Interleukin-31: The Inflammatory Cytokine Connecting Pruritus and Cancer.

Interleukin 31 (IL-31) is a proinflammatory cytokine, mainly secreted by Type II helper T cells. It signals through a heterodimeric receptor complex composed of IL-31 receptor α and oncostatin-M receptor ß chain. The hallmark feature of IL-31, in its pathological role, is its ability to induce pruritus in mammals. Pruritus is a common symptom and major reason of morbidity in cancer patients, compromising their quality of life. Although, IL-31 is differentially expressed in different tumor types and could promote or inhibit cancer progression, high expression of IL-31 is a contributing factor to advanced stage tumor and severity of pruritus. The simultaneous existence of pruritus and cancer could either result from the aberrations in common proteins that co-exist in both cancer and pruritus or the therapeutic treatment of cancer could indirectly induce pruritus. Although the biology of IL-31 has predominantly been described in skin diseases such as atopic dermatitis and other inflammatory diseases, the precise role of IL-31 in the tumor biology of different cancer types remains elusive. Herein, we summarize the current understanding on the role of this cytokine in the pathogenesis of different cancers.

Virus-Induced Host Chemokine CCL2 in COVID-19 Pathogenesis: Potential Prognostic Marker and Target of Anti-Inflammatory Strategy.

A wide variety of inflammatory mediators, mainly cytokines and chemokines, are induced during SARS CoV-2 infection. Among these proinflammatory mediators, chemokines tend to play a pivotal role in virus-mediated immunopathology. The C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) is a potent proinflammatory cytokine and strong chemoattractant of monocytes, macrophages and CD4+ T cells bearing C-C chemokine receptor type-2 (CCR2). Besides controlling immune cell trafficking, CCL2 is also involved in multiple pathophysiological processes including systemic hyperinflammation associated cytokine release syndrome (CRS), organ fibrosis and blood coagulation. These pathological features are commonly manifested in severe and fatal cases of COVID-19. Given the crucial role of CCL2 in COVID-19 pathogenesis, the CCL2:CCR2 axis may constitute a potential therapeutic target to control virus-induced hyperinflammation and multi-organ dysfunction. Herein we describe recent advances on elucidating the role of CCL2 in COVID-19 pathogenesis, prognosis, and a potential target of anti-inflammatory interventions.

Metabolomics analyses reveal the crucial role of ERK in regulating metabolic pathways associated with the proliferation of human cutaneous T-cell lymphoma cells treated with Glabridin.

Cutaneous T-cell lymphomas (CTC) are a heterogeneous group of T-cell lymphoproliferative malignancies of the skin with limited treatment options, increased resistance and remission. Metabolic reprogramming is vital in orchestrating the uncontrolled growth and proliferation of cancer cells. Importantly, deregulated signalling plays a significant role in metabolic reprogramming. Considering the crucial role of metabolic reprogramming in cancer-cell growth and proliferation, target identification and the development of novel and multi-targeting agents are imperative. The present study explores the underlying mechanisms and metabolic signalling pathways associated with Glabridin mediated anti-cancer actions in CTCL. Our results show that Glabridin significantly inhibits the growth of CTCL cells through induction of programmed cell death (PCD) such as apoptosis, autophagy and necrosis. Interestingly, results further show that Glabridin induces PCD in CTCL cells by targeting MAPK signalling pathways, particularly the activation of ERK. Further, Glabridin also sensitized CTCL cells to the anti-cancer drug, bortezomib. Importantly, LC-MS-based metabolomics analyses further showed that Glabridin targeted multiple metabolites and metabolic pathways intricately involved in cancer cell growth and proliferation in an ERK-dependent fashion. Overall, our findings revealed that Glabridin induces PCD and attenuates the expression of regulatory proteins and metabolites involved in orchestrating the uncontrolled proliferation of CTCL cells through ERK activation. Therefore, Glabridin possesses important features of an ideal anti-cancer agent.

Targeting of S-phase kinase associated protein 2 stabilized tumor suppressors leading to apoptotic cell death in squamous skin cancer cells.

