yale University, West Haven, CT 06516, USA. Electronic address:

Advances in genetic code expansion have enabled the production of proteins containing site-specific, authentic post-translational modifications. Here, we use a recoded bacterial strain with an expanded genetic code to encode phosphoserine into a human kinase protein. We directly encode phosphoserine into WNK1 (with-no-lysine [K] 1) or WNK4 kinases at multiple, distinct sites, which produced activated, phosphorylated WNK that phosphorylated and activated SPAK/OSR kinases, thereby synthetically activating this human kinase network in recoded bacteria. Read More

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Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21.

Cancer Immunol Immunother 2021 Jul 20. Epub 2021 Jul 20.

Research Center for Cancer Immunotherapy, Gwangju, South Korea.

Background: Natural killer (NK) cell-based immunotherapy is a promising treatment approach for multiple myeloma (MM), but obtaining a sufficient number of activated NK cells remains challenging. Here, we report an improved method to generate ex vivo expanded NK (eNK) cells from MM patients based on genetic engineering of K562 cells to express OX40 ligand and membrane-bound (mb) IL-18 and IL-21.

Methods: K562-OX40L-mbIL-18/-21 cells were generated by transducing K562-OX40L cells with a lentiviral vector encoding mbIL-18 and mbIL-21, and these were used as feeder cells to expand NK cells from peripheral blood mononuclear cells of healthy donors (HDs) and MM patients in the presence of IL-2/IL-15. Read More

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Single-cell transcriptome and TCR profiling reveal activated and expanded T cell populations in Parkinson's disease.

Cell Discov 2021 Jul 20;7(1):52. Epub 2021 Jul 20.

School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, China.

Given the chronic inflammatory nature of Parkinson's disease (PD), T cell immunity may be important for disease onset. Here, we performed single-cell transcriptome and TCR sequencing, and conducted integrative analyses to decode composition, function and lineage relationship of T cells in the blood and cerebrospinal fluid of PD. Combined expression and TCR-based lineage tracking, we discovered a large population of CD8 T cells showing continuous progression from central memory to terminal effector T cells in PD patients. Read More

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The Durability of Mortar Containing Alkali Activated Fly Ash-Based Lightweight Aggregate.

Materials (Basel) 2021 Jul 4;14(13). Epub 2021 Jul 4.

Magnel-Vandepitte Laboratory for Structural Engineering and Building Materials, Ghent University, Technologiepark Zwijnaarde 60, B-9052 Ghent, Belgium.

Beneficiating fly ash as valuable construction material such as artificial lightweight aggregate (LWA) could be an alternative solution to increase the utilization of the industrial by-product. However, generally, LWA is characterized by high porosity and a related high water absorption, which on the one hand allows production of lightweight mortar, but on the other hand can affect its performance. Thus, in this research, the durability performance of mortar composed with alkali-activated fly ash-based LWA, and commercial expanded clay (EC) LWA was investigated. Read More

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Exposure to Plasma From Non-alcoholic Fatty Liver Disease Patients Affects Hepatocyte Viability, Generates Mitochondrial Dysfunction, and Modulates Pathways Involved in Fat Accumulation and Inflammation.

Front Med (Lausanne) 2021 2;8:693997. Epub 2021 Jul 2.

AGING Project, Department of Translational Medicine, University East Piedmont, Novara, Italy.

Changes of lipidic storage, oxidative stress and mitochondrial dysfunction may be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Although the knowledge of intracellular pathways has vastly expanded in recent years, the role and mechanisms of circulating triggering factor(s) are debated. Thus, we tested the hypothesis that factors circulating in the blood of NAFLD patients may influence processes underlying the disease. Read More

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p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models.

Nat Genet 2021 Jul 15. Epub 2021 Jul 15.

Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.

In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Read More

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Hairy cell leukemia: a brief update on current knowledge and treatment prospects.

Curr Opin Oncol 2021 Jul 8. Epub 2021 Jul 8.

Department of Hematology, Medical University of Lodz, Lodz, Poland.

Purpose Of Review: This article provides a brief update on the recommended diagnosis and treatment strategies for patients with the classic form of hairy cell leukemia (HCL) and HCL variant (HCLv).

