Type 2 diabetes is associated with increased circulating levels of 3-hydroxydecanoate activating GPR84 and neutrophil migration

iScience

2022 Nov 01

Mikkelsen, R;Arora, T;Trošt, K;Dmytriyeva, O;Jensen, S;Meijnikman, A;Olofsson, L;Lappa, D;Aydin, Ö;Nielsen, J;Gerdes, V;Moritz, T;van de Laar, A;de Brauw, M;Nieuwdorp, M;Hjorth, S;Schwartz, T;Bäckhed, F;
| DOI: 10.1016/j.isci.2022.105683

Obesity and diabetes are associated with inflammation and altered plasma levels of several metabolites, which may be involved in disease progression. Some metabolites can activate G protein-coupled receptors (GPCRs) expressed on immune cells where they can modulate metabolic inflammation. Here we find that 3-hydroxydecanoate is enriched in the circulation of obese individuals with type 2 diabetes (T2D) compared with non-diabetic controls. Administration of 3-hydroxydecanoate to mice promotes immune cell recruitment to adipose tissue, which was associated with adipose inflammation and increased fasting insulin levels. Furthermore, we demonstrate that 3-hydroxydecanoate stimulates migration of primary human and mouse neutrophils, but not monocytes, through GPR84 and Gαi signaling in vitro. Our findings indicate that 3-hydroxydecanoate is a T2D-associated metabolite that increases inflammatory responses and may contribute to the chronic inflammation observed in diabetes.

Spatiotemporal Omics-Refining the landscape of precision medicine

Life Medicine

2022 Nov 14

Zhang, J;Yin, J;Heng, Y;Xie, K;Chen, A;Amit, I;Bian, X;Xu, X;
| DOI: 10.1093/lifemedi/lnac053

Current streamline of precision medicine uses histomorphological and molecular information to indicate individual phenotypes and genotypes to achieve optimal outcome of treatment. The knowledge of detected mutations and alteration can hardly describe molecular interaction and biological process which can finally be manifested as a disease. With molecular diagnosis revising the modalities of disease, there is a trend in precision medicine to apply multi-omic and multi-dimensional information to decode tumors, regarding heterogeneity, pathogenesis, prognosis, etc. Emerging state-of-art spatiotemporal omics provides a novel vision for in discovering clinicopathogenesis associated findings, some of which show a promising potential to be translated to facilitate clinical practice. Here, we summarize the available spatiotemporal omic technologies and algorithms, highlight the novel scientific findings and explore potential applications in the clinical scenario. Spatiotemporal omics present the ability to provide impetus to rewrite clinical pathology and to answer outstanding clinical questions. This review emphasizes the novel vision of spatiotemporal omics to refine the landscape of precision medicine in the clinic.

SCAMPR, a single-cell automated multiplex pipeline for RNA quantification and spatial mapping

Cell reports methods

2022 Oct 24

Ali Marandi Ghoddousi, R;Magalong, VM;Kamitakahara, AK;Levitt, P;
PMID: 36313803 | DOI: 10.1016/j.crmeth.2022.100316

Spatial gene expression, achieved classically through in situ hybridization, is a fundamental tool for topographic phenotyping of cell types in the nervous system. Newly developed techniques allow for visualization of multiple mRNAs at single-cell resolution and greatly expand the ability to link gene expression to tissue topography, yet there are challenges in efficient quantification and analysis of these high-dimensional datasets. We have therefore developed the single-cell automated multiplex pipeline for RNA (SCAMPR), facilitating rapid and accurate segmentation of neuronal cell bodies using a dual immunohistochemistry-RNAscope protocol and quantification of low- and high-abundance mRNA signals using open-source image processing and automated segmentation tools. Proof of principle using SCAMPR focused on spatial mapping of gene expression by peripheral (vagal nodose) and central (visual cortex) neurons. The analytical effectiveness of SCAMPR is demonstrated by identifying the impact of early life stress on gene expression in vagal neuron subtypes.

