The coronavirus disease 2019 (COVID-19) pandemic is a public health crisis that has quickly overwhelmed our healthcare system. It has led to significant shortages in personal protective equipment ...(PPE), ventilators, and intensive care unit beds across the nation. As the initial entry point for patients with suspected COVID illness, emergency departments (ED) have had to adapt quickly to prioritize the safety of patients and providers while still delivering optimal, timely patient care. COVID-19 has presented many challenges for the ED that also extend to all inpatient services. Some of these key challenges are the fundamental tasks of communicating with patients in respiratory isolation while minimizing PPE usage and enabling all patients who have been affected by hospitals' visitor restrictions to connect with their families. We discuss the design principles behind implementing a robust in-hospital telehealth system for patient-provider and patient-family communication, provide a review of the strengths and weaknesses of potential videoconferencing options, and deliver concise, step-by-step guides for setting up a secure, low-cost, user-friendly solution that can be rapidly deployed.
Introduction: The advent of checkpoint blockade immunotherapy has revolutionized cancer treatment, but clinical response to immunotherapies is highly heterogeneous among individual patients and ...between cancer types. This represents a challenge to oncologists when choosing specific immunotherapies for personalized medicine. Thus, biomarkers that can predict tumor responsiveness to immunotherapies before and during treatment are invaluable.
Areas covered: We review the latest advances in 'liquid biopsy' biomarkers for noninvasive prediction and in-treatment monitoring of tumor response to immunotherapy, focusing primarily on melanoma and non-small cell lung cancer. We concentrate on high-quality studies published within the last five years on checkpoint blockade immunotherapies, and highlight significant breakthroughs, identify key areas for improvement, and provide recommendations for how these diagnostic tools can be translated into clinical practice.
Expert opinion: The first biomarkers proposed to predict tumor response to immunotherapy were based on PD1/PDL1 expression, but their predictive value is limited to specific cancers or patient populations. Recent advances in single-cell molecular profiling of circulating tumor cells and host cells using next-generation sequencing has dramatically expanded the pool of potentially useful predictive biomarkers. As immunotherapy moves toward personalized medicine, a composite panel of both genomic and proteomic biomarkers will have enormous utility in therapeutic decision-making.
Abstract
During implantation, a symphony of interaction between the trophoblast originated from the trophectoderm of the implanting blastocyst and the endometrium leads to a successful pregnancy. ...Defective interaction between the trophoblast and endometrium often results in implantation failure, pregnancy loss, and a number of pregnancy complications. Owing to ethical concerns of using in vivo approaches to study human embryo implantation, various in vitro culture models of endometrium were established in the past decade ranging from two-dimensional cell-based to three-dimensional extracellular matrix (ECM)/tissue-based culture systems. Advanced organoid systems have also been established for recapitulation of different cellular components of the maternal–fetal interface, including the endometrial glandular organoids, trophoblast organoids and blastoids. However, there is no single ideal model to study the whole implantation process leaving more research to be done pursuing the establishment of a comprehensive in vitro model that can recapitulate the biology of trophoblast-endometrium interaction during early pregnancy. This would allow us to have better understanding of the physiological and pathological process of trophoblast-endometrium interaction during implantation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The maternal immune system needs to tolerate the semi-allogeneic fetus in pregnancy. The adaptation occurs locally at the maternal-fetal interface as well as systemically through the maternal ...circulation. Failure to tolerate the paternal antigens may result in pregnancy complications, such as pregnancy loss and pre-eclampsia. However, the mechanism that regulates maternal immune tolerance, especially at the systemic level, is still an enigma. Here we report that the first-trimester placenta-derived exosomes (pEXOs) contribute to maternal immune tolerance by reprogramming the circulating monocytes.
pEXOs predominantly target monocytes and pEXO-educated monocytes exhibit an immunosuppressive phenotype as demonstrated by reduced expression of marker genes for monocyte activation, T-cell activation and antigen-process/presentation at the transcriptomic level. They also have a greater propensity towards M2 polarization when compared to the monocytes without pEXO treatment. The inclusion of pEXOs in a monocyte-T-cell coculture model significantly reduces proliferation of the T helper cells and cytotoxic T cells and elevates the expansion of regulatory T cells. By integrating the microRNAome of pEXO and the transcriptomes of pEXO-educated monocytes as well as various immune cell functional assays, we demonstrate that the pEXO-derived microRNA miR-29a-3p promotes the expression of programmed cell death ligand-1, a well-known surface receptor that suppresses the adaptive immune system, by down-regulation of phosphatase and tensin homolog in monocytes.
