Molecular Mechanism Analysis of Intensive Light-Induced Retinal Damages.

Introduction: The retina is a light-sensitive tissue, and intensive light exposure leads to light-induced retinal damage. It is pointed out that photoreceptor damage is responsible for the decrease in retina function. The aim of this study was to detect the main genes and biological terms which are involved in retinal response to intensive light exposure. Methods: The effect of intensive light on the mouse retina function was searched in the Gene Expression Omnibus (GEO) database. The data of GSE22818 were assessed by the GEO2R program. The significant differentially expressed genes (DEGs) were determined and evaluated via directed protein-protein interaction (PPI) network analysis. The critical significant DEGs were enriched via gene ontology analysis to find the related biological processes, molecular function, and biochemical pathways. Results: Data analysis indicates that the high intensity of light induces gene expression alteration in the retina. 105 significant DEGs were identified as the main responsive genes to light damage in the retina. STAT3, JUN, IL6ST, SOCS3, ATF3, JUNB, FOSL1, CCL2, ICAM1, FGF2, AGT, MYC, LIF, CISH, and EGR1 were introduced as the critical affected genes. STAT3, JUN, IL6ST, SOCS3, and ATF3 and "Positive regulation of the receptor signaling pathway via JAK-STAT" were highlighted as the key elements of molecular events. Conclusion: It can be concluded that regulation of the key DEGs and the dependent biological terms can effectively provide tools to prevent the development of light-induced retinal damage.

Integrating protein interaction and pathway crosstalk network reveals a promising therapeutic approach for psoriasis through apoptosis induction.

Psoriasis is a complex inflammatory skin disease manifested by altered proliferation and differentiation of keratinocytes with dysfunctional apoptosis. This study aimed to identify regulatory factors and comprehend the underlying mechanisms of inefficient apoptosis to open up promising therapeutic approaches. Incorporating human protein interactions, apoptosis proteins, and physical relationships of psoriasis-apoptosis proteins helped us to generate a psoriasis-apoptosis interaction (SAI) network. Subsequently, topological and functional analyses of the SAI network revealed effective proteins, functional modules, hub motifs, dysregulated pathways and transcriptional gene regulatory factors. Network pharmacology, molecular docking and molecular dynamics simulation methods identified the potential drug-target interactions. RELA, MAPK1, MAPK3, MMP9, IL1B, AKT1 and STAT1 were revealed as effective proteins. The MAPK1-MAPK3-RELA motif was identified as a hub regulator in the crosstalk between 41 pathways. Among all pathways, "lipid and atherosclerosis" was found to be the predominant pathway. Acetylcysteine, arsenic-trioxide, ß-elemene, bortezomib and curcumin were identified as potential drugs to inhibit pathway crosstalk. Experimental verifications were performed using the literature search, GSE13355 and GSE14905 microarray datasets. Drug-protein-pathway interactions associated with apoptosis were deciphered. These findings highlight the role of hub motif-mediated pathway-pathway crosstalk associated with apoptosis in the complexity of psoriasis and suggest crosstalk inhibition as an effective therapeutic approach.

Efficacy Evaluation of Treatment of Psoriasis Via Narrow Band-Ultraviolet Radiation.

Introduction: Psoriasis is a common autoimmune skin disease associated with genetically influenced chronic inflammation accompanied by remitting and deteriorating scaly skin. T-cell targeted biologics, IL-17 inhibitors, IL-12/IL-23 inhibitors, TNF-α inhibitors, PDE4 inhibitors, and ultraviolet (UV) radiation are applied to treat psoriasis. Efficacy evaluation of narrow band UVB (NB-UVB) radiation was the aim of this study. Methods: Data were extracted from Gene Expression Omnibus (GEO) and were pre-evaluated via the GEO2R program. The significant differentially expressed genes (DEGs) were included in the protein-protein interaction (PPI) network analysis. The hubs, bottlenecks, and hub-bottleneck DEGs were introduced as central genes. Activation, inhibition, and expression relationship between central genes were assessed to explore the critical individuals. Results: Among 513 analyzed significant DEGs, 22 hub-bottleneck genes were identified. Further analysis revealed that FN1, STAT3, HIF1A, IL1B, P4HB, SOD2, MMP2, and STAT1 were the crucial genes in psoriasis samples targeted by NB-UVB radiation. Conclusion: In conclusion, NB-UVB radiation as a treatment targets critical genes in peri-lesion skin tissue biopsy of psoriasis patients via a complicated mechanism. This therapeutic method downregulates STAT3, HIF1A, IL1B, and P4HB to treat psoriasis but downregulates STAT1 and SOD2 and upregulates MMP2 and FN1 to develop disease.