S-phase kinase-associated protein 2 (Skp2) is an F-box protein overexpressed in human cancers and linked with poor prognosis. It triggers cancer pathogenesis, including stemness and drug resistance. In this study, we have explored the potential role of Skp2 targeting in restoring the expression of tumor suppressors in human cutaneous squamous cell carcinoma (cSCC) cells. Our results showed that genetic and pharmacological Skp2 targeting markedly suppressed cSCC cell proliferation, colony growth, spheroid formation, and enhanced sensitization to chemotherapeutic drugs. Further, western blot results demonstrated restoration of tumor suppressor (KLF4) and CDKI (p21) and suppression of vimentin and survivin in Skp2-knocked-down cSCC cells. Importantly, we also explored that Skp2 targeting potentiates apoptosis of cSCC cells through MAPK signaling. Moreover, co-targeting of Skp2 and PI3K/AKT resulted in increased cancer cell death. Interestingly, curcumin, a well-known naturally derived anticancer agent, also inhibits Skp2 expression with concomitant CDKI upregulation. In line, curcumin suppressed cSCC cell growth through ROS-mediated apoptosis, while the use of N-acetyl cysteine (NAC) reversed curcumin-induced cell death. Curcumin treatment also sensitized cSCC cells to conventional anticancer drugs, such as cisplatin and doxorubicin. Altogether, these data suggest that Skp2 targeting restores the functioning of tumor suppressors, inhibits the expression of genes associated with cell proliferation and stemness, and sensitizes cancer cells to anticancer drugs. Thus, genetic, and pharmacological ablation of Skp2 can be an important strategy for attenuating cancer pathogenesis and associated complications in skin squamous cell carcinoma.

Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans.

Non-melanoma skin cancer (NMSC), encompassing basal and squamous cell carcinoma, is the most prevalent cancer in the United States. While surgical removal remains the conventional therapy with a 95% 5-year cure rate, there is a growing interest in exploring alternative treatment strategies. In this study, we investigated the role of Bortezomib (BTZ), a proteasome inhibitor, in NMSC. Using two NMSC cell lines (A431 and A388), we examined the effects of BTZ treatment. Our results demonstrated that 48 h of BTZ treatment led to downregulating Skp2 expression in both A431 and A388 cells while upregulating p53 expression, specifically in A388 cells. These alterations resulted in impaired cellular growth and caspase-dependent cell death. Silencing Skp2 in A388 cells with siRNA confirmed the upregulation of p53 as a direct target. Furthermore, BTZ treatment increased the Bax to Bcl-2 ratio, promoting mitochondrial permeability and the subsequent release of cytochrome C, thereby activating caspases. We also found that BTZ exerted its antitumor effects by generating reactive oxygen species (ROS), as blocking ROS production significantly reduced BTZ-induced apoptotic cell death. Interestingly, BTZ treatment induced autophagy, which is evident from the increased expression of microtubule-associated proteins nucleoporin p62 and LC-3A/B. In addition to cell lines, we assessed the impact of BTZ in an in vivo setting using Caenorhabditis elegans (C. elegans). Our findings demonstrated that BTZ induced germline apoptosis in worms even at low concentrations. Notably, this increased apoptosis was mediated through the activity of CEP-1, the worm's counterpart to mammalian p53. In summary, our study elucidated the molecular mechanism underlying BTZ-induced apoptosis in NMSC cell lines and C. elegans. By targeting the skp2/p53 axis, inducing mitochondrial permeability, generating ROS, and promoting autophagy, BTZ demonstrates promising anti-cancer activity in NMSC. These findings provide novel insights into potential therapeutic strategies for controlling the unregulated growth of NMSC.

Emerging Role of the IL-36/IL-36R Axis in Multiple Inflammatory Skin Diseases.

IL-36 is a most recent member of the IL-1 cytokine family, primarily expressed at barrier sites of the body such as the skin, lungs, and intestine. It plays a vital role in inflammation and is implicated in the development of various cutaneous; intestinal; and pulmonary disorders, including psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. IL-36 comprises 4 isoforms: the proinflammatory IL-36α, IL-36ß, and IL-36γ and the anti-inflammatory IL-36R antagonist. An imbalance between proinflammatory and anti-inflammatory IL-36 isoforms can contribute to the inflammatory fate of cells and tissues. IL-36 cytokines signal through an IL-36R heterodimer mediating their function through canonical signaling cacade, including the NF-B pathway. Prominent for its role in psoriasis, IL-36 has recently been associated with disease mechanisms in atopic dermatitis, hidradenitis suppurativa, neutrophilic dermatoses, autoimmune blistering disease, and Netherton syndrome. The major cutaneous source of IL-36 cytokines is keratinocytes, pointing to its role in the communication between the epidermis, innate (neutrophils, dendritic cells) immune system, and adaptive (T helper [Th]1 cells, Th17) immune system. Thus, cutaneous IL-36 signaling is crucial for the immunopathological outcome of various skin diseases. Consequently, the IL-36/IL-36R axis has recently been recognized as a promising drug target for the treatment of inflammatory disorders beyond psoriasis. This review summarizes the current update on IL-36 cytokines in inflammatory skin diseases.

