Eccrine Glands Research Articles

RG6234, a GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Intravenous (IV) and First Subcutaneous (SC) Results from a Phase I Dose-Escalation Study

Background: Despite advances in treatment, almost all pts with newly diagnosed multiple myeloma (MM) eventually relapse and progression-free survival decreases with each subsequent line of therapy. New treatments that target novel antigens and/or have novel mechanisms of action (MOAs) are needed. GPRC5D is a G-protein coupled receptor that is overexpressed on malignant plasma cells. Expression on normal tissue is limited to skin (hair follicles and eccrine glands) and testis (seminiferous tubules). In a Phase I study (NCT04557150), RG6234, a GPRC5DxCD3 T-cell engaging bispecific antibody with a novel 2:1 configuration, was highly active in pts with RRMM and had a safety profile consistent with its MOA and target distribution when given IV (Hasselbalch Riley et al. EHA 2022). We report updated IV and first SC results. Methods: All pts had RRMM for which no established therapy was available, appropriate or tolerable and had received ≥1 prior IMiD and ≥1 prior PI. Prior CAR T-cells, antibody-drug conjugates and bispecific antibodies were allowed. RG6234 was initiated with step-up dosing, reaching the target dose 2 weeks after the initial step dose, and was given for up to 1 year unless disease progression or unacceptable toxicity occurred. All pts who received RG6234 in the dose-escalation phase of the study were included in the analysis (IV dose range: 6-10000µg; SC dose range: 30-7200µg). Results: At data cut-off (June 8, 2022), 51 pts had been enrolled into the IV cohorts (median age: 62 years; min-max: 27-78) and 54 into the SC cohorts (64 years; 46-79). Median number of prior lines was 5 (min-max: 2-15) and 4 (2-14), respectively. Many pts were triple-class refractory (IV: 63.3%; SC: 73.1%), some were penta-class refractory (IV: 30.6%; SC: 42.3%), and some had received prior anti-BCMA therapies (IV: 19.6%; SC: 20.4%). High-risk cytogenetics (t(4;14), t(14:16), del(17p)) were common (IV: 46.7% of 30 evaluable pts; SC: 50.0% of 28). Across all tested doses, cytokine release syndrome (CRS) was the most common adverse event (AE; IV: 82.4% of pts; SC: 77.8%). Grade (Gr) ≥3 CRS was uncommon (IV: 2.0%; SC: 1.9%) and most events were confined to Cycle 1. CRS management often involved tocilizumab (IV: 39.2% of pts; SC: 25.9%) and corticosteroids (IV: 52.9%; SC: 25.9%). ICANS-like AEs were infrequent and mostly mild (any Gr: 9 pts [8.6%]; Gr ≥3: 2 pts [1.9%]). AEs related to on-target, off-tumor effects included dermal and epidermal conditions (IV: 72.5%; Gr 3: 11.8%; SC: 81.5%; Gr 3: 14.8%), hair and nail changes (IV: 17.6% [all Gr 1-2]; SC: 22.2% [all Gr 1-2]), and AEs affecting the gastrointestinal mucosal epithelium or tongue (IV: 70.6% [all Gr 1-2]; SC: 74.1%; Gr 3: 5.6%). Gr ≥3 hematologic AEs were infrequent (anemia: IV 13.7%, SC 5.2%; thrombocytopenia: IV 13.8%, SC 18.5%; neutropenia: IV 11.8%, SC 16.7%). Infections were common (IV: 56.9%; Gr ≥3: 19.6%; SC: 37.0%; Gr ≥3: 24.1%). RG6234-related AEs leading to treatment discontinuation occurred in 2 pts (3.9%) in the IV group and 2 pts (3.7%) in the SC group. One RG6234-related Gr 5 (fatal) AE (1.9%) of acute respiratory failure was reported in the SC group. Median follow-up among efficacy evaluable pts in the IV group (7.1 months; min-max: 0.5-16.8; n=49 pts) was longer than in the SC group (3.9 months; min-max: 1.1-10.5; n=48 pts). Overall response rates were 71.4% and 60.4%, respectively (Figure). Responses were observed in 10/18 pts (55.6%) overall who had received prior anti-BCMA therapies and 18/28 pts (64.2%) who had high-risk cytogenetics. Median time to first response in the IV and SC cohorts was 1.4 months (95% CI: 1.2-1.8) and 1.6 months (1.2-2.1), respectively. Duration of response (DoR) data were immature at cut-off. Responses were ongoing in 24/35 pts (68.6%) in the IV cohorts and in 26/29 (89.7%) in the SC cohorts, with a maximum DoR of 12.9 months and 8.8 months, respectively. Biomarker data demonstrated rapid T-cell activation and T cell-mediated anti-MM activity irrespective of administration route (Dekhtiarenko et al. ASH 2022). Anti-drug antibody incidence was low (IV: 7.8%; SC: 1.8%), and impacted RG6234 PK and efficacy in one pt (1.0%) only. Conclusions: RG6234 is highly active in pts with heavily pretreated RRMM when administered IV or SC. AEs are consistent with its MOA and target distribution. Evaluation and optimization of IV and SC dosing is ongoing. Updated data will be presented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CeruminousSyringocystadenoma papilliferum: An Extremely Rare Neoplasm of the External Ear

