Publications by authors named "Martin Steinhoff"

192 Publications

Vergleichende Metaanalyse zur Behandlung atropher Aknenarben mit Erbium-Laser versus CO -Laser.

J Dtsch Dermatol Ges 2021 Nov;19(11):1559-1570

Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.

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http://dx.doi.org/10.1111/ddg.14546_gDOI Listing
November 2021

Sanguinarine mediated apoptosis in Non-Small Cell Lung Cancer via generation of reactive oxygen species and suppression of JAK/STAT pathway.

Biomed Pharmacother 2021 Dec 28;144:112358. Epub 2021 Oct 28.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar. Electronic address:

Effective treatment of lung cancer remains a significant clinical challenge due to its multidrug resistance and side effects of the current treatment options. The high mortality associated with this malignancy indicates the need for new therapeutic interventions with fewer side effects. Natural compounds offer various benefits such as easy access, minimal side effects, and multi-molecular targets and thus, can prove useful in treating lung cancer. Sanguinarine (SNG), a natural compound, possesses favorable therapeutic potential against a variety of cancers. Here, we examined the underlying molecular mechanisms of SNG in Non-Small Cell Lung Cancer (NSCLC) cells. SNG suppressed cell growth and induced apoptosis via downregulation of the constitutively active JAK/STAT pathway in all the NSCLC cell lines. siRNA silencing of STAT3 in NSCLC cells further confirmed the involvement of the JAK/STAT signaling cascade. SNG treatment increased Bax/Bcl-2 ratio, which contributed to a leaky mitochondrial membrane leading to cytochrome c release accompanied by caspase activation. In addition, we established the antitumor effects of SNG through reactive oxygen species (ROS) production, as inhibiting ROS production prevented the apoptosis-inducing potential of SNG. In vivo xenograft tumor model further validated our in vitro findings. Overall, our study investigated the molecular mechanisms by which SNG induces apoptosis in NSCLC, providing avenues for developing novel natural compound-based cancer therapies.
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http://dx.doi.org/10.1016/j.biopha.2021.112358DOI Listing
December 2021

Comparative appraisal with meta-analysis of erbium vs. CO lasers for atrophic acne scars.

J Dtsch Dermatol Ges 2021 Nov 23;19(11):1559-1568. Epub 2021 Sep 23.

Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.

Recent advances in laser technology allowed the development of systems that improve texture, appearance and pliability of skin in acne scars (AS). Currently, comprehensive comparative studies on the efficacy of the most commonly used fractional systems in AS are lacking. Thus, the aim of this work was to appraise and compare the clinical response to erbium versus CO lasers in AS in the form of a meta-analysis. The databases MEDLINE, EMBASE, Cochrane library were searched. Main clinical outcomes were investigator-reported scar improvement and participant-reported scar improvement. Five studies were included in this meta-analysis. Scar improvement was similar for both types of laser in terms of investigator-reported scar improvement (RR: 0.60 95 % CI: 0.35-1.02) and participant-reported scar improvement (RR: 0.99 95 % CI: 0.79-1.25). A sensitivity analysis that excluded studies with high risk of bias found the CO lasers to be superior to the erbium lasers (RR: 0.47 95 % CI: 0.24-0.93): However, the subgroup analysis showed the CO laser not to be significantly different from either the non-ablative erbium (RR: 0.65 95 % CI: 0.34-1.24) or the ablative erbium laser (RR: 0.60 95 % CI: 0.35-1.02). The CO laser produced a slightly greater clinical response compared to the erbium lasers based on the physician's assessment. Overall, the two devices do not differ largely in terms of efficacy but may be complementary, with each resurfacing laser better suited for different clinical tasks.
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http://dx.doi.org/10.1111/ddg.14546DOI Listing
November 2021

Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis.

Brain Behav Immun 2021 Nov 13;98:28-39. Epub 2021 Aug 13.

School of Life Sciences, Henan University, China; National Institute for Cellular Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin 9, Ireland. Electronic address:

The clinical significance and regulators of IL-13Rα2 in itch and atopic dermatitis (AD) remain unclear. To identify disease-driven regulatory circuits of IL-13Rα2, transcriptomic/pathological analysis was performed in skin from patients with AD, psoriasis, healthy subjects, and murine AD model. Functionality was investigated in sensory neurons, keratinocytes and animal model, by using knockdown (KD), calcium imaging, RNA-seq, cytokine arrays, pharmacological assays, and behavioural investigations. In our study, an upregulated IL-13Rα2 expression was revealed in skin of AD patients, but not psoriasis, in a disease activity-dependent manner. In cultured human keratinocytes, IL-13 increased IL-13Rα2 transcription levels, and this were downregulated by IL-13Rα1KD. IL-13Rα2KD reduced transcription levels of EDNRA, CCL20, CCL26. In contrast, sensory neuron-derived IL-13Rα2 was upregulated by TLR2 heterodimer agonists, Pam3CSK4 and FSL-1. In a mouse cheek model, pre-administration of Pam3CSK4 and FSL-1 enhanced IL-13-elicited scratching behaviour. Consistently, in cultured sensory neurons Pam3CSK4 enhanced IL-13-elicted calcium transients, increased number of responders, and orchestrated chemerin, CCL17 and CCL22 release. These release was inhibited by IL-13Rα2KD. Collectively, IL-13 regulates keratinocyte-derived IL-13Rα2 and TLR2 to modulate neuronal IL-13Rα2, thereby promoting neurogenic inflammation and exacerbating AD and itch. Thus, the cutaneous IL-13-IL-13Rα2 and neuronal TLR2-IL-13Rα2 pathway represent important targets to treat AD and itch.
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http://dx.doi.org/10.1016/j.bbi.2021.08.211DOI Listing
November 2021