Mechanical epilation exerts complex biological effects on human hair follicles and perifollicular skin: An ex vivo study approach.

OBJECTIVE: Electrical epilation of unwanted hair is a widely used hair removal method, but it is largely unknown how this affects the biology of human hair follicles (HF) and perifollicular skin. Here, we have begun to explore how mechanical epilation changes selected key biological read-out parameters ex vivo within and around the pilosebaceous unit. METHODS: Human full-thickness scalp skin samples were epilated ex vivo using an electro-mechanical device, organ-cultured for up to 6 days in serum-free, supplemented medium, and assessed at different time points by quantitative (immuno-)histomorphometry for selected relevant read-out parameters in epilated and sham-epilated control samples. RESULTS: Epilation removed most of the hair shafts, often together with fragments of the outer and inner root sheath and hair matrix. This was associated with persistent focal thinning of the HF basal membrane, decreased melanin content of the residual HF epithelium, and increased HF keratinocyte apoptosis, including in the bulge, yet without affecting the number of cytokeratin 15+ HF epithelial stem cells. Sebocyte apoptosis in the peripheral zone was increased, albeit without visibly altering sebum production. Epilation transiently perturbed HF immune privilege, and increased the expression of ICAM-1 in the bulge and bulb mesenchyme, and the number of perifollicular MHC class II+ cells as well as mast cells around the distal epithelium and promoted mast cell degranulation around the suprabulbar and bulbar area. Moreover, compared to controls, several key players of neurogenic skin inflammation, itch, and/or thermosensation (TRPV1, TRPA1, NGF, and NKR1) were differentially expressed in post-epilation skin. CONCLUSION: These data generated in denervated, organ-cultured human scalp skin demonstrate that epilation-induced mechanical HF trauma elicits surprisingly complex biological responses. These may contribute to the delayed re-growth of thinner and lighter hair shafts post-epilation and temporary post-epilation discomfort. Our findings also provide pointers regarding the development of topically applicable agents that minimize undesirable sequelae of epilation.

OBJECTIF: L'épilation électrique des poils indésirables est une méthode d'épilation largement utilisée, mais on ne connaît pas l'ampleur de son effet sur la biologie des follicules pileux humains (FP) et de la peau périfolliculaire. Dans cette étude, nous avons commencé à explorer comment l'épilation mécanique modifie certains paramètres de mesures biologiques clés ex vivo à l'intérieur et autour de l'unité pilo­sébacée. MÉTHODES: Des échantillons de peau du cuir chevelu humain de pleine épaisseur ont été épilés ex vivo à l'aide d'un dispositif électromécanique, cultivés biologiquement pendant un maximum de 6 jours dans un milieu complet sans sérum, et évalués à différents moments par (immuno­)histomorphométrie quantitative pour certains paramètres de mesures pertinents dans des échantillons avec épilation et des échantillons témoins avec épilation simulée. RÉSULTATS: L'épilation a enlevé la plupart des poils, souvent avec des fragments de la gaine de la racine externe et de la matrice pileuse. Cela a été associé à un amincissement focal persistant de la membrane basale du FP, à une diminution de la teneur en mélanine de l'épithélium résiduel du FP et à une augmentation de l'apoptose des kératinocytes du FP, y compris dans la surface arrondie, mais sans affecter le nombre de cellules souches épithéliales du FP positives pour la cytokératine 15. L'apoptose des sébocytes de la zone périphérique était augmentée, sans pour autant altérer visiblement la production de sébum. L'épilation a temporairement perturbé l'immunoprivilège du FP et a augmenté l'expression de l'ICAM­1 dans la surface arrondie et le mésenchyme du bulbe, ainsi que le nombre de cellules périfolliculaires du CMH de classe II et des mastocytes autour de l'épithélium distal, et a favorisé la dégranulation des mastocytes autour de la zone supra­bulbaire et bulbaire. En outre, par rapport aux échantillons témoins, plusieurs acteurs clés de l'inflammation neurogène cutanée, de la démangeaison et/ou de la thermosensation (TRPV1, TRPA1, NGF et NKR1) ont été exprimés de manière différentielle dans la peau après l'épilation. CONCLUSION: Ces données générées dans la peau du cuir chevelu humain dénervée et cultivée biologiquement démontrent que le traumatisme du FP induit par l'épilation mécanique provoque des réponses biologiques étonnamment complexes. Celles­ci peuvent contribuer à retarder la repousse des poils plus fins et plus clairs après l'épilation, et à provoquer une gêne temporaire après l'épilation. Nos résultats fournissent également des pistes concernant le développement d'agents applicables par voie topique qui minimisent les séquelles indésirables de l'épilation.

