Integrating multi-omics approaches in deciphering atopic dermatitis pathogenesis and future therapeutic directions.

Atopic dermatitis (AD), a complex and heterogeneous chronic inflammatory skin disorder, manifests in a spectrum of clinical subtypes. The application of genomics has elucidated the role of genetic variations in predisposing individuals to AD. Transcriptomics, analyzing gene expression alterations, sheds light on the molecular underpinnings of AD. Proteomics explores the involvement of proteins in AD pathophysiology, while epigenomics examines the impact of environmental factors on gene expression. Lipidomics, which investigates lipid profiles, enhances our understanding of skin barrier functionalities and their perturbations in AD. This review synthesizes insights from these omics approaches, highlighting their collective importance in unraveling the intricate pathogenesis of AD. The review culminates by projecting future trajectories in AD research, particularly the promise of multi-omics in forging personalized medicine and novel therapeutic interventions. Such an integrated multi-omics strategy is poised to transform AD comprehension and management, steering towards more precise and efficacious treatment modalities.

Generalized Pustular Psoriasis and Systemic Organ Dysfunctions.

This review explores the intricate relationship between generalized pustular psoriasis (GPP) and various systemic diseases, shedding light on the broader impacts of this severe skin condition beyond its primary dermatological manifestations. GPP is identified as not only a profound contributor to skin pathology but also a significant risk factor for systemic diseases affecting cardiovascular, hepatic, renal, pulmonary, and skeletal systems, as well as associated with an increased incidence of anemia, depression, anxiety, and arthritis. The research highlights the complex interplay of cytokines, particularly IL-17 and IL-36, which are central to the pathophysiology of GPP and implicated in the exacerbation of systemic conditions. Key findings indicate a higher incidence of cardiovascular events in GPP patients compared to those with other severe forms of psoriasis, notably with a stronger correlation between myocardial infarction history and GPP development. Liver disturbances, frequently reversible upon psoriasis remission, suggest a cytokine-mediated link to hepatic health. Renal dysfunction appears elevated in GPP sufferers, with IL-17 and IL-36 potentially driving renal fibrosis. Similarly, interstitial lung disease and osteoporosis in GPP patients underscore the systemic reach of inflammatory processes initiated in the skin. The associations with anemia, depression, anxiety, and arthritis further complicate the clinical management of GPP, requiring a multidisciplinary approach. The study concludes that managing GPP effectively requires a holistic approach that addresses both the cutaneous and systemic dimensions of the disease, advocating for continued research into the mechanisms that connect GPP with broader health implications to refine therapeutic strategies.

The incidence of Jarisch-Herxheimer reactions and associated risk factors in pregnant women and nonpregnant women: A retrospective chart review at a university hospital in Japan.

AIMS: Jarisch-Herxheimer reactions (JHR) is a transient adverse event that occurs during initial antimicrobial treatment for syphilis patients, and is known to develop uterine contractions and fetal distress in pregnant women complicated with syphilis. The aim of this study is to identify risk factors for JHR in patients with syphilis, and to clarify whether pregnancy status is a risk factor for JHR, and to describe the characteristics of pregnant women who develop JHR. METHODS: This was a retrospective chart review in a singleton university hospital in Japan. We collected data of syphilis patients who were diagnosed and treated at department of obstetrics and gynecology, dermatology between January 2010 and May 2022. There were no validated diagnostic criteria for JHR, we defined JHR as one or more of the following in addition to raised body temperature (≧38.0°C) within 24 h of initial antibiotic treatment: headache, chills, myalgias, tachycardia (≧110 bpm), new rash. RESULTS: There were 30 syphilis patients. Of whom nine (30%) were pregnant women and all their neonates were not diagnosed with congenital syphilis. Five patients (17%) developed JHR at the time of initial treatment (JHR group, n = 5). There was no difference between JHR group and non-JHR group (n = 25) in pregnancy status. Secondary syphilis was an only significant risk factor for JHR. Two pregnant women with JHR were both treated for secondary syphilis in the third trimester of pregnancy. CONCLUSION: Pregnancy status was not a risk factor for JHR in syphilis patients. Further research is needed.