Th2 Modulation of Transient Receptor Potential Channels: An Unmet Therapeutic Intervention for Atopic Dermatitis.

Front Immunol 2021 30;12:696784. Epub 2021 Jun 30.

School of Life Sciences, Henan University, Kaifeng, China.

Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.
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http://dx.doi.org/10.3389/fimmu.2021.696784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278285PMC
June 2021

F-box proteins in cancer stemness: An emerging prognostic and therapeutic target.

Drug Discov Today 2021 Dec 12;26(12):2905-2914. Epub 2021 Jul 12.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar.

Cancer is a complex heterogenic disease with significant therapeutic challenges. The presence of cancer stem cells (CSCs) in cancer tissue orchestrates tumor growth, progression, and metastasis, the tumor heterogeneity, disease relapse, and therapeutic resistance. Hence, it is imperative to explore how progenitor or cancer-initiating cells acquire stemness features and reprogram different biological mechanisms to maintain their sustained oncogenicity. Interestingly, deregulation of F-box proteins (FBPs) is crucial for cancer stemness features, including drug resistance and disease relapse. In this review, we highlight recent updates on the clinical significance of targeting FBPs in cancer therapy, with emphasis on eliminating CSCs and associated therapeutic challenges. Moreover, we also discuss novel strategies for the selective elimination of CSCs by targeting FBPs.
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http://dx.doi.org/10.1016/j.drudis.2021.07.006DOI Listing
December 2021

In vitro Interleukin-7 treatment partially rescues MAIT cell dysfunction caused by SARS-CoV-2 infection.

Sci Rep 2021 07 8;11(1):14090. Epub 2021 Jul 8.

Department of Human Genetics, Research Branch, Sidra Medicine, 26999, Doha, Qatar.

MAIT cells have been shown to be activated upon several viral infections in a TCR-independent manner by responding to inflammatory cytokines secreted by antigen-presenting cells. Recently, a few studies have shown a similar activation of MAIT cells in response to severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. In this study, we investigate the effect of SARS-CoV-2 infection on the frequency and phenotype of MAIT cells by flow cytometry, and we test in vitro stimulation conditions on the capacity to enhance or rescue the antiviral function of MAIT cells from patients with coronavirus disease 2019 (COVID-19). Our study, in agreement with recently published studies, confirmed the decline in MAIT cell frequency of hospitalized donors in comparison to healthy donors. MAIT cells of COVID-19 patients also had lower expression levels of TNF-alpha, perforin and granzyme B upon stimulation with IL-12 + IL-18. 24 h' incubation with IL-7 successfully restored perforin expression levels in COVID-19 patients. Combined, our findings support the growing evidence that SARS-CoV-2 is dysregulating MAIT cells and that IL-7 treatment might improve their function, rendering them more effective in protecting the body against the virus.
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http://dx.doi.org/10.1038/s41598-021-93536-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266862PMC
July 2021

Light-based therapies in the management of rosacea: a systematic review with meta-analysis.

Int J Dermatol 2021 Jun 5. Epub 2021 Jun 5.

Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.

Background: The current scenario and position of laser and light-based therapies (LLBT) in the therapeutic rosacea scheme are lacking evidence-based recommendations and comparisons on efficacy and tolerability among different devices. This article aimed to systematically compare the efficacy, acceptability, and tolerability of the pulsed dye laser (PDL) versus other devices.

Method: A literature search was conducted in March 2020. Four domains were analyzed throughout the following six outcomes: Spectrophotometer erythema index and percentage of reduction for background erythema, telangiectasia grading scale for telangiectasias, visual analog scale for pain, and physician's assessment and patient's satisfaction for treatment success.

Results: Our search yielded 423 potentially relevant studies. After removing the excluded and duplicated records, 12 records were assessed for eligibility in the meta-analysis. Erythema (RR:0.38 95%CI: -0.20-0.95), telangiectasias (RR:0.54 95%CI: -0.87-1.94), and the treatment success throughout the physician's assessment (RR:1.23 95%CI: 0.74-2.04) and the patient's satisfaction (RR:1.15 95%CI: 0.73-1.82) were not significantly different between pulsed dye laser and other LLBT. In the pain domain, PDL was as painful as other LLBT (RR:-0.23 95%CI: -0.96-0.49) but more painful than neodymium: yttrium-aluminum-garnet laser (RR:0.84 95%CI: 0.53-1.14) and less than intense pulsed light (RR:-1.18 95%CI: -1.56-0.80).