Abstract Introduction/Objective Syringocystadenoma papilliferum (SCAP) is a rare benign adnexal tumor derived from the apocrine or the eccrine sweat glands on the face or the scalp. Ceruminous glands are modified apocrine glands in the external auditory canal and produce cerumen that helps the ear canal against physical damage and microbial invasion. Neoplastic transformation of these glands is even rarer among these benign tumors. Methods/Case Report Here we report a case of a 29-year-old female with a three-month history of progressively worsening right-sided ear pain, muffled hearing, aural fullness, and right-sided shooting aches. She reported that her ear felt sensitive to touch and was painful if she lay on it. Previous treatments included steroids and oral antibiotics without any improvement in symptoms. A physical exam revealed a right narrow ear canal with a cystic mass to the superior lateral canal wall. A CT Temporal Bone showed a 1 cm oval soft tissue lesion in the lateral osseous portion of the right external auditory canal with no underlying osseous erosions identified. This is nonspecific, and neoplasm cannot be excluded. The decision was made for excision. The mass ruptured during excision with dishwater appearing fluid. Microscopic examination showed papillae lined by bilayered glandular epithelium projecting into a cystic lumen. Well defined myoepithelial cell layer is appreciated. Decapitation secretions and plasma cells are noted to be present in the stroma. A final diagnosis of Syringocystadenoma papilliferum is made. Results (if a Case Study enter NA) NA. Conclusion Ceruminous Syringocystadenoma papilliferum is an extremely rare benign tumor of the ceruminous glands of the external ear. Complete excision is the treatment of choice

Syringotropic Mycosis Fungoides: A Variant of Folliculotropic or a Distinct Subtype of Adnexotropic Mycosis Fungoides?

Mycosis fungoides (MF) is a slowly progressive form of cutaneous T-cell lymphomas (CTCL). MF is classified into 4 subtypes including folliculotropic MF (FMF). Infiltration of both hair follicles and eccrine glands is included in the FMF classification and designated as syringotropic MF (STMF), an exceedingly rare form of CTCL. We report an additional case of STMF. The clinical course of syringotropic CTCL is more benign than FMF, suggesting that despite similar clinical presentations, they are molecularly distinct diseases. Clinical characteristics can help differentiate STMF from FMF. Skin-directed therapies are less effective in STMF than FMF. With distinct clinical characteristics, histopathologic findings, and disease course, syringotropic CTCL should be considered a subtype entity in the spectrum of adnexotropic MF. J Drugs Dermatol. 2022;21(12):1362-1364. doi:10.36849/JDD.6779.

Hamartome angio-eccrine : A propos de deux observations a Dakar, Sénégal

Angio eccrine hamartoma (EAH) is a rare, benign tumoral lesion composed of eccrine glands and vascular structures in the mid dermis. We report on two observations in Dakar. Observation 1: A four-month-old infant was seen for an erythematous plaque, rounded, with a smooth surface, asymptomatic, localized to the right thigh, evolving for three months. The clinical appearance suggested a spitz tumour. Cutaneous histology confirmed the diagnosis of angioeccrine hamartoma. Observation 2: The second case was concerned with a ten-month-old infant received for an erythematous, atrophic plaque, localized at the level of the inter-gluteal fold, evolving since birth. This clinical aspect was suggestive of a sclero-atropic lichen. Cutaneous histology confirmed the diagnosis of angioeccrine hamartoma. Discussion: We reported two observations of HAE original by the rarity and the clinical presentations leading to confusion with a nevus of Spitz and the sclero-atrophic lichen. Cutaneous histology was of considerable contribution.

