Prognostic biomarkers of cutaneous melanoma.

BACKGROUND/PURPOSE: Melanomas account for only approximately 4% of diagnosed skin cancers in the United States but are responsible for the majority of deaths caused by skin cancer. Both genetic factors and ultraviolet (UV) radiation exposure play a role in the development of melanoma. Although melanomas have a strong propensity to metastasize when diagnosed late, melanomas that are diagnosed and treated early pose a low mortality risk. In particular, the identification of patients with increased metastatic risk, who may benefit from early adjuvant therapies, is crucial, especially given the advent of new melanoma treatments. However, the accuracy of classic clinical and histological variables, including the Breslow thickness, presence of ulceration, and lymph node status, might not be sufficient to identify such individuals. Thus, there is a need for the development of additional prognostic melanoma biomarkers that can improve early attempts to stratify melanoma patients and reliably identify high-risk subgroups with the aim of providing effective personalized therapies. METHODS: In our current work, we discuss and assess emerging primary melanoma tumor biomarkers and prognostic circulating biomarkers. RESULTS: Several promising biomarkers show prognostic value (eg, exosomal MIA (ie, melanoma inhibitory activity), serum S100B, AMLo signatures, and mRNA signatures); however, the scarcity of reliable data precludes the use of these biomarkers in current clinical applications. CONCLUSION: Further research is needed on several promising biomarkers for melanoma. Large-scale studies are warranted to facilitate the clinical translation of prognostic biomarker applications for melanoma in personalized medicine.

Cytotoxic T cell depletion with increasing epithelial abnormality in women with benign breast disease.

PURPOSE: We quantified cytotoxic T cells in nonmalignant breast tissues from women with and without subsequent breast cancer to assess evidence of whether immunosurveillance may be suppressed prior to tumor development. METHODS: We used an age-matched set of breast tissues from women with benign breast disease (BBD) who subsequently developed breast cancer (BBD with later BC), women with BBD who remained cancer free (BBD cancer-free), and normal Komen Tissue Bank (KTB) tissue donors (KTB controls). We evaluated terminal duct lobular units (lobules) for degree of epithelial abnormality and density of dual-positive CD8/CD103 T cells, as CD103+ cells are thought to be a subset of CD8+ cytotoxic T cells located primarily in the intraepithelial compartment. RESULTS: In 10 sets of age-matched women, 256 breast lobules were studied: 85 in BBD women with later BC, 85 in BBD cancer-free women, and 86 in KTB donors. The majority of all lobules were histologically normal (N = 143, 56%), with 65 (25%) nonproliferative fibrocystic change, and 48 (19%) proliferative epithelial change (with or without atypia). In BBD women with later BC, median CD8+/CD103+ cell density was 39.6, 31.7, and 10.5 cells/mm2 (p = 0.002) for normal, nonproliferative, and proliferative lobules. In BBD cancer-free women, median CD8+/CD103+ cell density values were 46.7, 14.3, and 0 cells/mm2 (p = 0.004) respectively. In KTB donors, CD8+/CD103+ cell density was not significantly different across the lobule types (medians 0, 5.8, 10.7, p = 0.43). CONCLUSION: In women with BBD, breast lobules with increasing epithelial abnormality show significant decreases in cytotoxic T cells as measured by CD8/CD103 staining, suggesting that impaired immunosurveillance may be a component of the earliest stages of breast cancer development.

Increased Trend of Cosmetic Procedures in Patients With Psoriasis Who Attain 75% or Greater Improvement.