Conclusion: This work based on previously published literature demonstrates that the quality of evidence to support any recommendation on LLBT in rosacea is low-to-moderate. Among all the available devices, PDL holds the most robust evidence, although in the meta-analysis the effectiveness was comparable to other LLBT, such as neodymium: yttrium-aluminum-garnet laser (Nd-YAG) or IPL.
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http://dx.doi.org/10.1111/ijd.15680DOI Listing
June 2021

Effectiveness of ustekinumab in patients with atopic dermatitis: analysis of real-world evidence.

J Dermatolog Treat 2021 Aug 25:1-6. Epub 2021 Aug 25.

Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.

Introduction: Atopic dermatitis (AD) is a common chronic inflammatory condition. Ustekinumab is a human monoclonal antibody approved for psoriasis, that targets the interleukin (IL)-12 and IL-23, and it may also play a role in AD. Administration of ustekinumab in AD is presented in anecdotal reports with conflicting results. Our aim was to evaluate the precise value of ustekinumab on AD.

Material And Method: We systematically reviewed published data involving AD treated with ustekinumab. The main outcome was clinical improvement. We classified this in three categories: 'complete response,' 'partial response,' and 'no response.' A multivariant model was used to assess the effectiveness and the following potential predictive factors: gender, age, duration of AD, asthma, previous use of biologics, previous systemic therapies,levels of IgE and duration of ustekinumab therapy.

Results: Data on 23 patients were analyzed. Complete AD remission was reported in 8 patients (34.8%), while the absence of response was observed also in 8 patients (34.8%). Partial response was reported in 7 patients (30.4%). No differences were observed with the predictive factors.

Conclusion: The IL-12/23 pathway is likely not an attractive target for AD. Other effective treatments are available and should be prioritized with a good safety profile. WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?Administration of ustekinumab in AD (atopic dermatitis) has been presented in anecdotical reports with conflicting results.WHAT DOES THIS STUDY ADD?This work presents the largest cohort of AD patients treated with ustekinumab in a real-world setting.Ustekinumab resulted in similar rates of complete, partial, and negative responses.Our findings demonstrate the IL-12/23 pathway is not an attractive target in AD.More novel and effective treatments for AD are available and should be prioritized.The impact of anti-IL-12/IL-23p40 therapy in AD is still unclarified due to limited controlled trials.
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http://dx.doi.org/10.1080/09546634.2021.1914315DOI Listing
August 2021

Neurokinin 1 Receptor Antagonists for Pruritus.

Drugs 2021 Apr 6;81(6):621-634. Epub 2021 Mar 6.

Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar.

Pruritus, commonly known as itch, is a very common symptom in numerous dermatological disorders and systemic diseases. It can manifest as acute, or when lasting longer than 6 weeks, it is considered chronic and can lead to significant distress and reduced quality-of-life of those suffering. Current therapeutics are limited and are lacking in efficacy, and the development of more effective treatments is needed. The neurokinin 1 receptor (NK1R) antagonists are a novel class of drugs that possess several properties such as antidepressant, anxiolytic and antiemetic activities. Recently, several studies have described the antipruritic activity of NK1R antagonists for treating chronic pruritus. In this review we outline the pathogenesis of chronic pruritus, the mechanism by which the neuropeptide substance P (SP) and its receptor NK1R may be targeted to inhibit pruritic activity, and the efficacy and tolerability of NK1R antagonists, which have been, or are currently being investigated for treating conditions where chronic pruritus is a major symptom. Increasing evidence from ongoing and completed studies demonstrates the importance of SP and NK1R signalling in mediating pruritic activity. Several NK1R antagonists have shown significant antipruritic activity and thus targeting the SP-NK1R pathway may provide a therapeutic option for treating chronic pruritus of certain origin/s in the foreseeable future.
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http://dx.doi.org/10.1007/s40265-021-01478-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102458PMC
April 2021

Interleukin-31: The "itchy" cytokine in inflammation and therapy.

Allergy 2021 10 16;76(10):2982-2997. Epub 2021 Mar 16.

Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar.

The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper-reactivity. In AD, IL-31 has been identified as one of the main "drivers" of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. T 2 cells play a central role in AD and release high levels of T 2-associated cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL-31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL-31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future.
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http://dx.doi.org/10.1111/all.14791DOI Listing
October 2021

Efficacy and predictive factors of cyclosporine A in alopecia areata: a systematic review with meta-analysis.

J Dermatolog Treat 2021 Jul 26:1-9. Epub 2021 Jul 26.

Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.