Uncovering the Sweat Biofouling Components and Distributions in Electrochemical Sensors.

Interest is growing in the creation of wearable sweat sensors for continuous, low-cost, and noninvasive health diagnosis at the molecular level. The biofouling phenomenon leads to degradation of sweat sensors' performance over time, further limiting the successive monitoring of human health status. However, to date, the mechanism of sweat fouling is still unclear, with the inability to provide effective guidance on antifouling strategies. This study clarifies chemical compositions in sweat fouling and fouling distributions on the surface of sensors. Gold film electrodes were prepared on glass and poly(ethylene terephthalate) (PET) substrates and contaminated by human facial sweat (from eccrine sweat glands and apocrine sweat glands) and palm sweat (only from eccrine sweat glands). A scanning electron microscope (SEM), an optical microscope (OM), and an atomic force microscope (AFM) were employed to study the surface morphology of biofouling electrodes. The existence of sweat fouling was characterized by AFM adhesion force, a Fourier transform infrared spectrometer (FTIR), and X-ray photoelectron spectra (XPS). FTIR along with XPS was adopted to analyze the biofouling components, and differential reflectance spectroscopy (DRS) was undertaken to observe the distribution of biofouling on the surface of the electrodes. As a result, we found that neither skin cell pieces nor recognized protein adsorption is the dominant source of biofouling, but the lipids in sweat form an inhomogeneous fouling layer on the electrode surface to reduce the electrochemical reactivity of sensors. This study provides deeper insights into sweat biofouling components and distributions and points out the right direction for resolving the problem of limited continuity in wearable sweat sensors.

Store-operated calcium channels in skin.

The skin is a complex organ that acts as a protective layer against the external environment. It protects the internal tissues from harmful agents, dehydration, ultraviolet radiation and physical injury as well as conferring thermoregulatory control, sensation, immunological surveillance and various biochemical functions. The diverse cell types that make up the skin include 1) keratinocytes, which form the bulk of the protective outer layer; 2) melanocytes, which protect the body from ultraviolet radiation by secreting the pigment melanin; and 3) cells that form the secretory appendages: eccrine and apocrine sweat glands, and the sebaceous gland. Emerging evidence suggests that store-operated Ca2+ entry (SOCE), whereby depletion of intracellular Ca2+ stores triggers Ca2+ influx across the plasma membrane, is central to the normal physiology of these cells and thus skin function. Numerous skin pathologies including dermatitis, anhidrotic ectodermal dysplasia, hyperhidrosis, hair loss and cancer are now linked to dysfunction in SOCE proteins. Principal amongst these are the stromal interaction molecules (STIMs) that sense Ca2+ depletion and Orai channels that mediate Ca2+ influx. In this review, the roles of STIM, Orai and other store-operated channels are discussed in the context of keratinocyte differentiation, melanogenesis, and eccrine sweat secretion. We explore not only STIM1-Orai1 as drivers of SOCE, but also independent actions of STIM, and emerging signal cascades stemming from their activities. Roles are discussed for the elusive transient receptor potential canonical channel (TRPC) complex in keratinocytes, Orai channels in Ca2+-cyclic AMP signal crosstalk in melanocytes, and Orai isoforms in eccrine sweat gland secretion.