Background: The relationship between the clearance of psoriasis and improved quality of life together with an increased uptake of cosmetic procedures has not been reported to date. Objective: A survey was conducted at a single dermatology center to determine if there was an increased trend in cosmetic procedures in patients with moderate to severe psoriasis who attained 75% or greater reduction of the body surface area (BSA) with biologic agents and oral systemic therapies, and if this was related to an improvement in quality of life following psoriasis clearance. Study Design: In this case series, 138 patients with a history of moderate to severe psoriasis who attained 75% or greater body surface area (BSA) reduction with biologic agents or oral systemic therapies and had undergone at least one cosmetic procedure in the past 2 years were surveyed. Patient characteristics were collected including age, sex, percent BSA at initiation of therapy, the class of biologic or oral systemic therapies, and the different types of cosmetic procedures. Patients were asked to answer a 5-question survey on quality of life improvement, satisfaction with treatment, and correlation with the cosmetic procedure they had undergone, Patients also completed the Dermatology Quality of Life Index (DLQI) questionnaire in the survey. Results: The majority of patients who had undergone a cosmetic procedure after achieving 75% BSA stated that their psoriasis had previously prevented them from undergoing a cosmetic procedure. Regardless of therapy, all patients felt their quality of life had improved as a result of their treatment, and 91% of patients stated this was the impetus to undergo a cosmetic procedure. The mean DLQI score prior to therapy was 14.3 and 71% of patients reported a DLQI score of 0/1 after their psoriasis improved. Conclusion: There was a correlation between improvement in quality of life in patients who had achieved at least a 75% reduction in BSA with either a biologic agent, oral agent, or both, and the uptake of cosmetic procedures. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.5104R1.

Interaction of body mass index or waist-to-hip ratio and sun exposure associated with nonmelanoma skin cancer: A prospective study from the Women's Health Initiative.

BACKGROUND: The incidence of nonmelanoma skin cancer (NMSC) exceeds the incidence of all other types of cancers combined. Cumulative sun exposure and intermittent sun exposure are known risk factors for the development of NMSC. Because obesity has been shown to decrease the risk of NMSC incidence, this study investigated whether the risk of NMSC with sun exposure was consistent across different levels of body size. METHODS: Body size was assessed with the body mass index (BMI) and the waist-to-hip ratio (WHR). Sun exposure was assessed in watts and langleys and by the amount of time spent outdoors per day in the summer during a person's 30s. RESULTS: Among 71,645 postmenopausal women eligible for inclusion in this study, 13,351 participants (18.6%) developed NMSC. A BMI ≥ 25 kg/m2 or a WHR ≥ 0.80 was associated with lower NMSC hazard rates (hazard ratio for BMI, 0.78; hazard ratio for WHR, 0.89); however, the association between higher levels of sun exposure and a higher risk of NMSC was more apparent among women with a BMI ≥ 25 kg/m2 or a WHR ≥ 0.80 in comparison with those of a normal weight (P for interaction for BMI < .001; P for interaction for WHR = .022). CONCLUSIONS: Although most studies have considered sun exposure as a covariate, none have addressed the potential interaction of body size with sun exposure; therefore, the effect size of being overweight or obese may have been overestimated. In comparison to the normal-weight group, those in the overweight group had increasingly higher hazard rates with increasing sun exposure. Further studies are warranted to investigate how increased weight interacts with sun exposure to influence skin cancer pathogenesis.

The Negative Impact of Body Mass Index on the Tumor Microenvironment in Colon Cancer: Results of a Prospective Trial.

BACKGROUND: The association between tumor mismatch repair status and obesity in colon cancer is not well understood. The authors of this study hypothesized that mismatch repair deficiency in colon cancer may be associated with a lower Body Mass Index (BMI) and improved patient outcome due to an enhanced tumor immune microenvironment. METHODS: For this study, 70 patients were randomly selected from a prospective trial evaluating nodal ultrastaging for colon cancer. The mismatch repair status of tumors and immunomarker expression were correlated with clinicopathologic characteristics and evaluated for disease-free survival. RESULTS: Patients with mismatch repair-deficient tumors (n = 11) had a lower mean BMI than those with mismatch repair-proficient tumors (n = 59) (22.16 vs. 26.30 kg/m2, respectively; p = 0.029).The findings showed that CD3+ T cells were inversely associated with mismatch repair proficiency (p = 0.048). Mismatch repair-proficient tumors in nonobese patients (BMI < 30 kg/m2) versus obese patients had a higher density of CD8+ (p = 0.008) and FOXP3+ (p = 0.005) T cells. Multivariable analysis linked CD4+ (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.35-0.76), CD8+ (HR 0.67; 95% CI 0.50-0.89), and number of tumor-positive lymph nodes (HR 1.19; 95% CI 1.03-1.36) to disease-free survival for patients with mismatch repair-proficient tumors. CONCLUSIONS: Tumor mismatch repair status and obesity are correlated in patients with colon cancer. Increased intratumoral T cells in nonobese patients suggests an unexplored link between tumor mismatch repair and immunoprofile.

