Prevention and Treatment of Chemotherapy-Induced Alopecia: What Is Available and What Is Coming?

Millions of new cancer patients receive chemotherapy each year. In addition to killing cancer cells, chemotherapy is likely to damage rapidly proliferating healthy cells, including the hair follicle keratinocytes. Chemotherapy causes substantial thinning or loss of hair, termed chemotherapy-induced alopecia (CIA), in approximately 65% of patients. CIA is often ranked as one of the most distressing adverse effects of chemotherapy, but interventional options have been limited. To date, only scalp cooling has been cleared by the US Food and Drug Administration (FDA) to prevent CIA. However, several factors, including the high costs not always covered by insurance, preclude its broader use. Here we review the current options for CIA prevention and treatment and discuss new approaches being tested. CIA interventions include scalp cooling systems (both non-portable and portable) and topical agents to prevent hair loss, versus topical and oral minoxidil, photobiomodulation therapy (PBMT), and platelet-rich plasma (PRP) injections, among others, to stimulate hair regrowth after hair loss. Evidence-based studies are needed to develop and validate methods to prevent hair loss and/or accelerate hair regrowth in cancer patients receiving chemotherapy, which could significantly improve cancer patients' quality of life and may help improve compliance and consequently the outcome of cancer treatment.

Dichotomous role of miR193b-3p in diabetic foot ulcers maintains inhibition of healing and suppression of tumor formation.

Despite the hyperproliferative environment marked by activation of ß-catenin and overexpression of c-myc, the epidermis surrounding chronic diabetic foot ulcers (DFUs) is clinically hypertrophic and nonmigratory yet does not undergo malignant transformation. We identified miR193b-3p as a master regulator that contributes to this unique cellular phenotype. We determined that induction of tumor suppressor miR193b-3p is a unique feature of DFUs that is not found in venous leg ulcers, acute wounds, or cutaneous squamous cell carcinoma (SCC). Genomic analyses of DFUs identified suppression of the miR193b-3p target gene network that orchestrates cell motility. Inhibition of migration and wound closure was further confirmed by overexpression of miR193b-3p in human organotypic and murine in vivo wound models, whereas miR193b-3p knockdown accelerated wound reepithelialization in human ex vivo and diabetic murine wounds in vivo. The dominant negative effect of miR193b-3p on keratinocyte migration was maintained in the presence of promigratory miR31-5p and miR15b-5p, which were also overexpressed in DFUs. miR193b-3p mediated antimigratory activity by disrupting stress fiber formation and by decreasing activity of GTPase RhoA. Conversely, miR193b-3p targets that typically participate in malignant transformation were found to be differentially regulated between DFUs and SCC, including the proto-oncogenes KRAS (Kirsten rat sarcoma viral proto-oncogene) and KIT (KIT proto-oncogene). Although miR193b-3p acts as a tumor suppressor contributing to low tumor incidence in DFUs, it also acts as a master inhibitor of cellular migration and epithelialization in DFUs. Thus, miR193b-3p may represent a target for wound healing induction, cancer therapeutics, and diagnostics.

Targeting mitochondria in dermatological therapy: beyond oxidative damage and skin aging.

INTRODUCTION: The analysis of the role of the mitochondria in oxidative damage and skin aging has been a significant aspect of dermatological research. Mitochondria generate most reactive oxygen species (ROS) which, in excess, are cytotoxic and DNA-damaging and promote (photo-)aging. However, ROS also possesses key physiological and regulatory functions and mitochondrial dysfunction is prominent in several not primarily senescence-associated skin diseases and skin cancers. Although many standard dermatotherapeutics modulate mitochondrial function, dermatological therapy rarely targets the mitochondria. Accordingly, there is a rationale for 'mitochondrial dermatology'-based approaches to be applied to therapeutic research, as we advocate here. AREAS COVERED: This paper examines the functions of mitochondria in cutaneous physiology beyond energy (ATP) and ROS production. Keratinocyte differentiation and epidermal barrier maintenance, appendage morphogenesis and homeostasis, photoaging and skin cancer are considered. Based on related PubMed search results, the paper evaluates thyroid hormones, glucocorticoids, Vitamin D3 derivatives, retinoids, cannabinoid receptor agonists, PPARγ agonists, thyrotropin, and thyrotropin-releasing hormone as instructive lead compounds. Moreover, the mitochondrial protein MPZL3 as a promising new drug target for future 'mitochondrial dermatology' is highlighted. EXPERT OPINION: Future dermatological therapeutic research should have a mitochondrial medicine emphasis. Focusing on selected lead agents, protein targets, in silico drug design, and model diseases will fertilize a mito-centric approach.

Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression.

Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1ß were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.

A folliculocentric perspective of dandruff pathogenesis: Could a troublesome condition be caused by changes to a natural secretory mechanism?

Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under-investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune-modulatory properties, including the creation of an immunoinhibitory, immune-privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance of yeast and bacterial species, along with increasing proinflammatory sebum by-products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune-microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs.

Mitochondrially localized MPZL3 emerges as a signaling hub of mammalian physiology.

MPZL3 is a nuclear-encoded, mitochondrially localized, immunoglobulin-like V-type protein that functions as a key regulator of epithelial cell differentiation, lipid metabolism, ROS production, glycemic control, and energy expenditure. Recently, MPZL3 has surfaced as an important modulator of sebaceous gland function and of hair follicle cycling, an organ transformation process that is also governed by peripheral clock gene activity and PPARγ. Given the phenotype similarities and differences between Mpzl3 and Pparγ knockout mice, we propose that MPZL3 serves as a signaling hub that is regulated by core clock gene products and/or PPARγ to translate signals from these nuclear transcription factors to the mitochondria to modulate circadian and metabolic regulation. Conservation between murine and human MPZL3 suggests that human MPZL3 may have similarly complex functions in health and disease. We summarize current knowledge and discuss future directions to elucidate the full spectrum of MPZL3 functions in mammalian physiology.

Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds.

Although impaired keratinocyte migration is a recognized hallmark of chronic wounds, the molecular mechanisms underpinning impaired cell movement are poorly understood. Here, we demonstrate that both diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) exhibit global deregulation of cytoskeletal organization in genomic comparison to normal skin and acute wounds. Interestingly, we found that DFUs and VLUs exhibited downregulation of ArhGAP35, which serves both as an inactivator of RhoA and as a glucocorticoid repressor. Since chronic wounds exhibit elevated levels of cortisol and caveolin-1 (Cav1), we posited that observed elevation of Cav1 expression may contribute to impaired actin-cytoskeletal signaling, manifesting in aberrant keratinocyte migration. We showed that Cav1 indeed antagonizes ArhGAP35, resulting in increased activation of RhoA and diminished activation of Cdc42, which can be rescued by Cav1 disruption. Furthermore, we demonstrate that both inducible keratinocyte specific Cav1 knockout mice, and MßCD treated diabetic mice, exhibit accelerated wound closure. Taken together, our findings provide a previously unreported mechanism by which Cav1-mediated cytoskeletal organization prevents wound closure in patients with chronic wounds.

Intense Pulsed Light as a Treatment for Senile Purpura: A Pilot Study.