The effect of topical tranexamic acid with micro-needling and micro-needling alone in treatment of macular amyloidosis.

BACKGROUND: Macular amyloidosis is a form of primary localized cutaneous amyloidosis presented by pruritic pigmented macules in rippled or reticulate pattern. The aim of this study was to assess the efficacy of using topical tranexamic acid with micro-needling comparing to micro-needling alone in patients with macular amyloidosis. MATERIALS AND METHODS: Patients with bilaterally located macular amyloidosis on trunk or upper extremities were recruited in this trial. The skin lesions in all patients were divided into two parts which were randomly assigned to the group of treatment with micro-needling plus tranexamic acid and the group of micro-needling alone. There were four sessions of treatment with 2 weeks interval. The percentage of improvement in pigmentation (based on photographs and dermoscopy) and rippling of each group was determined by three blinded dermatologists. The level of patient satisfaction and reduction of pruritus was measured by a questionnaire and defined as a percentage. RESULTS: Twenty females were enrolled in this study. The mean (SD) patients' age was 39.7 (±10.13) years. Both groups showed improvement in pigmentation based on images, dermoscopy, and rippling pattern. Patients' satisfaction was 46.5% in tranexamic acid group and 47.5% in micro-needling alone. Nevertheless, there was no significant difference between both groups (p value >0.05). Interestingly, the pruritus improved 61.66% after four sessions of treatment in both groups. CONCLUSION: Micro-needling is a suitable modality for decreasing pruritus and pigmentation in macular amyloidosis. However, topical application of tranexamic acid does not lead to additional improvement.

Evaluation of Laser Intensity Effect on Photodynamic Therapy Efficacy.

Introduction: Intensity is one of the important parameters of laser radiation in photodynamic therapy. Effective treatment requires the selection of a suitable power of laser. This study aimed to evaluate laser effectiveness in photodynamic therapy via high and low intensity by the analysis of the gene expression profiles of the treated cells. Methods: The gene expression profiles of human SK-ChA-1 cells which are treated by 500mW and 50mW laser radiation were retrieved from the Gene Expression Omnibus (GEO) database. Data were assessed by the GEO2R program, and the significant differentially expressed genes (DEGs) were investigated via expression examination and protein-protein interaction (PPI) network analysis. Results: Analyses revealed that the higher intensity of radiation is associated with wide gene expression changes relative to the lower mode. 196 significant DEGs were identified and assessed. The extremely dysregulated DEGs except MMP1 were down-regulated. STAT1, IRF7, IL1B, DDX58, ISG15, RSAD2, DHX58, OASL, OAS1, STAT2, DDX60, OAS2, USP18, and IFI44L were introduced as hubs of the main component of the PPI network. Final analysis showed that STAT1, IRF7, IL1B, DDX58, and STAT2 are the critical DEGs. Conclusion: Compared to the 50 mW mode of radiation, 500 mW laser intensity effectively changed apoptosis, differentiation, cell proliferation and angiogenesis, regulation of other inflammation-related molecules, innate immunity, and maintaining immune homeostasis.

Angiokeratoma of Fordyce-A rare complication of laser hair removal: A case report of two patients.

Key Clinical Message: This study highlights the first documented cases of angiokeratoma of Fordyce following laser hair removal (LHR) emphasizing the importance of patient selection and careful laser use. It underscores the importance of understanding LHR-associated risks, particularly for patients with darker skin. The efficacy of topical rapamycin as an alternative treatment for angiokeratomas is also discussed. Abstract: Laser hair removal (LHR) has emerged as a widely accepted method for achieving long-term hair reduction. While generally considered safe, it is important to study the possible adverse events to optimize patient care. Here, we present a unique case report of angiokeratoma of Fordyce, a rare vascular lesion, following LHR. Two patients experienced the development of these lesions subsequent to LHR treatment sessions, characterized by a severe burning sensation during the procedure. Interestingly, both individuals exhibited varicose veins on their legs, suggesting a potential risk factor for this complication. Our findings highlight the importance of understanding the mechanisms underlying LHR-induced adverse events and the need for further research to elucidate associated risk factors and management strategies. This case report serves to enhance awareness among clinicians and emphasizes the significance of patient counseling regarding the potential side effects of LHR.