Langerhans Cells Maintain Local Tissue Tolerance in a Model of Systemic Autoimmune Disease.

Systemic autoimmune diseases such as lupus affect multiple organs, usually in a diverse fashion where only certain organs are affected in individual patients. It is unclear whether the "local" immune cells play a role in regulating tissue specificity in relation to disease heterogeneity in systemic autoimmune diseases. In this study, we used skin as a model to determine the role of tissue-resident dendritic cells (DCs) in local and systemic involvement within a systemic lupus disease model. Skin-resident DCs, namely, Langerhans cells (LCs), have been implicated in regulating tolerance or autoimmunity using elegant transgenic models, however, their role in local versus systemic immune regulation is unknown. We demonstrate that although lymphocytes from skin-draining lymph nodes of autoimmune-prone MRL/MpJ-Fas(lpr/lp) (r) (MRL-lpr) mice react spontaneously to a physiological skin self-Ag desmoglein-3, epicutaneous applications of desmoglein-3 induced tolerance that is dependent on LCs. Inducible ablation of LCs in adult preclinical MRL-lpr and MRL/MpJ-Fas(+/+) mice resulted in increased autoantibodies against skin Ags and markedly accelerated lupus dermatitis with increased local macrophage infiltration, but had no effect on systemic autoantibodies such as anti-dsDNA Abs or disease in other organs such as kidneys, lung, and liver. Furthermore, skin-draining lymph nodes of LC-ablated MRL-lpr mice had significantly fewer CD4(+) T cells producing anti-inflammatory cytokine IL-10 than LC-intact controls. These results indicate that a skin-resident DC population regulates local tolerance in systemic lupus and emphasize the importance of the local immune milieu in preventing tissue-specific autoimmunity, yet have no effect on systemic autoimmunity.

Interleukin-1ß triggers the differentiation of macrophages with enhanced capacity to present mycobacterial antigen to T cells.

The rapid differentiation of monocytes into macrophages (MΦ) and dendritic cells is a pivotal aspect of the innate immune response. Differentiation is triggered following recognition of microbial ligands that activate pattern recognition receptors or directly by pro-inflammatory cytokines. We demonstrate that interleukin-1ß (IL-1ß) induces the rapid differentiation of monocytes into CD209(+) MΦ, similar to activation via Toll-like receptor 2/1, but with distinct phenotypic and functional characteristics. The IL-1ß induced MΦ express higher levels of key markers of phagocytosis, including the Fc-receptors CD16 and CD64, as well as CD36, CD163 and CD206. In addition, IL-1ß-induced MΦ exert potent phagocytic activity towards inert particles, oxidized low-density lipoprotein and mycobacteria. Furthermore, IL-1ß-induced MΦ express higher levels of HLA-DR and effectively present mycobacterial antigens to T cells. Therefore, the ability of IL-1ß to induce monocyte differentiation into MΦ with both phagocytosis and antigen-presenting function is a distinct part of the innate immune response in host defence against microbial infection.

Neutrophil-derived IL-1ß is sufficient for abscess formation in immunity against Staphylococcus aureus in mice.

Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis and in vivo multispectral noninvasive imaging during the S. aureus infection revealed a strong functional and temporal association between neutrophil recruitment and IL-1ß/IL-1R activation. Unexpectedly, neutrophils but not monocytes/macrophages or other MHCII-expressing antigen presenting cells were the predominant source of IL-1ß at the site of infection. Furthermore, neutrophil-derived IL-1ß was essential for host defense since adoptive transfer of IL-1ß-expressing neutrophils was sufficient to restore the impaired neutrophil abscess formation in S. aureus-infected IL-1ß-deficient mice. S. aureus-induced IL-1ß production by neutrophils required TLR2, NOD2, FPR1 and the ASC/NLRP3 inflammasome in an α-toxin-dependent mechanism. Taken together, IL-1ß and neutrophil abscess formation during an infection are functionally, temporally and spatially linked as a consequence of direct IL-1ß production by neutrophils.

Galectin-3 regulates the innate immune response of human monocytes.

Galectin-3 is a ß-galactoside-binding lectin widely expressed on epithelial and hematopoietic cells, and its expression is frequently associated with a poor prognosis in cancer. Because it has not been well-studied in human infectious disease, we examined galectin-3 expression in mycobacterial infection by studying leprosy, an intracellular infection caused by Mycobacterium leprae. Galectin-3 was highly expressed on macrophages in lesions of patients with the clinically progressive lepromatous form of leprosy; in contrast, galectin-3 was almost undetectable in self-limited tuberculoid lesions. We investigated the potential function of galectin-3 in cell-mediated immunity using peripheral blood monocytes. Galectin-3 enhanced monocyte interleukin 10 production to a TLR2/1 ligand, whereas interleukin 12p40 secretion was unaffected. Furthermore, galectin-3 diminished monocyte to dendritic cell differentiation and T-cell antigen presentation. These data demonstrate an association of galectin-3 with unfavorable host response in leprosy and a potential mechanism for impaired host defense in humans.

Quantitative Aggregation of Microbiome Sequencing Data Provides Insights into the Associations between the Skin Microbiome and Psoriasis.

Although prior studies have reported distinct skin microbiome profiles associated with psoriasis, differences in methods and analyses limit generalizable conclusions. Individual studies have actually reported conflicting findings; for example, Propionibacterium and Staphylococcus have been significantly associated with both psoriatic lesions and healthy skin. Qualitative reviews have attempted to summarize this body of work, but there is great variability across the studies' findings and methods. To better unify these data, we created a meta-analysis of all publicly available datasets by utilizing a uniform bioinformatics pipeline and reference database to investigate associations of the skin microbiome in psoriasis. A total of 977 skin swab samples (341 lesional, 295 nonlesional, and 341 healthy) from 6 studies were analyzed. The aggregated analysis revealed a higher relative abundance of microorganisms, including Staphylococcus aureus and Corynebacterium simulans, among others, from patients with psoriasis than those from healthy swab samples; in addition, Cutibacterium acnes, Lawsonella unclassified, and S warneri were significantly higher in healthy samples. Furthermore, comparison of functional pathways predicted from 16S gene markers showed that L-ornithine biosynthesis and L-histidine biosynthesis were lower in psoriatic lesions than in healthy controls. Taken together, this meta-analysis allows for a more generalizable association between the skin microbiome and psoriasis.

N-Myristoyltransferase Inhibition causes Mitochondrial Iron Overload and Parthanatos in TIM17A-dependent Aggressive Lung Carcinoma.

Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by N-myristoyltransferases. Myristoylation is emerging as a promising cancer therapeutic target, however the molecular determinants of sensitivity to N-myristoyltransferase inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that N-myristoyltransferases are a novel therapeutic target in lung carcinoma cells with LKB1 and/or KEAP1 mutations in a KRAS mutant background. Inhibition of myristoylation decreases cell viability in vitro and tumor growth in vivo. Inhibition of myristoylation causes mitochondrial ferrous iron overload, oxidative stress, elevated protein poly (ADP)-ribosylation and death by parthanatos. Furthermore, NMT inhibitors sensitized lung carcinoma cells to platinum-based chemotherapy. Unexpectedly, the mitochondrial transporter Translocase of Inner Mitochondrial Membrane 17 homologue A (TIM17A) is a critical target of myristoylation inhibitors in these cells. TIM17A silencing recapitulated the effects of NMT inhibition at inducing mitochondrial ferrous iron overload and parthanatos. Furthermore, sensitivity of lung carcinoma cells to myristoylation inhibition correlated with their dependency on TIM17A. This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis N-myristoyltransferase-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas.