Occupational Skin Dermatitis among Healthcare Workers Associated with the COVID-19 Pandemic: A Review of the Literature.

The skin is the outermost layer of the human body and is continually exposed to numerous external stimuli, which can cause unwanted skin irritation. Occupational skin diseases are the most prevalent form of work-related illness and are found in a variety of sectors, particularly healthcare. During the recent COVID-19 pandemic, healthcare professionals experienced a variety of unexpected, unusual occupational skin diseases associated with COVID-19-engaged employment. Because the clinical characteristics of these types of skin inflammation are unique, this review focuses on the characteristics of a large category of occupational workers, namely COVID-19-engaged healthcare professionals. Furthermore, we examined the potential pathogeneses of occupational skin disorders associated with COVID-19-engaged labor, as well as different preventative methods.

Impact of Gemcitabine Plus S1 Neoadjuvant Chemotherapy on Borderline Resectable Perihilar Cholangiocarcinoma.

BACKGROUND: Surgical resection is the only curative strategy for perihilar cholangiocarcinoma (PHC), but recurrence rates are high even after purported curative resection. This study aimed to evaluate the efficacy and safety of gemcitabine/S-1 (GS) combination chemotherapy in the neoadjuvant setting. METHODS: In an open-label, single-arm, phase 2 study, neoadjuvant chemotherapy (NAC) with GS, repeated every 21 days, was administered for three cycles to patients with histologic or cytologically confirmed borderline resectable (BR) PHC who were eligible for inclusion in the study. In this study, BR PHC was defined as positive for lymph node metastasis and for cancerous vascular invasion or Bismuth type 4 on preoperative imaging. The primary end point consisted of the 3- and 5-year survival rates. The secondary end points were feasibility, resection rate, and pathologic effect. RESULTS: The study enrolled 60 patients between January 2011 and December 2016. With respect to toxicity, the major adverse effect was neutropenia, which reached grade 3 or 4 in 53.3% of cases. The overall disease control rate was 91.3%. The median survival time for the entire cohort was 30.3 months. For all the patients, the estimated 3-year survival rate was 44.1%, and the 5-year survival rate was 30.0%. Resection with curative intent was performed for 43 (71%) of the 60 patients. For 81% of the resected patients, R0 resection was performed, and Clavien-Dindo grade 3 complications or a higher morbidity rate was seen in 41% of the patients. The median survival time was 50.1 months for the resected and 14.8 months for the unresected patients. For the resected patients, the estimated 3-year survival rate was 55.8%, and the estimated 5-year survival rate was 36.4%. CONCLUSIONS: Gemcitabine/S-1 combination NAC has promising efficacy and good tolerability for patients with BR PHC.

Role of the Intramural Vascular Network of the Extrahepatic Bile Duct for the Blood Circulation in the Recipient Extrahepatic Bile Duct Used for Duct-to-Duct-Biliary-Anastomosis in Living Donor Liver Transplantation.

A duct-to-duct-biliary-anastomosis is the preferred biliary reconstruction technique in liver transplantation; biliary complications remain the major concerns for the technique. We examined the significance of the intramural vascular network of the extrahepatic bile duct (EBD) and its relevant vessels. We microscopically examined the axial sections of the EBD with 5 mm intervals of 10 formalin-fixed deceased livers. The luminal-areas of the 3 and 9 o'clock arteries correlated significantly and positively with the distance from the bifurcation of the right and left hepatic ducts (the 3 o'clock artery, r = 0.42, p < 0.001; the 9 o'clock artery, r = 0.39, p < 0.001); the ratios of the numbers of the intramural vessels to the areas of the corresponding sections of the EBD significantly correlated positively with the distance from the bifurcation of the right and left hepatic ducts (total vessels, r = 0.78, p < 0.001; arterioles, r = 0.52, p < 0.001; venules, r = 0.45, p < 0.001). This study demonstrated that there is a significant locoregional distributional heterogeneity of the intramural vessels among the EBD. The hepatic arteries neighboring the EBD primarily supply the blood flow to the EBD; thus, when the broader isolation of the EBD from the neighboring arteries is necessary, this locoregional distributional heterogeneity of the intramural vessels may render the EBD likely to suffer ischemia of the anastomotic site.