Introduction: Drugs for alopecia areata (AA) can induce hair regrowth, but do not change the disease course. Dual properties of cyclosporine A (CsA) as hypetrichotic and immunosuppressive agent have encouraged use in AA. We aimed to determine the most meaningful efficacy of CsA and reveal features helping enhance its efficacy and reduce relapses.

Method: Efficacy of CsA and predictive factors were investigated. Cochrane, MEDLINE, Pubmed and Embase databases were searched.

Results: 2,189 papers were retrieved. Based on 344 patients, mean proportion of responders was 73%. CsA monotherapy showed proportion of hair regrowth of 66%, whereas CsA combined with systemic corticosteroids yielded 78%. Overall efficacy in studies with duration of CsA treatment <6 months was: 74% (53-88%), while in those with duration ≥6 months was: 73% (47-89%). Recurrence with CsA monotherapy was 55% (6-96%) whereas when CsA was combined with systemic corticosteroids it was 28% (6-72%).

Conclusion: CsA confers a favorable therapeutic effect and concomitant use of steroids slightly enhances efficacy, but it dramatically decreases relapses. Longer treatments seem to lead to less relapse likelihood, but daily dose does not influence recurrence. Optimal CsA dosage is 5 mg/kg/day in single therapy regimen, whereas it is 3 mg/kg/day in the steroid-associated regimen. KEY POINTS Most treatments for alopecia areata have not been critically evaluated. Current outcomes about the efficacy and relapse rate of cyclosporine A (CsA) are inconsistent and predictive factors about the clinical response are lacking. CsA confers a favorable therapeutic hair regrowth. Longer treatment seems to lead to less likelihood of relapse of AA, but the daily dose does not exert any effect on the recurrence of the disease. The concomitant use of corticosteroids broadly decreases relapses, and it also enhances efficacy. The combination with corticosteroids is the most predictive feature to prevent relapse of AA, followed by the duration of CsA therapy. The daily dose of CsA is the feature with the least or null impact on the clinical course of AA.
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http://dx.doi.org/10.1080/09546634.2021.1886230DOI Listing
July 2021

Bewertung der Wirksamkeit sub-antimikrobieller Dosierungen von Doxycyclin bei Rosacea: Systematische Auswertung von klinischen Studien und Metaanalyse.

J Dtsch Dermatol Ges 2021 Jan;19(1):7-18

Translational Research Institute, Hamad Medical Corporation, Doha, Katar.

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http://dx.doi.org/10.1111/ddg.14247_gDOI Listing
January 2021

Laser and light-based therapies in the management of rosacea: an updated systematic review.

Lasers Med Sci 2021 Aug 3;36(6):1151-1160. Epub 2021 Jan 3.

Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.

Unlike other rosacea therapies which need daily takings or applications over long periods, the edge of lasers and light-based therapies (LLBT) is the limited number of sessions to achieve improvement. The proper selection of the adequate physical device in accordance with the patients' skin features and rosacea-related signs and symptoms should be considered and the management with physical sources should be updated as new data become available. This article reviews and discusses the current use of lasers and light-based therapies in rosacea with reference to all the available literature.This systematic review demonstrates the quality of evidence to support any recommendation on LLBT in rosacea is low-to-moderate. Among all the available devices, PDL holds the most robust evidence. Treatments options should be tailored for each specific clinical scenario as it is unlike that single modality results in complete resolution. Platforms that include two or more devices and combined therapies with topical agents are suitable and they warrant further investigations.
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http://dx.doi.org/10.1007/s10103-020-03200-1DOI Listing
August 2021

TRPV2: A Cancer Biomarker and Potential Therapeutic Target.

Dis Markers 2020 10;2020:8892312. Epub 2020 Dec 10.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

The Transient Receptor Potential Vanilloid type-2 (TRPV2) channel exhibits oncogenicity in different types of cancers. TRPV2 is implicated in signaling pathways that mediate cell survival, proliferation, and metastasis. In leukemia and bladder cancer, the oncogenic activity of TRPV2 was linked to alteration of its expression profile. In multiple myeloma patients, TRPV2 overexpression correlated with bone tissue damage and poor prognosis. In prostate cancer, TRPV2 overexpression was associated with the castration-resistant phenotype and metastasis. Loss or inactivation of TRPV2 promoted glioblastoma cell proliferation and increased resistance to CD95-induced apoptotic cell death. TRPV2 overexpression was associated with high relapse-free survival in triple-negative breast cancer, whereas the opposite was found in patients with esophageal squamous cell carcinoma or gastric cancer. Another link was found between TRPV2 expression and either drug-induced cytotoxicity or stemness of liver cancer. Overall, these findings validate TRPV2 as a prime candidate for cancer biomarker and future therapeutic target.
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http://dx.doi.org/10.1155/2020/8892312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746447PMC
September 2021

Mouse models of atopic dermatitis: a critical reappraisal.

Exp Dermatol 2021 03 9;30(3):319-336. Epub 2021 Jan 9.