578 Single-cell ribonucleic acid sequencing and cystic fibrosis transmembrane conductance regulator functional analysis of human eccrine sweat glands establish a viable method for investigating cystic fibrosis genotypic-phenotypic heterogeneity

578 Single-cell ribonucleic acid sequencing and cystic fibrosis transmembrane conductance regulator functional analysis of human eccrine sweat glands establish a viable method for investigating cystic fibrosis genotypic-phenotypic heterogeneity

Separate extraction of human eccrine sweat gland activity and peripheral hemodynamics from high- and low-quality thermal imaging data

Sweat gland activity and peripheral hemodynamics, which characterize the function of sympathetic cholinergic nerve fibers and the manifestation mechanisms of vascular tone regulation, respectively, can be detected via dynamic thermography of the skin. Thus, they are useful parameters for diagnosing various forms of neuropathy and functional circulatory disorders. Both parameters affect the dynamics of the skin temperature; therefore, for an adequate description of thermographic data, it is necessary to build models that consider both these coexisting components simultaneously. PurposeThe objective of this study was to determine the spatiotemporal and statistical features of dynamic thermograms of skin areas with sweat glands and to develop methods for the extraction of temperature components mediated by sweat gland activity (Tsweat) separately from hemodynamics (Tblood) based on thermograms of high and low temperature resolutions. MethodsTo separate the Tsweat and Tblood components, simultaneous thermographic and photoplethysmographic (PPG) measurements were performed in the area of the fingers during a deep inspiratory gasp (DIG). PPG data, which were obtained solely by hemodynamics, were converted into a temperature signal (Tblood) using the spectral filtering approach. By calculating the difference between the skin (Tskin) and blood (Tblood) temperature components, the Tsweat component was determined, which characterizes sweat gland activity and the integrity of the cholinergic sympathetic nerve fibers that innervate them. The Tsweat component was compared with the active sweat pore count curve, which was determined by the adaptive detection of local temperature minima. Thermographic and PPG measurements were performed for 3 min on a group of 15 volunteers during the DIG test. The skin temperature was measured using a cooled thermal imaging camera in the spectral range of 8–9 μm with a temperature sensitivity of 0.02 °C. PPG measurements were performed using a reflectance sensor with a central wavelength of 800 nm. Wavelet analysis with the Morlet basis function was used to preliminarily determine the spectrum of spontaneous temperature oscillations in an area of the skin with and without sweat pores. Statistical parameters of the histogram, such as the standard deviation and the statistical pore activation index (SPAI) - which is proposed in this paper were used in the DIG test to detect sweat gland activity with low-temperature resolution thermograms. The temporal dynamics of the statistical parameters were compared with the dynamics of the sweat pore count. ResultsThe Tsweat component was correlated with the sweat pore count on the thermogram with a coefficient of 0.75, confirming the dependence of this temperature component on the sweat gland activity and the need for considering this activity in the analysis of the spatiotemporal dynamics of the human skin temperature. The use of the proposed SPAI and standard deviation allows the detection of sweat gland activity even with thermograms of a low temperature resolution. The use of an integrated map of the sweat gland activity will help the specialist to assess the degree of integrity of the innervation of skin areas in a single image. The primary assessment of the spectrum of temperature oscillations at rest indicated that spontaneous sweat gland activity is accompanied by high-frequency oscillations in the skin temperature localized in the area of sweat pores, within the frequency range of 0.07–0.3 Hz. This suggests the possibility of spectral separation of the temperature component mediated by sweat gland activity from the hemodynamic component, which dominates in the region of <0.1 Hz. The proposed two-component approach for the analysis of skin temperature dynamics allows separate assessment of sympathetic innervation and rhythms of hemodynamic regulation using dynamic thermograms.

A large deletion encompassing exon 2 of the ectodysplasin A (EDA) gene in a British blue crossbred calf with hypohidrotic ectodermal dysplasia