Psoriasis and Systemic Inflammatory Disorders.

Psoriasis is a representative inflammatory skin disease occupied by large surface involvement. As inflammatory cells and cytokines can systemically circulate in various organs, it has been speculated that psoriatic skin inflammation influences the systemic dysfunction of various organs. Recent updates of clinical studies and experimental studies showed the important interaction of psoriasis to systemic inflammatory diseases. Furthermore, the importance of systemic therapy in severe psoriasis is also highlighted to prevent the development of systemic inflammatory diseases. In this review, we introduced representative systemic inflammatory diseases associated with psoriasis and the detailed molecular mechanisms.

Epigenetic Modification of PD-1/PD-L1-Mediated Cancer Immunotherapy against Melanoma.

Malignant melanoma is one of the representative skin cancers with unfavorable clinical behavior. Immunotherapy is currently used for the treatment, and it dramatically improves clinical outcomes in patients with advanced malignant melanoma. On the other hand, not all these patients can obtain therapeutic efficacy. To overcome this limitation of current immunotherapy, epigenetic modification is a highlighted issue for clinicians. Epigenetic modification is involved in various physiological and pathological conditions in the skin. Recent studies identified that skin cancer, especially malignant melanoma, has advantages in tumor development, indicating that epigenetic manipulation for regulation of gene expression in the tumor can be expected to result in additional therapeutic efficacy during immunotherapy. In this review, we focus on the detailed molecular mechanism of epigenetic modification in immunotherapy, especially anti-PD-1/PD-L1 antibody treatment for malignant melanoma.

Epigenetics of Cutaneous T-Cell Lymphomas.

Epigenetic modifications rarely occur in isolation (as single "epigenetic modifications"). They usually appear together and form a network to control the epigenetic system. Cutaneous malignancies are usually affected by epigenetic changes. However, there is limited knowledge regarding the epigenetic changes associated with cutaneous lymphomas. In this review, we focused on cutaneous T-cell lymphomas such as mycosis fungoides, Sézary syndrome, and anaplastic large cell lymphoma. With regard to epigenetic changes, we summarize the detailed chemical modifications categorized into DNA methylation and histone acetylation and methylation. We also summarize the epigenetic modifications and characteristics of the drug for cutaneous T-cell lymphoma (CTCL). Furthermore, we discuss current research on epigenetic-targeted therapy against cutaneous T-cell lymphomas. Although the current method of treatment with histone deacetylase inhibitors does not exhibit sufficient therapeutic benefits in all cases of CTCL, epigenetic-targeted combination therapy might overcome this limitation for patients with CTCL.

Involvement of Atopic Dermatitis in the Development of Systemic Inflammatory Diseases.

The skin is recognized as a peripheral lymphoid organ that plays an essential defensive action against external environmental stimuli. However, continuous stimulation of these factors causes chronic inflammation at the local site and occasionally causes tissue damage. Chronic inflammation is recognized as a trigger for systemic organ inflammation. Atopic dermatitis (AD) is a chronic inflammatory skin disease that is influenced by various external environmental factors, such as dry conditions, chemical exposure, and microorganisms. The pathogenesis of AD involves various Th2 and proinflammatory cytokines. Recently updated studies have shown that atopic skin-derived cytokines influence systemic organ function and oncogenesis. In this review, we focus on AD's influence on the development of systemic inflammatory diseases and malignancies.

Lifestyle Factors Involved in the Pathogenesis of Alopecia Areata.

Alopecia areata is a representative inflammatory skin disease that is associated with various environmental stimuli. While psychological stress is believed to be a major pathogenetic trigger in alopecia areata, infants and newborns also suffer from the disease, suggesting the possible presence of other environmental factors. Daily lifestyle is well known to be involved in various inflammatory diseases and influences the severity of inflammatory skin diseases. However, only a limited number of studies have summarized these influences on alopecia areata. In this review article, we summarize lifestyle factor-related influences on the pathogenesis of alopecia areata and focus on environmental factors, such as smoking, alcohol consumption, sleep, obesity, fatty acids, and gluten consumption.