Alcohol and Smoking Cessation as Potential Modulators for Smoking-Associated Psoriasis Risk in Postmenopausal Women: The Women's Health Initiative.

BACKGROUND: The association of alcohol with psoriasis has been inconsistent among studies. OBJECTIVES: We aimed (1) to determine whether alcohol consumption (by status, frequency, and subtype of alcohol) modulates smoking-related psoriasis risk in postmenopausal women while stratifying for smoking status and pack-years and (2) to evaluate the effect of smoking cessation on psoriasis risk in postmenopausal women. METHODS: This prospective cohort study included 106,844 postmenopausal women enrolled in the Women's Health Initiative between 1993 and 1998. Patients diagnosed with psoriasis were identified using fee-for-service Medicare International Classification of Diseases, Ninth Revision, Clinical Modification codes assigned by dermatologists or rheumatologists. Self-administered questionnaires were used to obtain information on demographics, medical history, and smoking and alcohol habits. Hazard ratios from Cox regression models were adjusted for ethnicity, income, body mass index, and history of non-melanoma skin cancer and were stratified on age and on randomization status in the Women's Health Initiative study components. RESULTS: In the initial statistical model, past and current alcohol drinkers had higher risks of psoriasis compared with never-drinkers (P-trend < 0.001). This association was not observed after adjusting for cigarette smoking (P-trend: 0.478). The effect of alcohol (by status, frequency, and alcohol subtype) isolated by stratifying the analysis by smoking status (i.e., among never smokers) showed no association with psoriasis. Smoking showed an increasing risk for psoriasis with greater pack-years compared with those who have never smoked (P-trend: < 0.001). Compared to smokers at baseline, past smokers had a lower risk of psoriasis across women who smoked 5-14 cigarettes per day (hazard ratio 0.67, 95% confidence interval 0.51-0.88) and across women who smoked for 5-24 years (hazard ratio 0.65, 95% confidence interval 0.46-0.90). CONCLUSIONS: These findings indicate that alcohol consumption does not modulate smoking-related psoriasis risk. Cigarette smoking, but not alcohol consumption, is an independent risk factor for psoriasis in postmenopausal women. As greater pack-years was associated with a higher risk of psoriasis and smoking cessation was conversely associated with a lower risk of psoriasis for moderate smokers, a greater emphasis on smoking abstinence and cessation counseling may benefit patients who already have other risk factors for psoriasis.

Acne Keloidalis Nuchae is Associated with Cutis Verticis Gyrata.

Purpose: Both acne keloidalis nuchae (AKN) and cutis verticis gyrata (CVG) are scalp conditions predominantly affecting men. Both are characterized by dermal thickening and fibroblast hyperactivity. AKN typically occurs in the nuchal area, often involving the naturally occurring folds in the occipital region. The aim of this study was to determine the relationship between excessive scalp folding (CVG) and AKN. Patients and methods: A total of 108 patients with AKN seen over 11 years from July 2009 and November 2020 were retrospectively evaluated. Patients with AKN concomitant with CVG were selected for analysis. Results: Seven of the 108 AKN patients had scalp-wide (widespread) AKN lesions, including 4 with CVG. In 3 of the 4 patients with concomitant AKN and CVG, the AKN was widespread, and its onset had preceded CVG by 1-2 years. In the fourth CVG patient, AKN lesions were confined to the nuchal area, and the CVG preceded AKN onset by several years. All patients were male, with a mean age of 35.8 years (overall) and 38.0 years (CVG group). Conclusion: We describe a previously unreported relationship between widespread AKN and CVG, with the development of AKN preceding CVG formation.

The Effect of Systemic Antibiotics for Suppurative Skin and Soft Tissue Infections on the Skin Microbiome.