Dr. Phillip Frost, Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.

Mouse models for atopic dermatitis (AD) are an indispensable preclinical research tool for testing new candidate AD therapeutics and for interrogating AD pathobiology in vivo. In this Viewpoint, we delineate why, unfortunately, none of the currently available so-called "AD" mouse models satisfactorily reflect the clinical complexity of human AD, but imitate more "allergic" or "irriant" contact dermatitis conditions. This limits the predictive value of AD models for clinical outcomes of new tested candidate AD therapeutics and the instructiveness of mouse models for human AD pathophysiology research. Here, we propose to initiate a rational debate on the minimal criteria that a mouse model should meet in order to be considered relevant for human AD. We suggest that valid AD models should at least meet the following criteria: (a) an AD-like epidermal barrier defect with reduced filaggrin expression along with hyperproliferation, hyperplasia; (b) increased epidermal expression of thymic stromal lymphopoietin (TSLP), periostin and/or chemokines such as TARC (CCL17); (c) a characteristic dermal immune cell infiltrate with overexpression of some key cytokines such as IL-4, IL-13, IL-31 and IL-33; (d) distinctive "neurodermatitis" features (sensory skin hyperinnervation, defective beta-adrenergic signalling, neurogenic skin inflammation and triggering or aggravation of AD-like skin lesions by perceived stress); and (e) response of experimentally induced skin lesions to standard AD therapy. Finally, we delineate why humanized AD mouse models (human skin xenotransplants on SCID mice) offer a particularly promising preclinical research alternative to the currently available "AD" mouse models.
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http://dx.doi.org/10.1111/exd.14270DOI Listing
March 2021

Development of a 43 color panel for the characterization of conventional and unconventional T-cell subsets, B cells, NK cells, monocytes, dendritic cells, and innate lymphoid cells using spectral flow cytometry.

Cytometry A 2020 Dec 18. Epub 2020 Dec 18.

Flow Cytometry Core Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

Although many flow cytometers can analyze 30-50 parameters, it is still challenging to develop a 40+ color panel for the phenotyping of immune cells using fluorochrome conjugated antibodies due to limitations in the availability of spectrally unique fluorochromes that can be excited by the commonly used laser lines (UV, Violet, Blue, Green/Yellow-green, and Red). Spectral flowcytometry is capable of differentiating fluorochromes with significant overlap in the emission spectra, enabling the use of spectrally similar fluorochrome pairs such as Brilliant Blue 515 and FITC in a single panel. We have developed a 43 color panel to characterize most of the immune subsets within the peripheral immune system, including conventional T cells, unconventional T cells such as invariant natural killer T cells (iNKT), Gamma delta (γδ) T-cell subsets (TCR Vδ2, TCR Vγ9) and mucosal-associated invariant T cells (MAIT), B-cell subsets, natural killer (NK) cells, plasmacytoid dendritic cells, dendritic cell subsets, hematopoietic progenitor cells, basophils, and innate lymphoid cell (ILC) subsets (CD117, CRTH2). The panel includes surface markers to analyze activation (CD38, HLA-DR, ICOS/CD278), differentiation (CD45RA, CD27, CD28, CD57), expression of cytokine and chemokine receptors (CD25, CD127, CCR10, CCR6, CCR4, CXCR3, CXCR5, CRTH2/CD294), and co-inhibitory molecules and exhaustion (PD-1, CD223/LAG-3, TIGIT), which enables a deep characterization of PBMCs from peripheral blood. Cells were analyzed on a 5-laser Cytek Aurora and data analysis was done using FlowJo. This panel can help to make a thorough interpretation of immune system, specifically when specimen quantity is low. The panel has not been completely optimized but would rather act as a guide toward the development of a workflow for optimized multicolor immunophenotyping panel.
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http://dx.doi.org/10.1002/cyto.a.24288DOI Listing
December 2020

Exosomes: Emerging Diagnostic and Therapeutic Targets in Cutaneous Diseases.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Skin is the largest human organ and is continuously exposed to various exogenous and endogenous trigger factors affecting body homeostasis. A number of mechanisms, including genetic, inflammatory and autoimmune ones, have been implicated in the pathogenesis of cutaneous diseases. Recently, there has been considerable interest in the role that extracellular vesicles, particularly exosomes, play in human diseases, through their modulation of multiple signaling pathways. Exosomes are nano-sized vesicles secreted by all cell types. They function as cargo carriers shuttling proteins, nucleic acids, lipids etc., thus impacting the cell-cell communications and transfer of vital information/moieties critical for skin homeostasis and disease pathogenesis. This review summarizes the available knowledge on how exosomes affect pathogenesis of cutaneous diseases, and highlights their potential as future targets for the therapy of various skin diseases.
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http://dx.doi.org/10.3390/ijms21239264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730213PMC
December 2020

Dupilumab in prurigo nodularis: a systematic review of current evidence and analysis of predictive factors to response.