Non-coding RNAs in the epigenetic landscape of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a type of cancer that affects skin, and is characterized by abnormal T-cells in the skin. Epigenetic changes have been found to play a significant role in the development and progression of CTCL. Recently, non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs, have been identified as key players in the regulation of gene expression in CTCL. These ncRNAs can alter the expression of genes involved in cell growth, differentiation, and apoptosis, leading to the development and progression of CTCL. In this review, we summarize the current understanding of the role of ncRNAs in CTCL, including their involvement in DNA methylation, and other biological processes. We also discuss the types of ncRNAs, their role as oncogenic or tumor suppressive, and their putative use as diagnostic and prognostic biomarkers, based on the emerging evidence from laboratory-based as well as patients-based studies. Moreover, we also present the potential targets and pathways affected by ncRNAs. A better understanding of the complex epigenetic landscape of CTCL, including the role of ncRNAs, has the potential to lead to the development of novel targeted therapies for this disease.

Embelin inhibits viability of cutaneous T cell lymphoma cell lines HuT78 and H9 by targeting inhibitors of apoptosis.

Cutaneous T cell lymphoma (CTCL) is a varied group of neoplasms that affects the skin. Acquired resistance against chemotherapeutic drugs and associated toxic side effects are limitations that warrant search for novel drugs against CTCL. Embelin (EMB) is a naturally occurring benzoquinone derivative that has gained attention owing to its anticancer pharmacological actions and nontoxic nature. We assessed the anticancer activity of EMB against CTCL cell lines, HuT78, and H9. EMB inhibited viability of CTCL cells in a dose-dependent manner. EMB activated extrinsic and intrinsic pathways of apoptosis as shown by the activation of initiator and executioner caspases. EMB-induced apoptosis also involved suppression of inhibitors of apoptosis, XIAP, cIAP1, and cIAP2. PARP cleavage and upregulation of pH2AX indicated DNA damage induced by EMB. In conclusion, we characterized a novel apoptosis-inducing activity of EMB against CTCL cells, implicating EMB as a potential therapeutic agent against CTCL.

Azithromycin downregulates ICOS (CD278) and OX40 (CD134) expression and mTOR activity of TCR-activated T cells to inhibit proliferation.

The precise mechanism of macrolide antibiotic azithromycin (AZM) mediated CD4+ T cell suppression is not fully understood. Given the crucial role of co-stimulatory signaling in T-lymphocyte function, we tested in vitro effects of AZM on two of the most extensively investigated costimulatory molecules, ICOS and OX40 in context to CD4+ T cell proliferation. Using multi-color flow cytometry approach on TCR-activated healthy donor peripheral blood mononuclear cells, we observed a marked reduction in the frequencies and surface expression of ICOS and OX40 receptors following AZM treatment. Functionally, in contrast to ICOS- and OX40- CD3+ CD4+ T cells, AZM treated ICOS+ and OX40+ displayed profound reduction in cell proliferation. Furthermore, AZM treated T cells displaying reduced levels of ICOS and OX40 found to be associated with suppressed mTOR activity as detected by phosphorylation levels of S6 ribosomal protein. This study provides new insights on potential mechanism of AZM mediated inhibition of T cell proliferation by targeting costimulatory pathways.

Epigenetic programing of cancer stemness by transcription factors-non-coding RNAs interactions.