Background: Skin and soft tissue infections (SSTIs) are very common bacterial infections. There are few data on the microbiome of persons with and without SSTIs and the effects of systemic antibiotic therapy. Methods: We sampled the skin microbiome from 10 outpatients with acute suppurative SSTI before and after systemic antibiotic therapy and enrolled 10 matched controls. Samples were collected at 6 skin body sites (occipital scalp, axilla, interdigital hand web spaces, gluteal crease, inguinal creases, and popliteal fossa), 2 mucosal sites (throat, anterior nares), and the site of skin infection (for case subjects) at baseline and a week later after abscess incision, drainage, and oral antibiotics. Result: Among 10 SSTI cases, mean age was 41.5 years and 3 had diabetes mellitus. The gluteal crease at baseline had higher α-diversity in controls vs cases (P = .039); ß-diversity analysis showed significant differences in overall bacterial community composition (P = .046). However, at other body sites there were no significant differences by either α- or ß-diversity. Systemic antibiotic use did not affect body site diversity indices except at the SSTI site (α-diversity increased, P = .001). Conclusions: We surprisingly found no significant differences in microbiome comparing noninfected skin sites before and after systemic SSTI antibiotic therapy nor significant differences at noninfected skin sites between SSTI cases and uninfected controls. We also found minimal significant differences between microbiome diversity and bacterial signatures at noninfected skin sites between patients with acute skin infection and uninfected controls. Our findings challenge the dogma that systemic antibiotics impact the skin microbiome.

BCG hydrogel promotes CTSS-mediated antigen processing and presentation, thereby suppressing metastasis and prolonging survival in melanoma.

BACKGROUND: The use of intralesional Mycobacterium bovis BCG (intralesional live BCG) for the treatment of metastatic melanoma resulted in regression of directly injected, and occasionally of distal lesions. However, intralesional-BCG is less effective in patients with visceral metastases and did not significantly improve overall survival. METHODS: We generated a novel BCG lysate and developed it into a thermosensitive PLGA-PEG-PLGA hydrogel (BCG hydrogel), which was injected adjacent to the tumor to assess its antitumor effect in syngeneic tumor models (B16F10, MC38). The effect of BCG hydrogel treatment on contralateral tumors, lung metastases, and survival was assessed to evaluate systemic long-term efficacy. Gene expression profiles of tumor-infiltrating immune cells and of tumor-draining lymph nodes from BCG hydrogel-treated mice were analyzed by single-cell RNA sequencing (scRNA-seq) and CD8+ T cell receptor (TCR) repertoire diversity was assessed by TCR-sequencing. To confirm the mechanistic findings, RNA-seq data of biopsies obtained from in-transit cutaneous metastases of patients with melanoma who had received intralesional-BCG therapy were analyzed. RESULTS: Here, we show that BCG lysate exhibits enhanced antitumor efficacy compared to live mycobacteria and promotes a proinflammatory tumor microenvironment and M1 macrophage (MΦ) polarization in vivo. The underlying mechanisms of BCG lysate-mediated tumor immunity are dependent on MΦ and dendritic cells (DCs). BCG hydrogel treatment induced systemic immunity in melanoma-bearing mice with suppression of lung metastases and improved survival. Furthermore, BCG hydrogel promoted cathepsin S (CTSS) activity in MΦ and DCs, resulting in enhanced antigen processing and presentation of tumor-associated antigens. Finally, BCG hydrogel treatment was associated with increased frequencies of melanoma-reactive CD8+ T cells. In human patients with melanoma, intralesional-BCG treatment was associated with enhanced M1 MΦ, mature DC, antigen processing and presentation, as well as with increased CTSS expression which positively correlated with patient survival. CONCLUSIONS: These findings provide mechanistic insights as well as rationale for the clinical translation of BCG hydrogel as cancer immunotherapy to overcome the current limitations of immunotherapies for the treatment of patients with melanoma.

Association between baseline insulin resistance and psoriasis incidence: the Women's Health Initiative.