BackgroundHypohidrotic ectodermal dysplasia (HED) is a congenital syndrome of mammals affecting organs and tissues of ectodermal origin characterized by absence or hypoplasia of hair, teeth, and eccrine glands. The disorder has been reported in several species, including humans, mice, dogs and cattle, associated with variants in genes affecting the ectodysplasin pathway, including the X-linked ectodysplasin A (EDA) gene. Until now, nine pathogenic variants have been found in the bovine EDA gene. Here we report a novel variant in EDA in a crossbreed male Belgian Blue calf with HED, and provide an overview of the phenotypic and allelic heterogeneity of EDA-related forms of HED in cattle.Case presentationA 45-day-old male crossbreed British Blue calf was referred with congenital hypotrichosis, oligodontia and omphalitis. On histopathological examination of the nasal planum, nasolabial glands and ducts were not observed. The density of hair follicles was low, and they were small, with a predominance of telogen-phase hairs, and some serocellular crusts. The phenotype of the calf resembled that of HED. Whole-genome sequencing (WGS) was performed and revealed a 21,899 base-pair deletion encompassing the coding exon 2 of EDA, predicted to result in an altered transcript and aberrant protein.ConclusionsThe clinicopathological and genetic findings were consistent with a case of X-linked HED. A very similar EDA deletion has been previously reported in a family of Holstein cattle with HED. The newly identified hemizygous EDA loss-of-function variant is certainly pathogenic and therefore is the genetic cause for the observed phenotype. This case report provides an additional example of the potential of WGS-based precise diagnostics in livestock species such as cattle to increase the diagnostic yield in rare diseases.

Ectodermal dysplasias: New perspectives on the treatment of so far immedicable genetic disorders.

The past decade has witnessed an expansion of molecular approaches facilitating the differential diagnosis of ectodermal dysplasias, a group of genetic diseases characterized by the lack or malformation of hair, teeth, nails, and certain eccrine glands. Moreover, advances in translational research have increased the therapeutic opportunities for such rare diseases, and new dental, surgical, and ophthalmic treatment options are likely to offer relief to many individuals affected by ectodermal dysplasias. In X-linked hypohidrotic ectodermal dysplasia (XLHED), the genetic deficiency of the signaling molecule ectodysplasin A1 (EDA1) may even be overcome before birth by administration of a recombinant replacement protein. This has been shown at least for the key problem of male subjects with XLHED, the nearly complete absence of sweat glands and perspiration which can lead to life-threatening hyperthermia. Prenatal treatment of six boys by injection of an EDA1 replacement protein into the amniotic fluid consistently induced the development of functional sweat glands. Normal ability to sweat has so far persisted for >5 years in the two oldest boys treated in utero. Thus, timely replacement of a missing protein appears to be a promising therapeutic strategy for the most frequent ectodermal dysplasia and possibly additional congenital disorders.

Extended Overview of Ocular Phenotype with Recent Advances in Hypohidrotic Ectodermal Dysplasia.

The term ectodermal dysplasias (EDs) describes a heterogeneous group of inherited developmental disorders that affect several tissues of ectodermal origin. The most common form of EDs is hypohidrotic ectodermal dysplasia (HED), which is characterized by hypodontia, hypotrichosis, and partial or total eccrine sweat gland deficiency. HED is estimated to affect at least 1 in 17,000 people worldwide. Patients with HED have characteristic facies with periorbital hyperpigmentation, depressed nasal bridge, malar hypoplasia, and absent or sparse eyebrows and eyelashes. The common ocular features of HED include madarosis, trichiasis, and ocular chronic surface disease due to dry eye syndrome, which manifests clinically with discomfort, photophobia, and redness. Dry eye is common in HED and results from a combination of ocular surface defects: mucus abnormalities (abnormal conjunctival mucinous glands), aqueous tear deficiency (abnormalities in the lacrimal gland) and lipid deficiency (due to the partial or total absence of the meibomian glands; modified sebaceous glands with the tarsal plate). Sight-threatening complications result from ocular surface disease, including corneal ulceration and perforation with subsequent corneal scarring and neovascularization. Rare ocular features have been reported and include bilateral or unilateral congenital cataracts, bilateral glaucoma, chorioretinal atrophy and atresia of the nasolacrimal duct. Recognition of the ocular manifestations of HED is required to perform clinical surveillance, instigate supportive and preventative treatment, and manage ocular complications.