Mild cognitive impairment in pemphigus.

BACKGROUND: Pemphigus is a group of autoimmune blistering disorders that have been associated with dementia in previous studies. Mild cognitive impairment (MCI) can be the first stage of progression into dementia. The objective of the present study was to evaluate the frequency of MCI in pemphigus patients compared to a control group. METHODS: This case-control study included 80 patients with pemphigus referred to the dermatology clinics of Shohadaye Tajrish and Loghman Hakim hospitals, Tehran, Iran, in 2021. A group of 80 individuals without pemphigus who visited the same clinics for cosmetic consultation or interventions were regarded as controls. Age, sex, marital status, and education were recorded for all participants. Disease duration, medications, and severity were noted for pemphigus patients. The Persian version of the Montreal Cognitive Assessment (MoCA) test was used to assess cognitive function. RESULTS: MCI was significantly more frequent in pemphigus patients than in controls (55% vs. 37.5%, P = 0.026). Furthermore, the total MoCA score was significantly lower in pemphigus patients compared to controls (23.98 ± 3.77 vs. 25.21 ± 3.45, P = 0.032); however, among MoCA's different domains, only the executive functions score was significantly lower in pemphigus patients (P = 0.010). After adjustment, multivariable logistic regression analysis revealed that every 1-year higher education in patients decreased the odds of MCI by 52% (adjusted odds ratio = 0.483, 95% confidence interval 0.326; 0.715, P < 0.001). CONCLUSIONS: The frequency of MCI was found to be significantly higher, and overall scores of the MoCA test, as well as its executive function domain, were significantly lower among pemphigus patients in this study compared to the control group. Additionally, a higher level of education was associated with decreased odds of MCI in pemphigus patients. Identifying pemphigus patients with MCI through the use of the MoCA test can facilitate early intervention, enabling them to seek help and support.

Knowledge, Attitude, and Practice toward Skin Cancer among Patients of Dermatology Clinics and Medical Students/General Practitioners.

This cross-sectional study assessed the knowledge, attitude, and practices (KAP) regarding skin cancer among dermatology clinic patients, medical students, and general practitioners (GPs) in Tehran, Iran. The researchers collected data using a validated questionnaire administered online, measuring KAP on scales of 0-31, 0-16, and 0-28, respectively, with scores above 16, 8, and 14 indicating "good" levels. Of 2243 participants (mean age 28 years), 59.4% had good knowledge, 19.8% had good attitudes, 31.8% had good practices, and 29.8% had good overall KAP. Medical students/GPs scored higher on knowledge and attitudes, while patients scored better on practices. Knowledge, attitudes, and practices were positively correlated in professionals but inversely correlated in patients. The findings suggest that while knowledge was moderate, attitudes and behaviors remained poor, particularly among patients. Immediate interventions are needed to improve attitudes and prevention practices, as public health initiatives must focus on positively influencing both to translate knowledge into meaningful action and find the reasons why good knowledge may not always lead to good practice. These findings underline the need for targeted interventions to bridge the gap between knowledge and preventive behaviors, to effectively reduce the burden of skin cancer in the population.

Acellular Fish Skin for Deep Dermal Traumatic Wounds Management; Introducing a Novel Dressing.

The optimal therapy for deep wounds is based on the early debridement of necrotic tissue followed by wound coverage to avoid a systemic inflammatory response and optimize scar-free healing. The outcomes are affected by available resources and underlying patient factors, which cause challenges in wound care and suboptimal outcomes. Here we report a patient with deep dermal injury wounds, who was treated with platelet-rich fibrin (PRF) gel, plasma rich in growth factor (PRGF) gel, and acellular fish skin. Patient's outcomes regarding healing and scar quality were collected objectively and subjectively for one year after the injury. Wounds treated with acellular fish skin demonstrated accelerated wound healing, a significantly higher water-storage capacity, and better pain relief. Furthermore, improved functional and cosmetic outcomes, such as elasticity, skin thickness, and pigmentation, were demonstrated. It seems that, the PRGF gel and PRF in combination with acellular fish skin grafts resulted in the faster healing of wounds and better functional and aesthetic outcomes than split-thickness skin grafts treatment.