Nasopharyngeal Carcinoma Ecology Theory: Cancer as Multidimensional Spatiotemporal “Unity of Ecology and Evolution” Pathological Ecosystem

Preprint

2022 Oct 17

Luo, W;
| DOI: 10.20944/preprints202210.0226.v1

Nasopharyngeal carcinoma (NPC) is generally regarded as a genetic disease with diverse extent of intertumor and intratumor heterogeneity. Here we propose that, NPC is not only a genetic disease; it could be conceptualized as a multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem. In the text, we first discuss NPC cells an invasive species and its metastasis as a multidirectional ecological dispersal, which consisting of four interdependent parts: primary ecosystem, circulating ecosystem, metastatic ecosystem and multidirectional ecosystem. We then interpreter the foundational ecological principles to understand NPC progression. The model of “mulberry-fish-ponds” can well illustrate the dynamic reciprocity of cancer ecosystem. Subsequently, we demonstrate that tumor-host interface is the ecological transition zone in cancers, and tumor buddings should be recognized as ecological islands separated from the mainland. Selection driving factors and ecological therapy including hyperthermia for NPC patients, and future perspectives of “ecological pathology”, “multidimensional spatiotemporal tumoriecology” and “integrated tumoriecology” are also pointed out. We advance that “nothing in cancer evolution or ecology makes sense except in the light of the other”. The essence of NPC and other human neoplasms should be pathological an “unity of ecology and evolution”. The establishment of “NPC ecology” might open up a new horizon, and provide a comprehensive framework for our understanding of the complex progression of this disease and development of potential preventive and therapeutic strategies for patients.

Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43- meta-analysis and interactive graphical database

Disease models & mechanisms

2022 Sep 01

Cao, MC;Scotter, EL;
PMID: 35946434 | DOI: 10.1242/dmm.049418

TDP-43 proteinopathy is the major pathology in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal dementia (FTD). Mounting evidence implicates loss of normal TDP-43 RNA-processing function as a key pathomechanism. However, the RNA targets of TDP-43 differ by report, and have never been formally collated or compared between models and disease, hampering understanding of TDP-43 function. Here, we conducted re-analysis and meta-analysis of publicly available RNA-sequencing datasets from six TDP-43-knockdown models, and TDP-43-immunonegative neuronal nuclei from ALS/FTD brain, to identify differentially expressed genes (DEGs) and differential exon usage (DEU) events. There was little overlap in DEGs between knockdown models, but PFKP, STMN2, CFP, KIAA1324 and TRHDE were common targets and were also differentially expressed in TDP-43-immunonegative neurons. DEG enrichment analysis revealed diverse biological pathways including immune and synaptic functions. Common DEU events in human datasets included well-known targets POLDIP3 and STMN2, and novel targets EXD3, MMAB, DLG5 and GOSR2. Our interactive database (https://www.scotterlab.auckland.ac.nz/research-themes/tdp43-lof-db/) allows further exploration of TDP-43 DEG and DEU targets. Together, these data identify TDP-43 targets that can be exploited therapeutically or used to validate loss-of-function processes. This article has an associated First Person interview with the first author of the paper.

On diabetic foot ulcer knowledge gaps, innovation, evaluation, prediction markers, and clinical needs

Journal of Diabetes and its Complications

2022 Sep 01

Schmidt, B;Holmes, C;Najarian, K;Gallagher, K;Haus, J;Shadiow, J;Ye, W;Ang, L;Burant, A;Baker, N;Katona, A;Martin, C;Pop-Busui, R;
| DOI: 10.1016/j.jdiacomp.2022.108317

Diabetic foot ulcers (DFUs) remain a very prevalent and challenging complication of diabetes worldwide due to high morbidity, high risks of lower extremity amputation and associated mortality. Despite major advances in diabetes treatment in general, there is a paucity of FDA approved technologies and therapies to promote successful healing. Furthermore, accurate biomarkers to identify patients at risk of non-healing and monitor response-to-therapy are significantly lacking. To date, research has been slowed by a lack of coordinated efforts among basic scientists and clinical researchers and confounded by non-standardized heterogenous collection of biospecimen and patient associated data. Novel technologies, especially those in the single and ‘multiomics’ arena, are being used to advance the study of diabetic foot ulcers but require pragmatic study design to ensure broad adoption following validation. These high throughput analyses offer promise to investigate potential biomarkers across wound trajectories and may support information on wound healing and pathophysiology not previously well understood. Additionally, these biomarkers may be used at the point-of-care. In combination with national scalable research efforts, which seek to address the limitations and better inform clinical practice, coordinated and integrative insights may lead to improved limb salvage rates.