Cutaneous Microvascular Function Following Ischemia-reperfusion Injury During Passive Heat Stress

Increased kidney injury risk during heat stress is mediated, in part, by renal ischemia-reperfusion (IR) injury. However, in vivo studies are not possible in humans. Eccrine sweat glands and the cutaneous circulation have been proposed as a model of the nephron given the physiological similarities (e.g., sodium reabsorption). We previously reported impairments in sweat gland sodium reabsorption following IR injury during passive heat stress, which could be contributed to by alterations in cutaneous microvascular function (i.e., oxygen supply). PURPOSE: Test the hypothesis that forearm cutaneous microvascular function is impaired following IR injury during passive heat stress. METHODS: Fifteen healthy subjects (10 women; age: 25 ± 3 y; body mass index: 23.7 ± 3.5 kg·m2) completed a cross-body design experiment consisting of ~160 min of passive heat stress (core body temperature: +1.5 ± 0.2 °C) utilizing a suit perfused with 50 °C water. At 60 min of whole-body heating, one forearm arm (randomized) was occluded (220 mmHg) for 20 min followed by reperfusion. Local thermal hyperemia tests were performed 20 min following reperfusion using a standard local heating protocol (39 °C for 40 min + 44 °C for 20 min). Forearm skin blood flow was measured continuously at two sites (one heated, one control) on each forearm using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as red blood cell flux/mean arterial pressure (PU/mmHg) and normalized to maximal CVC during local heating to 44 °C. Data are presented as mean ± SD. RESULTS: Maximal CVC was not different between IR and control arms (3.2 ± 0.7 vs. 3.4 ± 0.8 PU/mmHg, respectively; p = 0.48). Approximately 60 min after reperfusion, CVC at the control sites were not different between IR and control arms (78 ± 11 vs. 76 ± 11%, respectively; p = 0.65). Following 40 min of local heating (39 °C), CVC was not different between IR and control arms (80 ± 10 vs. 78 ± 10%, respectively; p = 0.59). CONCLUSION: Cutaneous microvascular function was maintained following IR during passive heat stress indicating that impaired sodium reabsorption is not mediated by reductions in oxygen supply necessary for active transport of sodium. Rather, a disruption in sodium transporter activity may mediate increased sodium excretion, but this remains unknown.

Ectodermal Dysplasia: A Rare Case Report

The ectodermal dysplasias (EDs) comprise a large, heterogeneous group of inherited disorders that are defined by primary defects in the development of two or more tissues derived from embryonic ectoderm. The primarily involved tissues are the skin and its appendages (hair follicles, eccrine glands, sebaceous glands, and nails) and teeth. Although Thurnam published the first report of a patient with ED in 1848, the term ED was not coined until 1929 by Weech. One such case report of ED is demonstrated here.

34089 Syringoma of the vulva associated with vulvar hypertrophy

Syringoma is a benign eccrine sweat gland tumor most commonly presenting in young adults as multiple, often clustered, soft 1-2 mm papules on the lower eyelids and cheeks. There is a female predominance and lesions tend to arise after puberty. Syringoma of the vulva is less common with fewer cases reported. Here we describe a case of a 35-year-old woman who presented with multiple pruritic skin-colored papules on the labia majora which had been present for 7 years and were increasing in size and number. The lesions were a source of distress with intimate encounters and the associated vulvar thickening was visible under some clothing. Examination revealed numerous coalescing, 2-4 mm skin-colored, slightly rubbery papules on the bilateral labia majora with associated vulvar hypertrophy. A biopsy showed small comma-shaped ducts and solid cords of epithelium surrounded by a fibrotic stroma compatible with a diagnosis of syringoma. Various treatment options were presented, including excision, carbon dioxide laser ablation, and topical atropine, although surgical excision was favored given the extent of the lesions and resultant hypertrophy. Our case highlights the importance of keeping vulvar syringoma in the differential diagnosis of patients with bilateral vulvar papules, vulvar pruritus and/or vulvar hypertrophy, as well as recognizing the potential impact of this benign condition on patient quality of life.

SARS-CoV-2 and Skin: New Insights and Perspectives.