Maresin-1 and Inflammatory Disease.

Inflammation is an essential action to protect the host human body from external, harmful antigens and microorganisms. However, an excessive inflammation reaction sometimes exceeds tissue damage and can disrupt organ functions. Therefore, anti-inflammatory action and resolution mechanisms need to be clarified. Dietary foods are an essential daily lifestyle that influences various human physiological processes and pathological conditions. Especially, omega-3 fatty acids in the diet ameliorate chronic inflammatory skin diseases. Recent studies have identified that omega-3 fatty acid derivatives, such as the resolvin series, showed strong anti-inflammatory actions in various inflammatory diseases. Maresin-1 is a derivative of one of the representative omega-3 fatty acids, i.e., docosahexaenoic acid (DHA), and has shown beneficial action in inflammatory disease models. In this review, we summarize the detailed actions of maresin-1 in immune cells and inflammatory diseases.

[A Case of Pemphigus Vulgaris Showing a Local Nose Erosion as the First Clinical Manifestation].

A 73-year-old male noticed a localized nose erosion that we thought was possibly an exacerbation of skin erosion due to the direct influence of friction from wearing a mask. Blood examination revealed a remarkable increase in serum anti-desmoglein-1 and anti-desmoglein-3 antibodies. A skin biopsy showed acantholysis in the epidermal granular layer. Based on the clinical manifestation and laboratory examination, we diagnosed his eruption as anti-desmoglein-1 and anti-desmoglein-3 antibody - positive pemphigus vulgaris. His skin eruption responded well to oral prednisolone and azathioprine and gradually improved. Pemphigus was a candidate as a differential diagnosis in this case, in which the direct mechanical friction from wearing a mask was thought to be an exacerbating factor of skin eruption.

[A Case of Contact Dermatitis Due to Ultrasonography Gel].

A 60-year-old female had a subcutaneous mass in the B region of the left breast. A needle aspiration cytologic examination revealed class IV, and she was referred to our surgical department for examination and treatment. She underwent an ultrasound echography on bilateral the mammary glands and axillary lymph nodes. Erythematous papules and plaques were revealed on her left breast, left axilla, and in the center of the chest area. The patient was referred to our dermatology department for evaluation of her skin eruption. Histopathological examination revealed the infiltration of lymphocytes and eosinophils in the perivascular of the upper dermis with spongiosis and liquid degeneration in the epidermis. A patch testing showed a positive reaction to ultrasonography gel. Based on the clinical course and examinations, we diagnosed her skin eruption as contact dermatitis due to ultrasonography gel. Her skin eruption improved rapidly by topical application of betamethasone butyrate propionate ointment. Recurrence of her skin eruption could be avoided by the removal of the gel after the ultrasonography examination. Our case report demonstrated to us that contact dermatitis could be prevented by promptly wiping off the ultrasonography gel from the skin after the examination.

[A Case of Psoriatic Arthritis Confirmed by Re-examination of Skin Biopsy].

A 30-year-old woman had recognized general fatigue and joint pain 5 years before her first visit to our hospital. Keratinized skin lesions were also observed on her hand, elbows, and other interstitial sites at the same time. She was referred to our department for evaluation of her skin eruption because psoriatic arthritis was suspected. A physical examination revealed hyperkeratotic, brownish plaques on her hand, elbows, and knees. Although a skin biopsy taken from her right hand could not confirm a diagnosis, another biopsy taken from her right elbow revealed hyperkeratosis and parakeratosis with agranulosis epithelial hyperplasia, indicating a diagnosis of psoriasis. Taking an additional skin biopsy from a site other than the main one can be helpful for a diagnosis of psoriatic arthritis.

[A Case of Occupational Contact Dermatitis Caused by Rubber Gloves].