Cancer 'stemness' is fundamental to cancer existence. It defines the ability of cancer cells to indefinitely perpetuate as well as differentiate. Cancer stem cell populations within a growing tumor also help evade the inhibitory effects of chemo- as well as radiation-therapies, in addition to playing an important role in cancer metastases. NF-κB and STAT-3 are representative transcription factors (TFs) that have long been associated with cancer stemness, thus presenting as attractive targets for cancer therapy. The growing interest in non-coding RNAs (ncRNAs) in the recent years has provided further insight into the mechanisms by which TFs influence cancer stem cell characteristics. There is evidence for a direct regulation of TFs by ncRNAs, such as, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) as well as circular RNAs (circRNAs), and vice versa. Additionally, the TF-ncRNAs regulations are often indirect, involving ncRNA-target genes or the sponging of other ncRNA species by individual ncRNAs. The information is rapidly evolving and this review provides a comprehensive review of TF-ncRNAs interactions with implications on cancer stemness and in response to therapies. Such knowledge will help uncover the many levels of tight regulations that control cancer stemness, providing novel opportunities and targets for therapy in the process.

CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances.

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy.

Pristimerin mediated anticancer effects and sensitization of human skin cancer cells through modulation of MAPK signaling pathways.

Squamous cell carcinoma is a frequent skin cancer still demanding to understand the underlying mechanisms for better clinical outcomes. Pristimerin, a natural quinonemethide triterpenoid, has shown promising therapeutic outcome due to its anti-cancer activity and multi-targeting potential. We explored the underlying mechanisms of pristimerin-induced programmed cell death of primary (A431) and metastatic (A388) cutaneous squamous cell carcinoma (cSCC) cells. Our results show that pristimerin inhibits growth and proliferation of cSCC through JNK activation. Moreover, pristimerin causes cell cycle arrest and induces cell death via apoptosis and autophagy. Interestingly, use of apoptosis (z-VAD-FMK) and autophagy (3-methyladenine) inhibitors confirmed vital role of programmed cell death in pristimerin-mediated anti-cancer actions. JNK inhibitor, SP600125, also mitigated pristimerin-induced apoptotic and autophagic actions. Moreover, pristimerin-mediated anti-cancer activity acts by generating reactive oxygen species (ROS) thereby inducing JNK signaling. Use of N-acetyl cystine (NAC), a universal ROS scavenger, significantly reversed pristimerin-induced programmed cell death through downregulation of JNK. Pristimerin sensitized skin cancer cells to conventional anticancer drugs cisplatin, azacytidine and doxorubicin through JNK activation, as confirmed by SP600125. Our results indicate that pristimerin mediates programmed cell death and sensitized skin cancer cells to conventional anti-cancer drugs via ROS-mediated JNK activation.

Targeting oncogenic transcription factors in skin malignancies: An update on cancer stemness and therapeutic outcomes.

The skin is the largest organ of the human body and prone to various diseases, including cancer; thus, provides the first line of defense against exogenous biological and non-biological agents. Skin cancer, a complex and heterogenic process, with steep incidence rate often metastasizes due to poor understanding of the underlying mechanisms of pathogenesis and clinical challenges. Indeed, accumulating evidence indicates that deregulation of transcription factors (TFs) due to genetic, epigenetic and signaling distortions plays essential role in the development of cutaneous malignancies and therapeutic challenges including cancer stemness features and reprogramming. This review highlights the recent developments exploring underlying mechanisms how deregulated TFs (e.g., NF-κB, AP-1, STAT etc.,) orchestrates cutaneous onco-pathogenesis, reprogramming, stemness and poor clinical outcomes. Along this line, bioactive drugs, and their derivatives from natural and or synthetic origin has gained attention due to their multitargeting potential, potentially safer and effective therapeutic outcome for human malignancies. We also discussed therapeutic importance of targeting aberrantly expressed TFs in skin cancers with bioactive natural products and or synthetic agents.

Targeting deregulated oxidative stress in skin inflammatory diseases: An update on clinical importance.