J Dermatolog Treat 2020 Dec 3:1-7. Epub 2020 Dec 3.

Hamad Medical Corporation, Translational Research Institute, Doha, Qatar.

Introduction: Dupilumab has been shown effective for prurigo nodularis (PN). However, precise data about efficacy of dupilumab as off-label use in PN is missing. We aggregated current evidence to assess efficacy of dupilumab in PN and to identify possible response predictors.

Material And Methods: Five electronic databases were searched. Our primary outcome was improvement in pruritus measured by numerical rating scale (NRS). We collected data on NRS before (NRSpre) and after (NRSpost) the dupilumab therapy and designed two categorical variables: 'NRS_50' and 'NRS_100' defined as whether one patient reaches 50% and 100% reduction of the NRSpre. Secondary outcomes included: time until patient perceived any improvement (Time_First) and time until patient reported absence of pruritus (Time_Final).

Results: Data on 45 patients from eleven articles were analyzed. The NRSpre was 8.58 ± 1.89 and the NRSpost was 1.78 ± 2.29. Time_First was 10.15 ± 10.56 weeks, while Time_Final was 19.28 ± 13.71 weeks. 22/45 patients (48.88%) presented with complete resolution (NRS_100) and 37/45 patients (82.22%) had itch half dropped (NRS_50). Time_First was significantly longer in subjects that did not reach NRS_100 (13.13 ± 13.77) than in subjects that did (7.34 ± 7.86, = .05). Time_First was significantly longer in atopic dermatitis (AD) patients (16.08 ± 16.18) than in subjects without AD (7.02 ± 5.69, =.01). NRS_50 and NRS_100 presented with a significant association (=.05).

Conclusion: Dupilumab is an effective target-to-treat agent. In comparison with AD, the clinical response to dupilumab initiates later and, two months of therapy are required until significant itch relieves. Complete remission is rarely observed before 4 months of therapy. Notably, AD-related PN patients need longer treatment than non-AD related PN patients to find any relief. Two early signs of improvement are promising predictors of response to dupilumab: The Time_First and NRS_50. Dupilumab has been shown to be an efficacious treatment for prurigo nodularis (PN)However, literature data on this topic are scattered. This work presents the largest cohort of PN patients treated with dupilumab.Our findings demonstrate dupilumab is a novel and effective choiceIn comparison with atopic dermatitis, the clinical response to dupilumab initiates later.Two months of therapy are required until the itch relieves. Complete remission is rarely observed before 4 months of therapy.Atopic dermatitis-related PN patients need more weeks of treatment than non-atopic dermatitis-related PN patients.
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http://dx.doi.org/10.1080/09546634.2020.1853024DOI Listing
December 2020

Evaluation of the efficacy of subantimicrobial dose doxycycline in rosacea: a systematic review of clinical trials and meta-analysis.

J Dtsch Dermatol Ges 2021 01 28;19(1):7-17. Epub 2020 Sep 28.

Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.

Background: Low-dose doxycycline (SDD) is an antimicrobial agent that appears to improve common inflammatory skin diseases. Few data are available regarding the overall effectiveness, appropriate length of treatment and optimal patient selection for rosacea. We therefore reviewed the efficacy of sub-antimicrobial doses of SDD in papulopustular rosacea (PPR) and aimed to determine the most suitable patients for this approach.

Methods: From July to September 2019, we carried out a comprehensive search of literature from five databases, using a combination of "rosacea" AND "doxycycline".

Results: Our search yielded 532 potentially relevant studies. Our meta-analysis showed no significant difference between SDD and a comparator (RR: 1.12, 95 % CI: 0.78-1.62, I =  86 %). Subgroup analysis of studies comparing doxycycline with placebo yielded a clear difference in favor of doxycycline (RR: 1.45, 95 % CI: 1.22-1.72, I =  31 %), while subgroup analysis of studies comparing active drugs revealed no difference between interventions (RR: 0.52, 95 % CI: 0.17-1.63, I =  90 %).

Conclusions: There is strong evidence that SDD is more effective than placebo. However, other drugs such as minocycline or isotretinoin have shown outcomes at least similar to that of SDD. We suggest that the anti-inflammatory properties of SDD may be of more value for mild cases of rosacea than for moderate to severe cases, for which higher (antimicrobial) doses of doxycycline may be a more suitable choice.
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http://dx.doi.org/10.1111/ddg.14247DOI Listing
January 2021

Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin.