A 42-year-old man working at a steel mill recognized itching and erythema on the dorsal surfaces of his hands for 2 weeks prior to his first visit to our department. Lichenized erythematous plaques were observed on the dorsal surfaces of his fingers and hands. A patch testing of the rubber part of the gloves showed a positive reaction. We also conducted a patch testing of metals to exclude a possibility of contact dermatitis mediated by metals as occupational materials. The patch testing of metals showed a positive reaction to zinc, which is not an occupational material in his steel mill, but his rubber gloves contained zinc in the rubber accelerators, which might have been the trigger that caused his allergic contact dermatitis. Contact dermatitis is the most common occupational skin disease, and various materials are the causative agents. Allergic reactions to rubber (latex) are classified into type I allergy and type IV allergy. Type IV allergic reaction is observed in rubber accelerators such as thiuram; however, our case showed that zinc allergy could be a possible causative agent in patients with contact dermatitis due to rubber gloves.

[A Case of a Subcutaneous Foreign Body Discovered by Coincidence During a Head MRI Imaging Examination].

An 80-year-old male was admitted to the department of neurology for intensive examination and treatment of peri-optic nerve inflammation. Magnetic resonance imaging examination could not be conducted because a magnetic resonance imaging examination at a previous clinic revealed a subcutaneous foreign body on his head, possibly a piece of metal. He was referred to our department for the removal of this foreign body. There was no traumatic scar in the skin and we could not identify this subcutaneous foreign body by physical examination and superficial echography, but radioscopy could find this subcutaneous material and we could remove this foreign body under the guidance of the radioscopy.

[Long-Term Survival after Surgical Resection for Small Cell Neuroendocrine Carcinoma of the Gallbladder].

A 60-year-old woman was not accompanied by any symptom. She had a gallstone which was identified 20 years prior. Ultrasonography performed by a local doctor revealed that the gallbladder was filled with small stones, and the patient was referred to our department for further examination and treatment for gallbladder stone. Tumor markers are elevated. Contrast- enhanced CT revealed gallbladder stones and thickening in the gallbladder body. PET-CT showed abnormal accumulation of FDG-PET with SUVmax 3.6 in the body of the gallbladder. With a diagnosis of gallbladder cancer, extended cholecystectomy and gallbladder bed resection with regional lymph node dissection were performed. The tumor was diagnosed histologically as small cell type neuroendocrine carcinoma of the gallbladder(pT2a[SS], pN0, pStage ⅡA; Japanese society of hepato-biliary-pancreatic surgery, the 7th edition). The postoperative course was uneventful. This patient has been followed up for 8 years without obvious signs of recurrence. R0 resection and lack of lymph node metastasis can allow long- term survival.

Daily Lifestyle and Cutaneous Malignancies.

Daily lifestyle is a fundamental part of human life and its influence accumulates daily in the human body. We observe that a good daily lifestyle has a beneficial impact on our health; however, the actual effects of individual daily lifestyle factors on human skin diseases, especially skin cancers, have not been summarized. In this review, we focused on the influence of daily lifestyle on the development of skin cancer and described the detailed molecular mechanisms of the development or regulation of cutaneous malignancies. Several daily lifestyle factors, such as circadian rhythm disruption, smoking, alcohol, fatty acids, dietary fiber, obesity, and ultraviolet light, are known to be associated with the risk of cutaneous malignancies, malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and Merkel cell carcinoma. Although the influence of some daily lifestyles on the risk of skin cancers is controversial, this review provides us a better understanding of the relationship between daily lifestyle factors and skin cancers.

Epigenetics of Cutaneous Sarcoma.

Epigenetic changes influence various physiological and pathological conditions in the human body. Recent advances in epigenetic studies of the skin have led to an appreciation of the importance of epigenetic modifications in skin diseases. Cutaneous sarcomas are intractable skin cancers, and there are no curative therapeutic options for the advanced forms of cutaneous sarcomas. In this review, we discuss the detailed molecular effects of epigenetic modifications on skin sarcomas, such as dermatofibrosarcoma protuberans, angiosarcoma, Kaposi's sarcoma, leiomyosarcoma, and liposarcoma. We also discuss the application of epigenetic-targeted therapy for skin sarcomas.