Chemical Effects on Breast Development, Function, and Cancer Risk: Existing Knowledge and New Opportunities

Current environmental health reports

2022 Aug 19

Kay, JE;Cardona, B;Rudel, RA;Vandenberg, LN;Soto, AM;Christiansen, S;Birnbaum, LS;Fenton, SE;
PMID: 35984634 | DOI: 10.1007/s40572-022-00376-2

Population studies show worrisome trends towards earlier breast development, difficulty in breastfeeding, and increasing rates of breast cancer in young women. Multiple epidemiological studies have linked these outcomes with chemical exposures, and experimental studies have shown that many of these chemicals generate similar effects in rodents, often by disrupting hormonal regulation. These endocrine-disrupting chemicals (EDCs) can alter the progression of mammary gland (MG) development, impair the ability to nourish offspring via lactation, increase mammary tissue density, and increase the propensity to develop cancer. However, current toxicological approaches to measuring the effects of chemical exposures on the MG are often inadequate to detect these effects, impairing our ability to identify exposures harmful to the breast and limiting opportunities for prevention. This paper describes key adverse outcomes for the MG, including impaired lactation, altered pubertal development, altered morphology (such as increased mammographic density), and cancer. It also summarizes evidence from humans and rodent models for exposures associated with these effects. We also review current toxicological practices for evaluating MG effects, highlight limitations of current methods, summarize debates related to how effects are interpreted in risk assessment, and make recommendations to strengthen assessment approaches. Increasing the rigor of MG assessment would improve our ability to identify chemicals of concern, regulate those chemicals based on their effects, and prevent exposures and associated adverse health effects.

Pathophysiology of Nociception and Rare Genetic Disorders with Increased Pain Threshold or Pain Insensitivity

Pathophysiology : the official journal of the International Society for Pathophysiology

2022 Aug 02

Cascella, M;Muzio, MR;Monaco, F;Nocerino, D;Ottaiano, A;Perri, F;Innamorato, MA;
PMID: 35997391 | DOI: 10.3390/pathophysiology29030035

Pain and nociception are different phenomena. Nociception is the result of complex activity in sensory pathways. On the other hand, pain is the effect of interactions between nociceptive processes, and cognition, emotions, as well as the social context of the individual. Alterations in the nociceptive route can have different genesis and affect the entire sensorial process. Genetic problems in nociception, clinically characterized by reduced or absent pain sensitivity, compose an important chapter within pain medicine. This chapter encompasses a wide range of very rare diseases. Several genes have been identified. These genes encode the Nav channels 1.7 and 1.9 (SCN9A, and SCN11A genes, respectively), NGFβ and its receptor tyrosine receptor kinase A, as well as the transcription factor PRDM12, and autophagy controllers (TECPR2). Monogenic disorders provoke hereditary sensory and autonomic neuropathies. Their clinical pictures are extremely variable, and a precise classification has yet to be established. Additionally, pain insensitivity is described in diverse numerical and structural chromosomal abnormalities, such as Angelman syndrome, Prader Willy syndrome, Chromosome 15q duplication syndrome, and Chromosome 4 interstitial deletion. Studying these conditions could be a practical strategy to better understand the mechanisms of nociception and investigate potential therapeutic targets against pain.

Primary Cutaneous Lymphoma: Recommendations for Clinical Trial Design and Staging Update from the ISCL, USCLC, and EORTC

Blood

2021 Nov 10

Olsen, EA;Whittaker, S;Willemze, R;Pinter-Brown, L;Foss, FM;Geskin, LJ;Schwartz, LH;Horwitz, SM;Guitart, J;Zic, J;Kim, YH;Wood, GS;Duvic, M;Ai, WZ;Girardi, M;Gru, A;Guenova, E;Hodak, E;Hoppe, RT;Kempf, W;Kim, EJ;Lechowicz, MJ;Ortiz-Romero, PL;Papadavid, E;Quaglino, P;Pittelkow, MR;Prince, HM;Sanches, JA;Sugaya, M;Vermeer, MH;Zain, J;Knobler, R;Stadler, R;Bagot, M;Scarisbrick, JJ;
PMID: 34758074 | DOI: 10.1182/blood.2021012057

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome (MF/SS), the most common type of PCL, none exist for the other PCLs. In addition, staging in the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