Recent Findings: HCL is a chronic B-cell malignancy with multiple treatment options. In recent years, many novel drugs have been assessed for HCL treatment with promising results. Read More

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Integrated Multiomic Analysis Reveals the High-Fat Diet Induced Activation of the MAPK Signaling and Inflammation Associated Metabolic Cascades via Histone Modification in Adipose Tissues.

Front Genet 2021 28;12:650863. Epub 2021 Jun 28.

Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: The number of diet induced obese population is increasing every year, and the incidence of type 2 diabetes is also on the rise. Histone methylation and acetylation have been shown to be associated with lipogenesis and obesity by manipulating gene expression via the formation of repression or activation domains on chromosomes.

Objective: In this study, we aimed to explore gene activation or repression and related biological processes by histone modification across the whole genome on a high-fat diet (HFD) condition. Read More

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The Impact of NK Cell-Based Therapeutics for the Treatment of Lung Cancer for Biologics: Targets and Therapy.

Biologics 2021 7;15:265-277. Epub 2021 Jul 7.

Department of Vascular Surgery, Medical University of Vienna, Vienna, Austria.

Lung cancer has a dismal prognosis and novel targeted therapies leave still room for major improvements and better outcomes. Immunotherapy targeting immune checkpoint (IC) proteins, either as single agents or in combination with chemotherapy, is active but responders constitute only approximately 10-15% of non-small cell lung cancer (NSCLC) patients. Other effector immune cells such as CAR-T cells or NK cells may help to overcome the limitations of the IC inhibitor therapies for lung cancer. Read More

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Comparison of mesenchymal stromal cells from peritoneal dialysis effluent with those from umbilical cords: characteristics and therapeutic effects on chronic peritoneal dialysis in uremic rats.

Stem Cell Res Ther 2021 Jul 13;12(1):398. Epub 2021 Jul 13.

Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada.

Background: A long-term of peritoneal dialysis (PD) using a hypertonic PD solution (PDS) leads to patient's peritoneal membrane (PM) injury, resulting in ultrafiltration failure (UFF) and PD drop-out. Our previous study shows that PD effluent-derived mesenchymal stromal cells (pMSCs) prevent the PM injury in normal rats after repeated exposure of the peritoneal cavity to a PDS. This study was designed to compare the cytoprotection between pMSCs and umbilical cord-derived MSCs (UC-MSCs) in the treatment of both PM and kidney injury in uremic rats with chronic PD. Read More

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Current Advances in Photoactive Agents for Cancer Imaging and Therapy.

Annu Rev Biomed Eng 2021 Jul;23:29-60

Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA.

Photoactive agents are promising complements for both early diagnosis and targeted treatment of cancer. The dual combination of diagnostics and therapeutics is known as theranostics. Photoactive theranostic agents are activated by a specific wavelength of light and emit another wavelength, which can be detected for imaging tumors, used to generate reactive oxygen species for ablating tumors, or both. Read More

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Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial.

Oncologist 2021 Jul 13. Epub 2021 Jul 13.

Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing, People's Republic of China.

Lessons Learned: Administration of autologous invariant natural killer T (iNKT) cells was safe and well-tolerated in patients with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage B/C). Expanded iNKT cells produced T-helper 1-like responses with possible antitumor activity. No severe adverse events were observed in any of the enrolled patients, including one patient who received 10 in vitro-expanded autologous iNKT cells as a single infusion. Read More

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Effector Vγ9Vδ2 T cell response to congenital Toxoplasma gondii infection.

JCI Insight 2021 Jul 13. Epub 2021 Jul 13.

Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles (ULB), Brussels, Belgium.

A major γδ T cell population in human adult blood are the Vγ9Vδ2 T cells that are activated and expanded in a T cell receptor (TCR)-dependent manner by microbe- and endogenous-derived phosphorylated prenyl metabolites (phosphoantigens). Vγ9Vδ2 T cells are also abundant in human fetal peripheral blood, but compared to their adult counterparts they have a distinct developmental origin, are hyporesponsive towards in vitro phosphoantigen exposure and they do not possess a cytotoxic effector phenotype. In order to obtain insight into the role of Vγ9Vδ2 T cells in the human fetus, we investigated their response to in utero infection with the phosphoantigen-producing parasite Toxoplasma gondii (T. Read More

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Lymphocytes subsets in correlation with clinical profile in CVID patients without monogenic defects.