This is the first report to show how human pEXO directly regulates monocyte functions and its molecular mechanism during early pregnancy. The results uncover the importance of pEXO in regulating the maternal systemic immune response during early pregnancy by reprogramming circulating monocytes. The study provides the basis for understanding the regulation of maternal immune tolerance to the fetal allograft.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on the mechanisms that regulate the activity and properties of Pol δ in DNA repair and ...replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ binding proteins, polymerase delta interaction protein 46 (PDIP46) and polymerase delta interaction protein 38 (PDIP38), both of which are multi-functional proteins. PDIP46 is a novel activator of Pol δ4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol δ3 and Pol δ4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the spliceosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, mouse double minute 2 homolog (Mdm2) alternative splicing and the regulation of the NADPH oxidase 4 (Nox4).
MicroRNAs interact with multiple mRNAs resulting in their degradation and/or translational repression. This report used the delayed implantation model to determine the role of miRNAs in blastocysts. ...Dormant blastocysts in delayed implanting mice were activated by estradiol. Differential expression of 45 out of 238 miRNAs examined was found between the dormant and the activated blastocysts. Five of the nine members of the microRNA lethal-7 (let-7) family were down-regulated after activation. Human blastocysts also had a low expression of let-7 family. Forced-expression of a family member, let-7a in mouse blastocysts decreased the number of implantation sites (let-7a: 1.1±0.4; control: 3.8±0.4) in vivo, and reduced the percentages of blastocyst that attached (let-7a: 42.0±8.3%; control: 79.0±5.1%) and spreaded (let-7a: 33.5±2.9%; control: 67.3±3.8%) on fibronectin in vitro. Integrin-β3, a known implantation-related molecule, was demonstrated to be a target of let-7a by 3'-untranslated region reporter assay in cervical cancer cells HeLa, and Western blotting in mouse blastocysts. The inhibitory effect of forced-expression of let-7a on blastocyst attachment and outgrowth was partially nullified in vitro and in vivo by forced-expression of integrin-β3. This study provides the first direct evidence that let-7a is involved in regulating the implantation process partly via modulation of the expression of integrin-β3.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A common bioengineering strategy to add function to a given molecule is by conjugation of a new moiety onto that molecule. Adding multiple functions in this way becomes increasingly challenging and ...leads to composite molecules with larger molecular weights. In this review, we attempt to gain a new perspective by looking at this problem in reverse, by examining nature’s strategies of multiplexing different functions into the same pleiotropic molecule using emerging analysis techniques such as machine learning. We concentrate on examples from the innate immune system, which employs a finite repertoire of molecules for a broad range of tasks. An improved understanding of how diverse functions are multiplexed into a single molecule can inspire new approaches for the deterministic design of multifunctional molecules.
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IJS, KILJ, NUK, PNG, UL, UM
Diversity of α-helical host defense peptides (αHDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure–function relationships ...among αHDPs is inherently difficult, even for artificial-intelligence–based methods that seek multifactorial trends rather than foundational principles. Here, bioinformatic and pattern recognition methods were applied to identify a unifying signature of eukaryotic αHDPs derived from amino acid sequence, biochemical, and three-dimensional properties of known αHDPs. The signature formula contains a helical domain of 12 residues with a mean hydrophobic moment of 0.50 and favoring aliphatic over aromatic hydrophobes in 18-aa windows of peptides or proteins matching its semantic definition. The holistic α-core signature subsumes existing physicochemical properties of αHDPs, and converged strongly with predictions of an independent machine-learning–based classifier recognizing sequences inducing negative Gaussian curvature in target membranes. Queries using the α-core formula identified 93% of all annotated αHDPs in proteomic databases and retrieved all major αHDP families. Synthesis and antimicrobial assays confirmed efficacies of predicted sequences having no previously known antimicrobial activity. The unifying α-core signature establishes a foundational framework for discovering and understanding αHDPs encompassing diverse structural and mechanistic variations, and affords possibilities for deterministic design of antiinfectives.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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