An introduction to spatial transcriptomics for biomedical research

Genome medicine

2022 Jun 27

Williams, CG;Lee, HJ;Asatsuma, T;Vento-Tormo, R;Haque, A;
PMID: 35761361 | DOI: 10.1186/s13073-022-01075-1

Single-cell transcriptomics (scRNA-seq) has become essential for biomedical research over the past decade, particularly in developmental biology, cancer, immunology, and neuroscience. Most commercially available scRNA-seq protocols require cells to be recovered intact and viable from tissue. This has precluded many cell types from study and largely destroys the spatial context that could otherwise inform analyses of cell identity and function. An increasing number of commercially available platforms now facilitate spatially resolved, high-dimensional assessment of gene transcription, known as 'spatial transcriptomics'. Here, we introduce different classes of method, which either record the locations of hybridized mRNA molecules in tissue, image the positions of cells themselves prior to assessment, or employ spatial arrays of mRNA probes of pre-determined location. We review sizes of tissue area that can be assessed, their spatial resolution, and the number and types of genes that can be profiled. We discuss if tissue preservation influences choice of platform, and provide guidance on whether specific platforms may be better suited to discovery screens or hypothesis testing. Finally, we introduce bioinformatic methods for analysing spatial transcriptomic data, including pre-processing, integration with existing scRNA-seq data, and inference of cell-cell interactions. Spatial -omics methods are already improving our understanding of human tissues in research, diagnostic, and therapeutic settings. To build upon these recent advancements, we provide entry-level guidance for those seeking to employ spatial transcriptomics in their own biomedical research.

LB981 Pandemic associated chilblain-like lesions result from an inducible type 1 interferon response to SARS-CoV-2

Journal of Investigative Dermatology

2022 Aug 01

Arkin, L;Costa da Silva, A;Mays, J;
| DOI: 10.1016/j.jid.2022.05.1004

Chilblain-like lesions (CLL), known in the lay press as “COVID toes,” increased significantly during the COVID-19 pandemic. The phenotypic similarity of chilblains in the monogenic type 1 interferonopathies, coupled with the consistent clinical phenotype across multiple countries and temporospatial association with COVID-19 spread, suggest a SARS-CoV-2 triggered immune phenomenon. Yet direct evidence of this relationship has been limited due to low rates of SARS-CoV-2 positivity utilizing conventional testing. We prospectively enrolled a cohort of 79 patients with CLL across 4 waves of the SARS-CoV-2 pandemic in Wisconsin collecting serial blood samples and lesional skin biopsies. Immunophenotyping including the type 1 interferon (IFN-1) signature was investigated utilizing multiplex immunohistochemistry in affected tissue. Proteomics and RNA sequencing were performed on the peripheral blood at serial time points. RNAscope for S gene and depositional immunohistochemistry for evidence of SARS-CoV-2 were performed on tissue. Antibody responses and T-cell specific responses to SARS-CoV-2 were performed and an animal model (golden hamster) provided mechanistic evidence of dissemination of viral RNA to acral sites with local IFN-1 activation. Our results support an inducible local and peripheral IFN-1 signature, which abrogates within weeks, with evidence of viral SARS-CoV-2 RNA as the trigger.

Genetics at the Cell Level

Handbook of Genetic Diagnostic Technologies in Reproductive Medicine

2022 May 10

Lorenzi, V;Vento-Tormo, R;
| DOI: 10.1201/9781003024941-2

The Human Cell Atlas (HCA) is an international consortium established at the end of 2016 with the mission of mapping and characterizing all cells in the human body in terms of their distinctive patterns of gene expression, physiological states, and location (Rozenblatt-Rosen et al., 2017); (Regev et al., 2017) (http://www.humancellatlas.org" xmlns:xlink="http://www.w3.org/1999/xlink">www.humancellatlas.org). It is an open and collaborative initiative, bringing together experts across multiple disciplines, and is meant to progress in phases. Recently, the first maps focused on specific organs and tissues (Ordovas-Montanes et al., 2018; Vento-Tormo et al., 2018; Popescu et al., 2019; Ramachandran et al., 2019; Smillie et al., 2019; Stewart et al., 2019; Vieira Braga et al., 2019) have laid the foundations for further work aimed at completing the atlas to include at least ten billion cells that fully represent the world's diversity.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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