BACKGROUND AND OBJECTIVES: Senile purpura is a common condition characterized by recurrent ecchymoses in the elderly on the extensor surfaces of the forearms, hands, and legs. Our objective is to assess the efficacy and safety of a protocol using intense pulsed light (BBL; Sciton Inc., Palo Alto, CA) to improve the appearance of senile purpura on subjects' extensor forearms. STUDY DESIGN/MATERIALS AND METHODS: Five subjects over 65 years of age, with ecchymotic lesions measuring over 1 cm on each forearm and five younger subjects under 35 years of age, without any ecchymotic lesions, were included in the study. The subjects were treated on one randomized forearm with a new intense pulsed light protocol for four weekly sessions. Photographs and subject questionnaires were taken weekly before each treatment as well as 1 month after all treatments. Skin biopsies were taken 1 day after the last of four weekly treatments. Histological analysis, including hematoxylin and eosin, elastic van Gieson, and Masson's Trichrome staining, were carried out to assess both the epidermal thickness and dermal connective tissue structure. The protocol consists of multiple passes using an intense pulsed light (BBL; Sciton Inc.) device in which the wavelength, filter, and fluence are adjusted for each step. Step 1 uses infrared light (800-1,400 nm), high intensity, a smooth adapter, and a constant motion technique. Step 2 employs a 590-nm filter with two different fluences and step 3 utilizes a 560-nm filter. The fluence of steps 2-3 is increased by 1 J each treatment if no side effects are noted. RESULTS: Using a new intense pulsed light protocol in subjects with senile purpura, both the number and square area of ecchymoses on the treated arm were significantly reduced (P = 0.02 and P = 0.04, respectively, paired t test) as compared with the untreated arm at 1 month after four weekly treatments. Despite this pilot study including challenging cases of subjects on both inhaled and injected corticosteroids and blood thinners, all subjects with senile purpura had at least a 50% reduction in the total square area of their ecchymoses on their treated arm. There were no significant or long-lasting side effects, and all subjects reported satisfaction with the treatment with a desire to continue treatments on their control arm. Blinded evaluators were able to select 100% of the time in the subjects with senile purpura, which was the treated arm as compared with the control arm when reviewing photographs from 1 month after the last treatment. In addition, several subjects were noted to have a significant improvement in the appearance of hemosiderin deposition and photodamage. Histologically, intense pulsed light treatments significantly increased epidermal thickness in elderly subjects by 21.14% (P = 0.0153, two-tailed, paired t test), to levels comparable with young subjects. Such restoration is consistent with the other histological observations by blinded evaluators of more abundant and organized collagen fibers in the dermis and reduced aggregates of disorganized elastin fibers. CONCLUSION: This new intense pulsed light protocol is safe and effective in improving the clinical appearance of senile purpura as well as preventing future lesions by improving the structure of the skin by increasing epidermal thickness and improving collagen and elastic fiber morphology. The treatment was well-tolerated, adverse effects were minimal, and there was high patient satisfaction. Lasers Surg. Med. 2020. © 2020 Wiley Periodicals LLC.

Examining the Safety and Efficacy of Low-Level Laser Therapy for Male and Female Pattern Hair Loss: A Review of the Literature.

PURPOSE: Pattern hair loss is the most common type of alopecia. Standard of care involves long-term use of topical medications with limited effectiveness. Low-level laser therapy (LLLT) has become a popular alternative treatment. Here, we examine published clinical trials to establish whether the breadth of evidence supports LLLT for pattern hair loss. METHODS: A literature search was conducted within the PubMed, Embase, Scopus, and Cochrane Trials databases to identify original articles evaluating hair regrowth following LLLT. Articles were selected based on use of 600-1,100 nm wavelengths, treatment time ≥16 weeks, and objective evaluation for hair regrowth. RESULTS: Ten randomized controlled trials were included, of which 8 compared LLLT to sham device and 1 to no treatment. The study populations varied, with 3 studies evaluating only women. All sham-device controlled studies demonstrated statistically significant increase in hair diameter or density (p < 0.01) following LLLT. DISCUSSION: Based on our review of the literature, LLLT appears to be effective for treating pattern hair loss in both men and women. These laser devices have good safety profiles, with only minor adverse effects reported. However, physicians should be cautious when drawing conclusions as some studies included have a relationship with industry.

Clues that mitochondria are involved in the hair cycle clock: MPZL3 regulates entry into and progression of murine hair follicle cycling.

The molecular nature of the hair cycle clock (HCC), the intrinsic oscillator system that drives hair follicle (HF) cycling, remains incompletely understood; therefore, all relevant key players need to be identified. Here, we present evidence that implicates myelin protein zero-like 3 (MPZL3), a multifunctional nuclear-encoded mitochondrial protein known to be involved in epidermal differentiation, in HCC regulation. By analysing global Mpzl3 knockout (-/-) mice, we show that in the absence of functional MPZL3, mice commence HF cycling with retarded first catagen-telogen transition after normal postnatal HF morphogenesis. However, Mpzl3 -/- mice subsequently display strikingly accelerated HF cycling, i.e. a precocious telogen-to-anagen transition during the second hair cycle, compared to controls, suggesting that MPZL3 inhibits anagen entry. We also show that intrafollicular MPZL3 protein expression fluctuates in a hair cycle-dependent manner. In telogen HFs, MPZL3 is localized to the secondary hair germ, an epicentre of hair cycle regulation, where it partially co-localizes with P-cadherin. In early anagen HF, MPZL3 is localized immediately distal to the proximal hair matrix. These findings introduce the novel concept that mitochondria are more actively involved in hair cycle control than previously recognized and that MPZL3 plays a central role in the HCC.