Front Oncol 2020 28;10:1744. Epub 2020 Aug 28.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

Colorectal cancer (CRC) forms one of the highest ranked cancer types in the world with its increasing incidence and mortality rates despite the advancement in cancer therapeutics. About 50% of human CRCs are reported to have defective p53 expression resultant of gene mutation often contributing to drug resistance. The current study was aimed to investigate the response of wild-type harboring HCT 116 and mutant harboring HT 29 colon cancer cells to chemotherapeutic drug oxaliplatin (OX) and to elucidate the underlying molecular mechanisms of sensitivity/resistance in correlation to their p53 status. OX inhibited growth of wild-type p53-harboring colon cancer cells via p53/p21-Bax mediated apoptosis. Our study revealed that dysregulated phosphorylation of p53, autophagy as well as cancer stemness attributes the mutant p53-harboring colon cancer cells impaired sensitivity to OX.
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http://dx.doi.org/10.3389/fonc.2020.01744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485421PMC
August 2020

The Unmet Need for Clinical Guidelines on the Management of Patients with Plaque Psoriasis in Africa and the Middle East.

Psoriasis (Auckl) 2020 20;10:23-28. Epub 2020 Aug 20.

Department of Dermatology and Venereology, Ain Shams University, Cairo, Egypt.

Purpose: Dermatologists practicing in African and Middle Eastern countries face numerous challenges when managing patients with plaque psoriasis, especially those with disease in a difficult-to-treat anatomic area or those who are a pediatric, geriatric, or pregnant patient. The publication of comprehensive, up-to-date, region-specific clinical guidelines may help to address some of these challenges and improve outcomes. We conducted a literature review to identify recent guidelines and other publications describing patients with plaque psoriasis in Africa and the Middle East.

Patients And Methods: An online literature search of the PubMed database was conducted to identify publications reporting clinical guidelines and research studies on plaque psoriasis. The search included all articles published from January 2008 to March 2020 inclusive. The titles and abstracts of all search results were screened by a reader to identify those that described patients in Africa or the Middle East.

Results: A total of 145 publications were identified by the literature search and screened by a reader. There were 10 publications that described patients in Africa or the Middle East: 4 research articles, 3 reviews, 2 guidelines, and 1 case study. The 2010 guidelines from South Africa made recommendations for treating plaque psoriasis of varying severity, although without specific recommendations for difficult-to-treat anatomic areas or pediatric, geriatric, or pregnant patients. The 2014 guideline on biologics from Saudi Arabia included recommendations for the use of these agents in patients with plaque psoriasis, including difficult-to-treat anatomic areas and pediatric patients (TNF inhibitors only), but provided no recommendations for pregnant or geriatric patients.

Conclusion: There is an urgent unmet need for comprehensive clinical guidelines on the management of patients with plaque psoriasis in Africa and the Middle East. Region-specific studies on the epidemiology, burden of disease, and the safety and effectiveness of newer pharmacotherapies are needed to support the development of such guidelines.
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http://dx.doi.org/10.2147/PTT.S264431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445502PMC
August 2020

Protease-Activated Receptor-2 Regulates Neuro-Epidermal Communication in Atopic Dermatitis.

Front Immunol 2020 12;11:1740. Epub 2020 Aug 12.

Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States.

Activation of protease-activated receptor-2 (PAR2) has been implicated in inflammation, pruritus, and skin barrier regulation, all characteristics of atopic dermatitis (AD), as well as Netherton syndrome which has similar characteristics. However, understanding the precise role of PAR2 on neuro-immune communication in AD has been hampered by the lack of appropriate animal models. We used a recently established mouse model with epidermal overexpression of PAR2 (PAR2OE) and littermate WT mice to study the impact of increased PAR2 expression in epidermal cells on spontaneous and house dust mite (HDM)-induced skin inflammation, itch, and barrier dysfunction in AD, and . PAR2OE newborns displayed no overt abnormalities, but spontaneously developed dry skin, severe pruritus, and eczema. Dermatological, neurophysiological, and immunological analyses revealed the hallmarks of AD-like skin disease. Skin barrier defects were observed before onset of skin lesions. Application of HDM onto PAR2OE mice triggered pruritus and the skin phenotype. PAR2OE mice displayed an increased density of nerve fibers, increased nerve growth factor and endothelin-1 expression levels, alloknesis, enhanced scratching (hyperknesis), and responses of dorsal root ganglion cells to non-histaminergic pruritogens. PAR2 in keratinocytes, activated by exogenous and endogenous proteases, is sufficient to drive barrier dysfunction, inflammation, and pruritus and sensitize skin to the effects of HDM in a mouse model that mimics human AD. PAR2 signaling in keratinocytes appears to be sufficient to drive several levels of neuro-epidermal communication, another feature of human AD.
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http://dx.doi.org/10.3389/fimmu.2020.01740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435019PMC
April 2021

Role of non-coding RNAs in the progression and resistance of cutaneous malignancies and autoimmune diseases.

Semin Cancer Biol 2020 Jul 25. Epub 2020 Jul 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar.

Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.
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http://dx.doi.org/10.1016/j.semcancer.2020.07.003DOI Listing
July 2020

EGFR/Ras-induced CCL20 production modulates the tumour microenvironment.

Br J Cancer 2020 09 30;123(6):942-954. Epub 2020 Jun 30.

Department of Dermatology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

Background: The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.

Methods: The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo.