Small-scale studies offer conflicting evidence regarding the relationship/association between psoriasis and insulin resistance by HOMA-IR (homeostasis model assessment of insulin resistance). The purpose of this study was to assess the association between baseline HOMA-IR and psoriasis incidence in a large-scale longitudinal cohort of postmenopausal women. The analysis included 21,789 postmenopausal women from the Women's Health Initiative. Psoriasis diagnosis was defined by fee-for-service Medicare ICD-9-CM codes assigned by dermatologists or rheumatologists, and a 2-year lookback period to exclude prevalent cases. Baseline HOMA-IR was calculated using the updated HOMA2 model. Hazard rates from the Cox regression models were stratified by age (10-year intervals), on WHI component (Clinical Trial or Observational Study), and on randomization status within each of the WHI clinical trials. The complete model also adjusted for ethnicity, waist-hip-ratio, and smoking and alcohol habits. Among participants free of psoriasis at entry, those with high baseline HOMA-IR (≥ 2) compared to low (< 1.4) had significantly higher risk for psoriasis over 21-year cumulative follow-up (HR: 1.39, 95% CI 1.08-1.79, P-trend: 0.011). In postmenopausal women, higher baseline HOMA-IR levels were significantly associated with higher incidence of psoriasis over 21-year cumulative follow-up. Results from this time-to-event analysis indicate that insulin resistance can precede and is associated with an increased risk of psoriasis. Study is limited by Medicare diagnostic code accuracy and cohort age.

Tocilizumab overcomes chemotherapy resistance in mesenchymal stem-like breast cancer by negating autocrine IL-1A induction of IL-6.

Triple-negative breast cancer (TNBC) patients with mesenchymal stem-like (MSL) subtype have responded poorly to chemotherapy whereas patients with basal-like 1 (BL1) subtype achieved the best clinical response. In order to gain insight into pathways that may contribute to the divergent sensitivity to chemotherapy, we compared the inflammatory profile of the two TNBC subtypes treated with docetaxel. Cellular signaling analysis determined that docetaxel activated MAPK pathway in MSL TNBCs but not BL1 TNBCs. The subsequent MAPK pathway activation in MSL TNBCs led to an IL-1A mediated cascade of autocrine inflammatory mediators including IL-6. Utilizing the humanized IL-6R antibody, tocilizumab, our in vitro and in vivo data show that MSL TNBCs treated with tocilizumab together with chemotherapy results in delayed tumor progression compared to MSL TNBCs treated with docetaxel alone. Our study highlights a molecular subset of TNBC that may be responsive to tocilizumab therapy for potential translational impact.

Activation of Fc gamma RI on monocytes triggers differentiation into immature dendritic cells that induce autoreactive T cell responses.

The formation of immune complexes results in activation of the innate immune system and subsequent induction of host inflammatory responses. In particular, the binding of IgG immune complexes to FcgammaR on monocytes triggers potent inflammatory responses leading to tissue injury in disease. We investigated whether activation of monocytes via FcgammaR induced cell differentiation, imparting specific inflammatory functions of the innate immune response. Human IgG alone induced monocytes to differentiate into cells with an immature dendritic cell (iDC) phenotype, including up-regulation of CD1b, CD80, CD86, and CD206. Differentiation into CD1b(+) iDC was dependent on activation via CD64 (FcgammaRI) and induction of GM-CSF. The human IgG-differentiated iDC were phenotypically different from GM-CSF-derived iDC at the same level of CD1b expression, with higher cell surface CD86, but lower MHC class II, CD32, CD206, and CD14. Finally, in comparison to GM-CSF-derived iDC, IgG-differentiated iDC were more efficient in activating T cells in both autologous and allogeneic mixed lymphocyte reactions but less efficient at presenting microbial Ag to T cells. Therefore, activation of FcgammaRI on monocytes triggers differentiation into specialized iDC with the capacity to expand autoreactive T cells that may contribute to the pathogenesis of immune complex-mediated tissue injury.