Seborrheic dermatitis-Looking beyond Malassezia.

Seborrhoeic Dermatitis (SD) is a very common chronic and/or relapsing inflammatory skin disorder whose pathophysiology remains poorly understood. Yeast of the genus Malassezia has long been regarded as a main predisposing factor, even though causal relationship has not been firmly established. Additional predisposing factors have been described, including sebaceous activity, host immunity (especially HIV infection), epidermal barrier integrity, skin microbiota, endocrine and neurologic factors, and environmental influences. Genetic studies in humans and mouse models-with particularly interesting insights from examining the Mpzl3 knockout mice and their SD-like skin phenotype, and patients carrying a ZNF750 mutation-highlight defects in host immunity, epidermal barrier and sebaceous activity. After synthesizing key evidence from the literature, we propose that intrinsic host factors, such as changes in the amount or composition of sebum and/or defective epidermal barrier, rather than Malassezia, may form the basis of SD pathobiology. We argue that these intrinsic changes provide favourable conditions for the commensal Malassezia to over-colonize and elicit host inflammatory response. Aberrant host immune activity or failure to clear skin microbes may bypass the initial epidermal or sebaceous abnormalities. We delineate specific future clinical investigations, complemented by studies in suitable SD animal models, that dissect the roles of different epidermal compartments and immune components as well as their crosstalk and interactions with the skin microbiota during the process of SD. This research perspective beyond the conventional Malassezia-centric view of SD pathogenesis is expected to enable the development of better therapeutic interventions for the management of recurrent SD.

Increased IL-17-expressing γδ T cells in seborrhoeic dermatitis-like lesions of the Mpzl3 knockout mice.

Seborrhoeic Dermatitis (SD) is a common inflammatory skin disorder, but its molecular pathogenesis remains elusive. Previously, we have established the Mpzl3 knockout (-/-) mice as a model for SD. In this study, we focused on early phases of skin inflammation and determined the cytokine profiles and identified immune cell types in the lesional skin in the Mpzl3 -/- mice. Using flow cytometry, we detected a significant increase of CD45+ leucocytes, CD3+ T lymphocytes and especially γδ T cells but not αß T cells in the lesional skin compared to control. We also detected high levels of IL-17 and determined that the γδ T cells were a major contributing source. CD3+ and γδ T cell localization in the skin was verified by indirect immunofluorescent staining. Since neither γδ T cells nor IL-17 had been implicated in SD, our study provides novel insights into the role of MPZL3 in the pathogenesis of SD-like skin inflammation.

A Modeling Conundrum: Murine Models for Cutaneous Wound Healing.

The complexity of the cutaneous wound healing process and its impairment in disease states, combined with the urgent clinical need for new therapies demand well-defined preclinical models that facilitate translation of research findings to clinical use. Many murine wound models are well suited for studying mechanisms of various aspects of wound healing, but they have shown limited utility for translating research findings to human conditions, thereby impeding therapeutic developments. Ansell et al. underscore the need for standardization of preclinical murine models by showing the impact of duration of diabetes, animal sex, and assessment methods on healing outcomes in the streptozotocin-induced diabetes mellitus rat model. Recognizing and understanding the limitations and advantages of preclinical murine wound models will facilitate more effective translation of experimental results to improved treatment of human chronic wounds.

Mesenchymal stromal cells prevent bleomycin-induced lung and skin fibrosis in aged mice and restore wound healing.