Screening the critical protein subnetwork to delineate potential mechanisms and protective agents associated with arsenic-induced cutaneous squamous cell carcinoma: A toxicogenomic study.

Recent studies show that complex mechanisms are involved in arsenic-induced malignant transformation of cells. This study aimed to decipher molecular mechanisms associated with arsenic-induced cutaneous squamous cell carcinoma (cSCC) and suggest potential protective factors. RNA-seq-based differentially expressed genes between arsenic-exposed human keratinocytes (HaCaT) and controls were used to construct a protein-protein interaction (PPI) network and discover critical subnetwork-based mechanisms. Protective compounds against arsenic toxicity were determined and their target interactions in the core sub-network were identified by the comparative toxicogenomic database (CTD). The binding affinity between the effective factor and target was calculated by molecular docking. A total of 15 key proteins were screened out as critical arsenic-responsive subnetwork (FN1, IL-1A, CCN2, PECAM1, FGF5, EDN1, FGF1, PXDN, DNAJB9, XBP1, ERN1, PDIA4, DNAJB11, FOS, PDIA6) and 7 effective protective agents were identified (folic acid, quercetin, zinc, acetylcysteine, methionine, catechin, selenium). The GeneMANIA predicted detailed interactions of the subnetwork and revealed terms related to unfolded protein response as the main processes. FN1, IL1A and CCN2, as top significant genes, had good docking affinity with folic acid and quercetin, as selected key compounds. Integration of gene expression and protein-protein interaction related to arsenic exposure in cSCC explored the potential mechanisms and protective agents.

Botulinium toxin applications in the lower face and neck: A comprehensive review.

BACKGROUND: Botulinum toxin has been widely and mainly used for the treatment of conditions affecting the upper and middle face; however, recent efforts have expanded the indications of botulinum toxin injection to the lower face and neck areas for cosmetic and medical purposes. AIMS: We have reviewed the latest updates on using botulinum toxin in the lower face and neck focusing on cosmetic purposes and have discussed the existing concerns as well as the adverse sequelae of these newer indications. PATIENTS/METHODS: A comprehensive literature search was performed using the following keywords [[botulinum] AND [[Toxin] OR [Neurotoxin]]] AND [[Lower AND Face] AND/OR [Neck]] within the main databases including Web of Science, PubMed, Embase and gray literature on and before February 2023. The data were screened using titles and abstracts and those relevant to the topic were included in the paper. RESULTS: Botulinum toxin injection has considerable cosmetic and therapeutic effect on facial contouring, masseteric hypertrophy, lower face and neck scars, gummy smile, drooping lip corner and even skin rejuvenation. CONCLUSION: BNT injection has been widely used for the treatment of different medical and cosmetic purposes. Low rates of side effects, which were self-limited in most cases, have been reported in the literature, making BNT a safe therapeutic medication in most cases. However, regulatory status needs to be updated and more accurately revised in many countries and more comprehensive research is required to address the existing gaps in this area including the site, dosage, and method of injection in each case.

Iranian psoriasis registry: Research protocol and preliminary results of a pilot study.

BACKGROUND: Psoriasis as a common cutaneous inflammatory disease affect many aspects of patients' life. Disease registries render it possible to collect valuable data regarding a disease prevalence and burden as well as long-term observations concerning possible therapeutic regimens. METHODS: This registry was designed for the ongoing systematic data collection on patients with psoriasis at two referral dermatology centers in Iran. The pilot phase of the registry was used to identify possible obstacles in the application and execution of systematic registration. RESULTS: A total of 281 patients were registered with the mean age of 42.02 years. The disease duration was 12.06 ± 10.90 years with the variety of clinical presentations. There was no significant difference between males and females in the age of disease onset (p = 0.53). Notably, 167 patients had children. Among them, 13 had children with psoriasis. The gender of the affected parent did not affect the possibility of psoriasis transmission to the child, and no significant difference was seen between the two sexes (P = 0.569). Regarding treatment, 99.4% of patients (n = 280) had used topical agents, 52.3% (n = 147) biologics, and 60.9% (n = 171) nonbiologic medications. CONCLUSION: Clinical trials report the efficacy and safety data regarding limited study populations in a restricted time window, and the results may differ from the general population. This highlights the importance of registry-based studies for collecting and analyzing longitudinal information. In terms of long-term disease complications such as malignancies, cardiovascular events, and serious adverse events, registry-based studies will help clinicians better recognize and manage each disease.