The SARS-CoV-2 pandemic has disrupted global health systems and brought the entire globe to its knees. Although born as a disease of the respiratory system, COVID-19 can affect different parts of the body, including the skin. Reports of ongoing skin manifestations of COVID-19 have gradually multiplied, pushing researchers to investigate the etiopathogenic mechanisms underlying these phenomena in more depth. In an attempt to investigate the possible association between SARS-CoV-2, ACE2, TMPRSS2 and skin manifestations, we performed immunohistochemical investigations of the ACE2 receptor and TMPRSS2 in nine skin samples from SARS-CoV-2-positive patients compared to a cohort of healthy controls. Furthermore, after consulting public databases regarding ACE2 mRNA expression in various cell populations resident in the skin, we conducted a literature review aimed at outlining the current state of this topic. We did not find statistically different immuno-expression of ACE2 and TMPRSS2 between the group of SARS-CoV-2-positive patients (nine skin biopsies) and the control group. Regarding ACE2, major immunolabeling was present in the epidermal keratinocytes and, rarely, in the fibroblasts and in the adenomeres of the eccrine sweat glands. Regarding the immune expression of TMPRSS2, we found no significant differences between the two groups, with a weak immune staining only in some skin cytotypes. From the review of the literature, we isolated 35 relevant articles according to the inclusion criteria adopted. ACE2 appears to be a target of SARS-CoV-2, although, other receptor molecules may potentially be implicated, such as TMPRSS2. Future studies with large cases and different molecular investigative methods are needed to further elucidate the mechanisms underlying the skin manifestations of SARS-CoV-2.

Notch1 down-regulation in lineage-restricted niches is involved in the development of mouse eccrine sweat glands.

Eccrine sweat gland (SG) restrictedly exists in mouse foot pads indicating that mouse plantar dermis (PD) contains the SG lineage-restricted niches. However, it is still unclear how these niches can affect stem cell fate towards SG. In this study, we tried to find the key cues by which stem cells sense and interact with the SG lineage-specific niches both in vivo and in vitro. Firstly, we used transcriptomics RNA sequencing analysis to screen differentially expressed genes between SG cells and epidermal stem cells (ES), and used proteomic analysis to screen differentially expressed proteins between PD and dorsal dermis (DD). Notch1 was found differentially expressed in both gene and protein levels, and was closely related to SG morphogenesis based on Gene Ontology (GO) enrichment analysis. Secondly, the spatial-temporal changes of Notch1 during embryonic and post-natal development of SG were detected. Thirdly, mouse mesenchymal stem cells (MSCs) were introduced into SG-like cells in vitro in order to further verify the possible roles of Notch1. Results revealed that Notch1 was continuously down-regulated along with the process of SG morphogenesis in vivo, and also along with the process that MSCs differentiated into SG-like cells in vitro. Hence, we suggest that Notch1 possibly acts as with roles of "gatekeeper" during SG development and regulates the interactions between stem cells and the SG lineage-specific niches. This study might help for understanding mechanisms of embryonic SG organogenesis.

Research advances on the regulatory mechanism of sweat secretion ion channels of eccrine sweat glands

Sweat glands are widely distributed in human skin, among which eccrine sweat glands play major roles in heat dissipation and sweat secretion. Sweat secretion is mainly regulated by nervous system and includes two processes of secretion of secretory coil and reabsorption of sweat duct, involving various ion channels and proteins such as calcium ion channel, potassium ion channel, sodium-potassium-chloride co-transporter 1, Best2 protein, aquaporin 5, cystic fibrosis transmembrane conductance regulator, and epithelial sodium ion channel. This paper reviews the nerve conduction system and various ion channels involved in sweat secretion of exocrine sweat glands in order to provide a theoretical basis for the study of regeneration, repair, and transformation of stem cells.

Differential distribution and genetic determination of eccrine sweat glands and hair follicles in the volar skin of C57BL/6 mice and SD rats

BackgroundEccrine sweat glands (ESGs) and hair follicles (HFs) are the prominent skin appendages regulating human body temperature. C57BL/6 mice and Sprague–Dawley (SD) rats are the most commonly used model animals for studying ESGs and HFs. Previous studies have shown the distribution of ESGs and HFs in volar hindfeet of C57BL/6 mice, but there are few or no reports on the distribution of ESGs and HFs in volar forefeet of C57BL/6 mice and volar feet of SD rats. Here, we investigated the differential distribution and genetic determination of ESGs and HFs in the volar skin of C57BL/6 mice and SD rats through gross observation, iodine-starch sweat test, double staining with Nile Blue A and Oil Red O, hematoxylin and eosin (HE) staining, double immunofluorescence staining of LIM Homeobox 2 (LHX2)/Na+-K+-ATPase α1(NKA) or LHX2/Na+-K+-2Cl－ cotransporter 1 (NKCC1), and qRT-PCR detection of ESG-related gene Engrailed 1 (En1) and HF-related gene LHX2.ResultsThe results showed ESGs but no HFs in the footpads of C57BL/6 mice and SD rats, both ESGs and HFs in the inter-footpads (IFPs) of C57BL/6 mice, and neither ESGs nor HFs in the IFPs of SD rats. The relative quantitative change in En1 was consistent with the differential distribution of ESGs, and the relative quantitative change of LHX2 was consistent with the differential distribution of HFs.ConclusionC57BL/6 mice and SD rats had their own characteristics in the distribution of ESGs and HFs in the volar skin, and researchers should choose mice or rats, and even forefeet or hindfeet as their research object according to different purposes. The study provides a basis for selection of optimal animal models to study development, wound healing and regeneration of skin appendages.