Results: Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system.

Conclusion: We propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.
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http://dx.doi.org/10.1038/s41416-020-0943-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493992PMC
September 2020

CAR-T Cell Therapies: An Overview of Clinical Studies Supporting Their Approved Use against Acute Lymphoblastic Leukemia and Large B-Cell Lymphomas.

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Chimeric Antigen Receptor (CAR)-T cell therapy is an exciting development in the field of cancer immunology, wherein immune T-cells from patients are collected, engineered to create 'CAR'-T cells, and infused back into the same patient. Currently, two CAR-T-cell-based therapies, Tisagenlecleucel and Axicabtagene ciloleucel, are approved by FDA for the treatment of hematological malignancies, acute lymphoblastic leukemia and large B-cell lymphomas. Their approval has been a culmination of several phase I and II clinical studies, which are the subject of discussion in this review article. Over the years, CAR-T cells have evolved to be significantly more persistent in patients' blood, resulting in a much-improved clinical response and disease remission. This is particularly significant given that the target patient populations of these therapies are those with relapsed and refractory disease who have often progressed on multiple therapies. Despite the promising clinical results, there are still several challenges that need to be addressed. Of particular note are the associated toxicities exemplified by cytokine release syndrome (CRS) and the neurotoxicity. CRS has been addressed by an FDA-approved therapy of its own-tocilizumab. This article focuses on the progress related to CAR-T therapy: the pertinent clinical studies and their major findings, their associated adverse effects, and future perspective.
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http://dx.doi.org/10.3390/ijms21113906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312930PMC
May 2020

Effects of skin care habits on the development of rosacea: A multi-center retrospective case-control survey in Chinese population.

PLoS One 2020 27;15(4):e0231078. Epub 2020 Apr 27.

Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Background: Certain cosmetic habits may trigger or aggravate rosacea, while there is little published epidemiologic evidence to support this point.

Purpose: To examine if daily skin care habits have an effect on the development of rosacea in Chinese population.

Methods: A multi-center retrospective case-control survey of 1,245 rosacea cases and 1,538 skin-healthy controls was conducted in China. Participants completed the questionnaire comprised of demographic characteristics, socioeconomic data and daily skin care habits. Data were collected retrospectively and analyzed using the chi-square test and t-test. Multivariate logistic regression analyses were used to predict rosacea.

Results: The multivariate logistic regression analysis highlighted some results: Dry, oily or mixed skin (OR = 6.3-6.9, P< .001), the usage of foaming cleanser (OR = 1.45, 95%CI 1.115-1.886, P = .01), make up more than 6 times a week (OR = 2.839, 95%CI 1.962-4.108, P< .001), using facial mask more than 4 times a week (OR = 2.56-3.069, P< .001), facial treatments at beauty salon more than once a week (OR = 4.946, 95%CI 2.005-12.198, P = .0018) and using beauty salon products (OR = 2.334, 95%CI 1.435-3.976, P = .0018) are positively correlated with the development of rosacea. Using of moisturizing products (OR = 0.602, 95%CI 0.386-0.983, P = .035) and sunscreen cream (OR = 0.303-0.507, P< .001 or P = .0167 for different frequency) presented significantly negative correlations with rosacea. Frequency of cleansing showed a nonlinear association with rosacea: using facial cleansers 1~3 times per week (OR = 0.647, 95%CI 0.429-0.975, P  =  .038) showed beneficial effects while using facial cleanser excessively (twice or more daily) (OR = 2.131, 95%CI 1.394-3.256, P< .001) positively correlated to rosacea strongly.

Conclusions: Excessive use of facial cleanser (twice or more a day) and facial mask (more than 4 times a week), frequent makeup (more than 6 times a week), regular skin care in beauty salon (more than once a week), and using beauty salon products were closely correlated to the development of rosacea in Chinese population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185582PMC
July 2020

Non-Coding RNAs as Regulators and Markers for Targeting of Breast Cancer and Cancer Stem Cells.

Cancers (Basel) 2020 Feb 4;12(2). Epub 2020 Feb 4.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a product generated from erroneous transcription. Even though understanding of biological and molecular functions of noncoding RNA remains enigmatic, researchers have established the pivotal role of these RNAs in governing a plethora of biological phenomena that includes cancer-associated cellular processes such as proliferation, invasion, migration, apoptosis, and stemness. In addition to this, the transmission of microRNAs and long non-coding RNAs was identified as a source of communication to breast cancer cells either locally or systemically. The present review provides in-depth information with an aim at discovering the fundamental potential of non-coding RNAs, by providing knowledge of biogenesis and functional roles of micro RNA and long non-coding RNAs in breast cancer and breast cancer stem cells, as either oncogenic drivers or tumor suppressors. Furthermore, non-coding RNAs and their potential role as diagnostic and therapeutic moieties have also been summarized.
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http://dx.doi.org/10.3390/cancers12020351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072613PMC
February 2020
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