The Combined Application of Bleomycin and Triamcinolone for Treating Refractory Keloids.

BACKGROUND: Triamcinolone acetate injections are considered the first treatment option for keloids, but quite high proportions of keloids either do not respond to triamcinolone or develop recurrence. Beneficial effects of intralesional bleomycin have been recently shown in the treatment of keloids and hypertrophic scars. However, the efficacy of combination therapy using intralesional triamcinolone and bleomycin remains undetermined. OBJECTIVE: The purpose of this study was to evaluate the efficacy of using bleomycin and triamcinolone mixture to treat refractory keloids. MATERIALS AND METHODS: In total, 33 patients with resistant keloids (including 8 men and 25 women) and a mean age of 36.52 years (age range of 18-65 years) were enrolled in this study. A mixture of bleomycin (1 u/cc) with triamcinolone acetonide (13.3 mg/cc) was injected intralesionally into the keloids every 4 to 6 weeks for a maximum of 6 cycles. The clinical improvement was evaluated using the Japan Scar Scale (JSS) and the physician's global assessment of the flattening of the lesions. Side effects were also noted and recorded. RESULTS: In all patients, the total JSS scores decreased significantly after treatment (2.33 ± 1.05), compared with baseline (11.61 ± 2.59), ( p < .001); 26 keloids (78.8%) showed an excellent response (75%-100% flattening), 7 keloids (21.2%) showed a fair response (25%-75% flattening), and 0 keloids (0%) showed a poor response (<25% flattening). Observed side effects were ulceration (33.3%), hyperpigmentation (33.3%), hypopigmentation (15.15%), secondary infection (33.3%), and telangiectasis (15.15%). CONCLUSION: The combined use of bleomycin and triamcinolone offers a promising treatment option for individuals who have not responded well to traditional therapies.

Assessment of the Response of Human Umbilical Vein Endothelial Cells to Photodynamic Therapy: Highlighting the Role of Il-17 Signaling Pathway.

Introduction: Photodynamic therapy (PDT) is a method based on the application of a photosensitive agent and the administration of light irradiation on the treated samples. PDT is applied as an effective tool with minimal side effects against tumor tissues. This study aimed to assess the targets of critical genes by PDT at the cellular level of cancer to provide a new perspective on its molecular mechanism. Methods: To assess the effect of PDT, we extracted the differentially expressed genes (DEGs) from the gene expression profiles of human umbilical vein endothelial cells (HUVECs) treated with PDT from Gene Expression Omnibus (GEO) databases. The queried DEGs were evaluated via a regulatory network and gene ontology enrichment to find the critical targets. Results: Among 76 queried significant DEGs, 27 individuals were interacted by activation, inhibition, and co-expression actions. Thirty DEGs were related to the five classes of biological terms. The IL-17 signaling pathway and PTGS2, CXCL8, FOS, JUN, CXCL1, ZFP36, and FOSB were identified as the crucial targets of PDT. Conclusion: PDT as a stimulator of gene expression and an activator of gene activity overexpressed and hyper-activated many genes. It seems that PDT introduces a number of genes and pathways that can be regulated by anticancer drugs to fight against cancers.

Assessment of Photosensitizer Concentration Effects on the Efficacy of Photodynamic Therapy.

Introduction: Photodynamic therapy (PDT) is an attractive approach in medicine. Due to its noninvasive nature and low side effects, PDT has been developed quickly. In the present study, the gene expression profiles of the human cell line that was treated via PDT in the sub-lethal concentration (LC50) and super-lethal concentration (LC90) of a photosensitizer (PS) from Gene Expression Omnibus (GEO) were extracted and the common differentially expressed genes (DEGs) were investigated. Methods: The gene expression profiles of the treated cells were compared with a control, and the common DEGs were determined. The common DEGs were assessed via protein-protein interaction (PPI) network analysis, and gene ontology enrichment was evaluated. The related biological terms for the common genes were identified. Results: Ninety-four common DEGs were selected to be analyzed. It appeared that the activation and increment of gene expression were prominent processes. Jun, Dusp1, Atf4, and Atf3 as four critical genes were highlighted. "Chromosomal and microsatellite instability in colorectal cancer" was identified as the main class of biological terms related to the assessed DEGs. Conclusion: The major molecular events which happened in both analyses indicated that PDT, independent from the concentration of PS, induced gross molecular changes such as the upregulation of Jun and Dusp1.