Sweat Proteomics in Cystic Fibrosis: Discovering Companion Biomarkers for Precision Medicine and Therapeutic Development.

In clinical routine, the diagnosis of cystic fibrosis (CF) is still challenging regardless of international consensus on diagnosis guidelines and tests. For decades, the classical Gibson and Cooke test measuring sweat chloride concentration has been a keystone, yet, it may provide normal or equivocal results. As of now, despite the combination of sweat testing, CFTR genotyping, and CFTR functional testing, a small fraction (1–2%) of inconclusive diagnoses are reported and justifies the search for new CF biomarkers. More importantly, in the context of precision medicine, with a view to early diagnosis, better prognosis, appropriate clinical follow-up, and new therapeutic development, discovering companion biomarkers of CF severity and phenotypic rescue are of utmost interest. To date, previous sweat proteomic studies have already documented disease-specific variations of sweat proteins (e.g., in schizophrenia and tuberculosis). In the current study, sweat samples from 28 healthy control subjects and 14 patients with CF were analyzed by nanoUHPLC-Q-Orbitrap-based shotgun proteomics, to look for CF-associated changes in sweat protein composition and abundance. A total of 1057 proteins were identified and quantified at an individual level, by a shotgun label-free approach. Notwithstanding similar proteome composition, enrichment, and functional annotations, control and CF samples featured distinct quantitative proteome profiles significantly correlated with CF, accounting for the respective inter-individual variabilities of control and CF sweat. All in all: (i) 402 sweat proteins were differentially abundant between controls and patients with CF, (ii) 68 proteins varied in abundance between F508del homozygous patients and patients with another genotype, (iii) 71 proteins were differentially abundant according to the pancreatic function, and iv) 54 proteins changed in abundance depending on the lung function. The functional annotation of pathophysiological biomarkers highlighted eccrine gland cell perturbations in: (i) protein biosynthesis and trafficking, (ii) CFTR proteostasis and membrane stability, and (iii) cell-cell adherence, membrane integrity, and cytoskeleton crosstalk. Cytoskeleton-related biomarkers were of utmost interest because of the consistency between variations observed here in CF sweat and variations previously documented in other CF tissues. From a clinical stance, nine candidate biomarkers of CF diagnosis (CUTA, ARG1, EZR, AGA, FLNA, MAN1A1, MIA3, LFNG, SIAE) and seven candidate biomarkers of CF severity (ARG1, GPT, MDH2, EML4 (F508del homozygous), MGAT1 (pancreatic insufficiency), IGJ, TOLLIP (lung function impairment)) were deemed suitable for further verification.

Malignant Nodular Hidradenoma of the Left Knee: A Malignant Mystery With an Overview of Literature

Malignant nodular hidradenoma is a rare eccrine sweat gland neoplasm characterized by recurrence, metastasis, and a locally aggressive course. In our case report, a 74-year-old man presented with a seemingly benign swelling which was persistent for the last 30 years, which was excised at an outside institute. Since the patient presented to the hospital during the peak of the pandemic, considering the age of the patient, the pandemic situation, the logistics of radiotherapy during such a situation, preserving the knee joint function in view of close proximity of the tumour to the joint, it was decided to keep the patient on follow up and continue expectant management. After a follow-up period of 24 months, no locoregional recurrence or metastasis has been observed. The patient is on annual follow-up with clinical examination and PET-CECT imaging.