Expert Rev Clin Immunol 2021 Jul 27:1-11. Epub 2021 Jul 27.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Common variable immunodeficiency (CVID) patients experience clinical manifestations rather than recurrent respiratory infections including autoimmunity, enteropathy, and lymphoproliferation. We evaluated the correlation of lymphocyte subpopulations with such manifestations. Twenty-six genetically unsolved CVID patients were subdivided into four phenotypes: infection only (IO), autoimmunity (AI), chronic enteropathy (CE), and lymphoproliferative disorders (LP) and examined for lymphocyte subsets by flow cytometry and TCD4 proliferation by Carboxyfluorescein succinimidyl ester (CFSE) test. Read More

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Quality of life-improving effect of autologous ex vivo expanded cytotoxic and opioid-producing lymphocytes for dogs with cancers.

Vet Immunol Immunopathol 2021 Aug 5;238:110292. Epub 2021 Jul 5.

Department of Advanced Pathobiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan. Electronic address:

Activated lymphocyte therapy is one of the immunotherapies for cancer patients that is expected to prolong life without any adverse effects and maintain satisfactory quality of life (QOL). However, the objective assessment and maintenance of a standardized evaluation of QOL are not easy. We aimed to evaluate activated autologous lymphocyte therapy for cancer dogs using the characteristics of the cultured cells and QOL as perceived by owners. Read More

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A cytokine in turmoil: Transforming growth factor beta in cancer.

Authors:
Alex Boye

Biomed Pharmacother 2021 Jul 13;139:111657. Epub 2021 May 13.

Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana. Electronic address:

Cancer remains one of the debilitating health threats to mankind in view of its incurable nature. Many factors are complicit in the initiation, progression and establishment of cancers. Early detection of cancer is the only window of hope that allows for appreciable management and possible limited survival. Read More

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Endonuclease IV-Regulated DNAzyme Motor for Universal Single-nucleotide Variation Discrimination.

Anal Chem 2021 Jul 8;93(28):9939-9948. Epub 2021 Jul 8.

School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Single-nucleotide variation (SNV) detection plays significant roles in disease diagnosis and treatment. Generally, auxiliary probe, restricted design rules, complicated detection system, and repeated experimental parameter optimization are needed to obtain satisfactory tradeoff between sensitivity and selectivity for SNV discrimination, especially when different mutant sites need to be distinguished. To overcome these limitations, we developed a universal, straightforward, and relatively cheap SNV discrimination strategy, which simultaneously possessed high sensitivity and selectivity. Read More

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Soluble Platelet Release Factors as Biomarkers for Cardiovascular Disease.

Front Cardiovasc Med 2021 21;8:684920. Epub 2021 Jun 21.

Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands.

Platelets are the main players in thrombotic diseases, where activated platelets not only mediate thrombus formation but also are involved in multiple interactions with vascular cells, inflammatory components, and the coagulation system. Although reactivity of platelets provides information on the function of circulating platelets, it is not a full reflection of the activation state, which may be relevant for thrombotic risk assessment in various disease conditions. Therefore, studying release markers of activated platelets in plasma is of interest. Read More

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Large organellar changes occur during mild heat shock in yeast.

J Cell Sci 2021 Jul 7. Epub 2021 Jul 7.

Department for Chemistry and Molecular Biology, University of Gothenburg, Sweden.

When the temperature is increased, the heat shock response is activated to protect the cellular environment. The transcriptomics and proteomics of this process are intensively studied, while information about how the cell responds structurally to heat stress is mostly lacking. Here, Saccharomyces cerevisiae were subjected to a mild continuous heat shock (38°C) and intermittently cryo-immobilized for electron microscopy. Read More

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The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients.

Arthritis Res Ther 2021 Jul 6;23(1):179. Epub 2021 Jul 6.

Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, 999 Phutthamonthon Sai 4 Road, Salaya, Nakhonpathom, 73170, Thailand.

Background: Autoreactive B cells are well recognized as key participants in the pathogenesis of systemic lupus erythematosus (SLE). However, elucidating the particular subset of B cells in producing anti-dsDNA antibodies is limited due to their B cell heterogeneity. This study aimed to identify peripheral B cell subpopulations that display autoreactivity to DNA and contribute to lupus pathogenesis. Read More

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