Skin, the largest vital organ of the human body, provides the first line of defense against biological, non-biological and xenobiotics exposure. Over the years, due to increased anthropogenic activities including industrialization and pollution, a steep increase in cutaneous pathological conditions such as malignancies, dermatitis, and psoriasis has been detected. Indeed, due to the complex nature of cutaneous inflammatory diseases, further investigations are required to produce a better outcome in patient care. However, research obtained over the last few decades has revolutionized the understanding of cutaneous disease pathogenesis and therapeutic developments. In this line, increasing data from pre-clinical and clinical studies implicates the crucial role of oxidative stress in pathogenesis and complications of cutaneous inflammatory diseases, including atopic dermatitis and psoriasis. Taking into consideration the current challenge, this review aims to highlight the novel updates exploring reactive oxygen species (ROS) induced mechanistic signaling mechanisms in conjunction with pathways converging towards atopic dermatitis and psoriasis. Additionally, an exploration of the clinical importance of natural products for management of cutaneous diseases has been included. Overall, this review highlights the therapeutic importance of targeting oxidative stress in the pathogenesis, symptoms, and complications of inflammatory diseases of the skin.

Real-world experience and long-term evaluation of tofacitinib in refractory alopecia areata: A prospective, open-label, single-center study in Asian Arab population.

Tofacitinib is a pan-janus kinase inhibitor (JAK) which has been tested off-label in alopecia areata (AA) with promising results. However, evidence of tofacitinib in real-life setting is still poor. We evaluated long-term efficacy and safety of tofacitinib for refractory AA. This is a prospective, open-label, observational, single-center cohort study conducted between January 2018 and December 2020. Primary end-point was the percent change in Severity of Alopecia Tool (SALT) at the basal visit and at the most recent follow-up visit. Three categories of treatment response were analyzed. Data on 47 participants of Arab-Asian heritage were analyzed. A complete and partial regrowth was observed in 18 patients (41.86%) and 11 patients (25.58%), respectively. In 12 patients (27.9%), no response was obtained. Most of the non-responders belonged to the alopecia universalis group (66.67%). No statistical differences were observed in rates of regrowth between pediatric and adult individuals (p = 0.52), nor between women and men. Significant differences in the average duration of tofacitinib treatment were obtained among the three categories of regrowth (p < 0.003), notably duration of AA did not impact the clinical regrowth (p = 0.62). To the best of our knowledge, this is the first prospective, observational, long-term study using tofacitinib in refractory AA. Rates of regrowth and side effects are analogous to previous works. Length of tofacinitib therapy should last for 12 months before considering any discontinuation or change, since early cessation can lead to treatment failures or incomplete regrowth. Maintenance therapy after complete regrowth has demonstrated to be safe and effective to prevent recurrences of hair loss.

Neuroimmune communication regulating pruritus in atopic dermatitis.

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system and the immune system. Dysregulation of neuroimmune circuits plays a key role in the pathophysiology of AD, causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors, transmitting itch stimuli to the brain. On stimulation, sensory nerve endings also release neuromediators into the skin, contributing again to inflammation, barrier dysfunction, and itch. In addition, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, and neuropathic itch, thus chronification and therapy resistance. Consequently, neuroimmune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, and ions excite/sensitize sensory nerve endings, which not only induces itch but further aggravates/perpetuates inflammation, skin barrier disruption, and pruritus as well. Thus, targeted therapies for neuroimmune circuits as well as pathway inhibitors (eg, kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or in topical form. Understanding neuroimmune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction, and pruritus.

Epigenetic regulation of CXCR4 signaling in cancer pathogenesis and progression.

Signaling involving chemokine receptor CXCR4 and its ligand SDF-1/CXL12 has been investigated for many years for its possible role in cancer progression and pathogenesis. Evidence emerging from clinical studies in recent years has further established diagnostic as well as prognostic importance of CXCR4 signaling. CXCR4 and SDF-1 are routinely reported to be elevated in tumors, distant metastases, which correlates with poor survival of patients. These findings have kindled interest in the mechanisms that regulate CXCR4/SDF-1 expression. Of note, there is a particular interest in the epigenetic regulation of CXCR4 signaling that may be responsible for upregulated CXCR4 in primary as well as metastatic cancers. This review first lists the clinical evidence supporting CXCR4 signaling as putative cancer diagnostic and/or prognostic biomarker, followed by a discussion on reported epigenetic mechanisms that affect CXCR4 expression. These mechanisms include regulation by non-coding RNAs, such as, microRNAs, long non-coding RNAs and circular RNAs. Additionally, we also discuss the regulation of CXCR4 expression through methylation and acetylation. Better understanding and appreciation of epigenetic regulation of CXCR4 signaling can invariably lead to identification of novel therapeutic targets as well as therapies to regulate this oncogenic signaling.