Recycled melanoma-secreted melanosomes regulate tumor-associated macrophage diversification.

Extracellular vesicles (EVs) are important mediators of communication between cells. Here, we reveal a new mode of intercellular communication by melanosomes, large EVs secreted by melanocytes for melanin transport. Unlike small EVs, which are disintegrated within the receiver cell, melanosomes stay intact within them, gain a unique protein signature, and can then be further transferred to another cell as "second-hand" EVs. We show that melanoma-secreted melanosomes passaged through epidermal keratinocytes or dermal fibroblasts can be further engulfed by resident macrophages. This process leads to macrophage polarization into pro-tumor or pro-immune cell infiltration phenotypes. Melanosomes that are transferred through fibroblasts can carry AKT1, which induces VEGF secretion from macrophages in an mTOR-dependent manner, promoting angiogenesis and metastasis in vivo. In melanoma patients, macrophages that are co-localized with AKT1 are correlated with disease aggressiveness, and immunotherapy non-responders are enriched in macrophages containing melanosome markers. Our findings suggest that interactions mediated by second-hand extracellular vesicles contribute to the formation of the metastatic niche, and that blocking the melanosome cues of macrophage diversification could be helpful in halting melanoma progression.

Alopecia Areata as a Proximal Risk Factor for the Development of Comorbid Depression: A Population-based Study.

Alopecia areata and depression tend to co-occur; however, their temporal association has not been comprehensively investigated. The aim of this study was to examine the temporal association between alopecia areata and depression. The study included only cases with a comorbid presentation of alopecia areata and depression (n = 1,936), extracted from the databases of the Clalit Health Services, Israel. Survival analyses were used to assess the cumulative probability of receiving alopecia areata as comorbid diagnosis in the years following depression, and vice versa, compared with the opposite trajectory. The results indicate that patients with alopecia areata had greater odds of subsequent depression within 2 years from alopecia areata diagnosis, and showed a steeper increase in cumulative probability of depression as time progressed (log-rank =336.38, p < 0.001), compared with the opposite trajectory. All patients with alopecia areata had comorbid depression within 10 years of alopecia areata, compared with 70% of depression patients receiving diagnoses of comorbid alopecia areata within the same time-frame.

The association between alopecia areata and anxiety, depression, schizophrenia, and bipolar disorder: a population-based study.

Although Alopecia areata (AA) has been found to be associated with psychological distress, the scope and nature of this association has not been fully delineated. The current study sought to examine the association of AA with anxiety, depression, schizophrenia, and bipolar disorder, utilizing a large-scale matched controlled cohort design. Patients suffering from AA (n = 41,055) were matched to control cases (n = 41,055) by age, sex, and socioeconomic status (SES). The prevalence of the four major mental disorders was assessed while stratifying the sample by age and sex, and after adjusting for marital status, smoking, BMI, hypertension, and diabetes. Data were accessed via the Clalit Health Services (CHS) database, a comprehensive health registry utilized by the largest managed healthcare company in Israel. Anxiety was independently and positively associated with AA (OR 1.22, 95% CI 1.13-1.31, p < 0.001), across all age groups above 30, with similar rates in males and females. Depression was also independently and positively associated with AA (OR 1.09, 95% CI 1.01-1.17, p < 0.005), particularly in the 30-49 age group, with a higher association among females. A negative association was found between AA and schizophrenia (OR 0. 71, 95% CI 0.61-0.83, p < 0.001). No association was found between AA and bipolar disease. Patients with AA are at risk for anxiety and depression, with female patients, and patients in the 30-49 age group being particularly vulnerable to develop a co-occurring mental disorder. Medical treatment should therefore include psychiatric evaluation and appropriate care.

Inflammatory bowel disease presenting with pyodermatitis-pyostomatitis vegetans in a pediatric patient: A case report and review of the literature.

Pyodermatitis-pyostomatitis vegetans (PD-PSV) is rarely reported in the pediatric population. Here, we provide a review of pediatric PD-PSV in the literature and report a case of widespread PD-PSV in a 15-year-old male without a previous history of inflammatory bowel disease or gastrointestinal symptoms. Clinical, histological, and immunopathological workup established PD-PSV and revealed subclinical Crohn's disease. Treatment with infliximab was effective in inducing rapid resolution of the lesions.

The association of chronic spontaneous urticaria (CSU) with anxiety and depression: a nationwide cohort study.

Chronic spontaneous urticaria (CSU) is a dermatological disease associated with significant impairment of overall quality of life as well as psychological distress. Previous studies have demonstrated significant comorbidity between CSU and a wide range of mental illnesses. In this study we aimed to focus on the association between CSU and anxiety and depression, using an optimized matched controlled design. A nationwide matched control study was conducted using the Clalit Health Services (CHS) database. The study included 12,539 CSU patients and 60,510 age and sex matched controls. Three multiple logistic regression models were conducted to assess the association between CSU and anxiety and depression, while adjusting for age, sex, socioeconomic status (SES), diabetes, obesity, hypertension, and smoking status. A higher frequency of anxiety and depression was found in CSU patients compared to that in controls (anxiety frequency of 9.6% vs. 5.7%, p < 0.001; depression frequency of 11% vs 7.9%, p < 0.001, respectively) after adjustment for demographic and clinical factors. The association of CSU with anxiety was the strongest in the 18-29 age group, and in the high SES group, while the association of CSU with depression was the highest in the 50-69 age group, and in the low SES group. Chronic spontaneous urticaria is associated with anxiety and depression. In light of the clinical implications of a comorbid mental disorder, dermatologists should consider employing mental health screening procedures, especially for patients from specific risk groups.

Hidradenitis Suppurativa and Bipolar Disorders: A Population-Based Study.

BACKGROUND: Psychological comorbidities have been reported in patients with hidradenitis suppurativa (HS), yet only a few studies have investigated the possible association between HS and severe psychiatric disorders. The current study aimed to assess the association between HS and bipolar disorder, a major, chronic, psychiatric disease. METHODS: A nationwide, population-based study was performed utilizing data from the Clalit Health Services (CHS) database in Israel. The study included 4,191 HS patients and 20,941 age- and gender-matched controls. A multivariate binary logistic regression, adjusted for demographic and behavioral risk factors, was performed. RESULTS: A higher proportion of bipolar disorders was found among HS patients compared to controls (0.7 vs. 0.1%, respectively). There was an increased proportion of active smokers among HS patients than among controls (53.4 vs. 13.5%, respectively). In the multivariate analysis, adjusting for age, sex, and smoking, HS was found to be independently and positively associated with bipolar disorders (OR 2.12, 95% CI 1.21-3.27, p < 0.01), yet after controlling for body mass this association became nonsignificant. CONCLUSIONS: Bipolar disorders are associated with HS. Future studies should explore whether cardiometabolic deficiencies might account for this association. Healthcare providers should consider this potential co-occurrence as it may impede patient compliance and require appropriate screening and treatment. Results also stress the need for a multidisciplinary approach to optimize management of the disease and its associated comorbidities.