Collagen Synthesis as a Prominent Process During the Interval between Two Laser Sessions.

Introduction: Many people suffer from skin photodamage, especially photoaging. The application of a laser to repair damages is a common therapeutic method that is used widely. In the present study, the effectiveness and molecular mechanism of an Er:Glass non-ablative fractional laser on the human skin was assessed via bioinformatics and network analysis. Methods: The gene expression profiles of 17 white female forearm skins which received an Er:Glass non-ablative fractional laser before and after laser treatment in two sessions were extracted from Gene Expression Omnibus (GEO). Data were evaluated via GEO2R and the significant differentially expressed genes (DEGs) were assessed via protein-protein interaction (PPI) network analysis. The central nodes were identified and discussed for the compared set of samples. Results: Five classes of samples were clustered in two categories: first, baseline, 7 and 14 days after the first session of laser treatment, and second, one day after the first laser session, 29 days after the first laser session, and 1 day after the second laser session. The gross cell functions such as cell division and cell cycle and immune response were highlighted as the early affected targets of the laser. Collagen synthesis was resulted after the first laser session. Conclusion: In conclusion, the time interval between laser sessions plays a critical role in the effectiveness of laser therapy. Findings indicate that the gross effect of laser application appears in a short time, and important processes such as collagen synthesis happen later.

Monkeypox Disease with a Focus on the 2022 Outbreak; a Narrative Review.

Monkeypox is a zoonotic disease caused by a double-stranded DNA virus belonging to the genus Orthopoxvirus. Despite being endemic in Central and West Africa, the disease has received relatively little research attention until recent times. As the Coronavirus disease 2019 (COVID-19) pandemic continues to affect the world, the rising number of monkeypox cases in non-endemic countries has further stoked global public health concerns about another pandemic. Unlike previous outbreaks outside Africa, most patients in the present outbreak had no history of travel to the endemic regions. The overwhelming majority of patients were initially identified amongst homosexual men, who had attended large gatherings. Mutations in the coding regions of the viral genome may have resulted in fitness adaptation, enhancement of immune evasion mechanisms, and more efficient transmissibility of the 2022 monkeypox virus. Multiple factors such as diminished cross-protective herd immunity (cessation of smallpox vaccination), deforestation, civil war, refugee displacement, farming, enhanced global interconnectedness, and even climate change may facilitate the unexpected emergence of the disease. In light of the increasing number of cases reported in the present outbreak, healthcare professionals should update their knowledge about monkeypox disease, including its diagnosis, prevention, and clinical management. Herein, we provide an overview of monkeypox, with a focus on the 2022 outbreak, to serve as a primer for clinical practitioners who may encounter the disease in their practice.

The emerging role of T cells in pemphigus vulgaris: a systematic review.

Pemphigus vulgaris is a potential life-threatening autoimmune bullous disorder. The significant role of autoreactive B cells in the pathogenesis of PV has been explained extensively by producing autoantibodies. Recently, attention has been directed toward the role of T cells in the pathogenesis of PV; in other words, the underlying etiology of PV depends on the interaction between T cells and B cells resulting in antibody secretion. Herein, we systematically review the current literature on the emerging role of T cells in PV. To perform this systematic review, an extensive search through EMBASE, PubMed, Scopus, and ISI databases was performed from 1976 through 2021. Articles investigating the function of T cell subgroups in the pathogenesis or treatment of pemphigus vulgaris were included and reviewed. It is evidenced that T cells play a pivotal role in PV pathogenesis. Th1 and Th2 dichotomy including Th1 suppression and Th2 elevation may induce antibody production against desmoglein in keratinocytes. Furthermore, increased level of Th17 and decreased level of regulatory T cells have been detected in PV patients. However, further studies on the exact role of γδ-T cells in PV are required in order to clarify the pathogenesis of PV. T cells and their subtypes can be involved in the pathogenesis of PV. Thus, they can be considered as tentative targets of novel therapies for PV.