Fibrosis can develop in nearly any tissue leading to a wide range of chronic fibrotic diseases. However, current treatment options are limited. In this study, we utilized an established aged mouse model of bleomycin-induced lung fibrosis (BLM) to test our hypothesis that fibrosis may develop simultaneously in multiple organs by evaluating skin fibrosis and wound healing. Fibrosis was induced in lung in aged (18-22-month-old) C57BL/6 male mice by intratracheal BLM administration. Allogeneic adipose-derived mesenchymal stromal cells (ASCs) or saline were injected intravenously 24 hr after BLM administration. Full thickness 8-mm punch wounds were performed 7 days later to study potential systemic anti-fibrotic and wound healing effects of intravenously delivered ASCs. Mice developed lung and skin fibrosis as well as delayed wound closure. Moreover, we observed similar changes in the expression of known pro-fibrotic factors in both lung and skin wound tissue, including miR-199 and protein expression of its corresponding target, caveolin-1, as well as phosphorylation of protein kinase B. Importantly, ASC-treated mice exhibited attenuation of BLM-induced lung and skin fibrosis and accelerated wound healing, suggesting that ASCs may prime injured tissues and prevent end-organ fibrosis.

Wound healing protects against chemotherapy-induced alopecia in young rats via up-regulating interleukin-1ß-mediated signaling.

Wound healing is a complex process regulated by various cell types and a plethora of mediators. While interactions between wounded skin and the hair follicles (HFs) could induce HF neogenesis or promote wound healing, it remains unknown whether the wound healing-associated signaling milieu can be manipulated to protect against alopecia, such as chemotherapy-induced alopecia (CIA). Utilizing a well-established neonatal rat model of CIA, we show here that skin wounding protects from alopecia caused by several clinically relevant chemotherapeutic regimens, and that protection is dependent on the time of wounding and hair cycle stage. Gene expression profiling unveiled a significant increase in interleukin-1 beta (IL-1ß) mediated signaling by skin wounding. Subsequently, we showed that IL-1ß is sufficient and indispensable for mediating the CIA-protective effect. Administration of IL-1ß alone to unwounded rats exhibited local CIA protection while IL-1ß neutralization abrogated CIA protection by wounding. Mechanistically, IL-1ß retarded postnatal HF morphogenesis, making HFs at the wound sites or IL-1ß treated areas damage-resistant while the rats developed total alopecia elsewhere. We conclude that wound healing switches the cutaneous cytokine milieu to an IL-1ß-dominated state thus retarding HF growth progression and rendering the HFs resistant to chemotherapy agents. In the future, manipulation of HF progression through interfering with the IL-1ß signaling milieu may provide therapeutic benefits to a variety of conditions, from prevention of CIA to inhibition of hair growth and treatment of hirsutism.

Low level laser therapy and hair regrowth: an evidence-based review.

Despite the current treatment options for different types of alopecia, there is a need for more effective management options. Recently, low-level laser therapy (LLLT) was evaluated for stimulating hair growth. Here, we reviewed the current evidence on the LLLT effects with an evidence-based approach, focusing more on randomized controlled studies by critically evaluating them. In order to investigate whether in individuals presenting with hair loss (male pattern hair loss (MPHL), female pattern hair loss (FPHL), alopecia areata (AA), and chemotherapy-induced alopecia (CIA)) LLLT is effective for hair regrowth, several databases including PubMed, Google Scholar, Medline, Embase, and Cochrane Database were searched using the following keywords: Alopecia, Hair loss, Hair growth, Low level laser therapy, Low level light therapy, Low energy laser irradiation, and Photobiomodulation. From the searches, 21 relevant studies were summarized in this review including 2 in vitro, 7 animal, and 12 clinical studies. Among clinical studies, only five were randomized controlled trials (RCTs), which evaluated LLLT effect on male and female pattern hair loss. The RCTs were critically appraised using the created checklist according to the Critical Appraisal for Therapy Articles Worksheet created by the Center of Evidence-Based Medicine, Oxford. The results demonstrated that all the performed RCTs have moderate to high quality of evidence. However, only one out of five studies performed intention-to-treat analysis, and only another study reported the method of randomization and subsequent concealment of allocation clearly; all other studies did not include this very important information in their reports. None of these studies reported the treatment effect of factors such as number needed to treat. Based on this review on all the available evidence about effect of LLLT in alopecia, we found that the FDA-cleared LLLT devices are both safe and effective in patients with MPHL and FPHL who did not respond or were not tolerant to standard treatments. Future randomized controlled trials of LLLT are strongly encouraged to be conducted and reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement to facilitate analysis and comparison.