ABSTRACT
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 (NMT). Myristoylation is emerging as a promising cancer therapeutic target; however, the molecular determinants of sensitivity to NMT inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that NMTs 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 homolog 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 NMT-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas. SIGNIFICANCE: KRAS-mutant lung carcinomas with LKB1 and/or KEAP1 co-mutations have intrinsic therapeutic resistance. We show that these tumors are sensitive to NMT inhibitors, which slow tumor growth in vivo and sensitize cells to platinum-based chemotherapy in vitro. Inhibition of myristoylation causes death by parthanatos and thus has the potential to kill apoptosis and ferroptosis-resistant cancer cells. Our findings warrant investigation of NMT as a therapeutic target in highly aggressive lung carcinomas.
Subject(s)
Acyltransferases , Iron Overload , Lung Neoplasms , Mitochondria , Mitochondrial Precursor Protein Import Complex Proteins , Humans , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/genetics , Animals , Mitochondria/drug effects , Mitochondria/metabolism , Acyltransferases/antagonists & inhibitors , Acyltransferases/genetics , Mice , Iron Overload/metabolism , Cell Line, Tumor , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Membrane Transport Proteins/metabolism , Membrane Transport Proteins/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , AMP-Activated Protein Kinase Kinases , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Xenograft Model Antitumor Assays , Mutation , Oxidative Stress/drug effectsABSTRACT
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.
ABSTRACT
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.
Subject(s)
Psoriasis , Smoking Cessation , Humans , Female , Aged , United States , Prospective Studies , Smoking , Postmenopause , Medicare , Women's Health , Risk Factors , Alcohol Drinking , Psoriasis/etiologyABSTRACT
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.
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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.
Subject(s)
Antigen Presentation , BCG Vaccine , Cathepsins , Lung Neoplasms , Melanoma , Animals , BCG Vaccine/therapeutic use , CD8-Positive T-Lymphocytes , Cathepsins/metabolism , Humans , Hydrogels/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Melanoma/drug therapy , Melanoma/pathology , Mice , Receptors, Antigen, T-Cell , Tumor MicroenvironmentABSTRACT
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 (Pâ =â .039); ß-diversity analysis showed significant differences in overall bacterial community composition (Pâ =â .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, Pâ =â .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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Melanoma , Skin Neoplasms , Biomarkers, Tumor , Humans , Melanoma/pathology , Prognosis , Skin Neoplasms/pathology , Melanoma, Cutaneous MalignantABSTRACT
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.
Subject(s)
Insulin Resistance , Psoriasis , Aged , Cohort Studies , Female , Humans , Incidence , Insulin , Medicare , Psoriasis/epidemiology , Risk Factors , United States/epidemiology , Women's HealthABSTRACT
The inducible nitric oxide signaling (iNOS) pathway is associated with poor prognosis in triple-negative breast cancer (TNBC). Prior studies using in vivo models showed that inhibition of the iNOS signaling pathway using the pan-NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) reduced tumor growth and enhanced survival in patients with TNBC. Here, we report a first-in-class phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemorefractory, locally advanced breast cancer (LABC) or metastatic TNBC. We also examined immune cell correlates of chemotherapy response. 35 patients with metastatic TNBC were recruited: 15 in the phase 1 trial and 24 in the phase 2 trial (including 4 recommended phase 2 dose patients from the phase 1 trial). The overall response rate was 45.8% (11 of 24): 81.8% (9 of 11) for patients with LABC and 15.4% (2 of 13) for patients with metastatic TNBC. Among the patients with LABC, three patients had a pathological complete response at surgery (27.3%). Grade ≥3 toxicity was noted in 21% of patients; however, no adverse events were attributed to L-NMMA. Immune cells analyzed by CyTOF indicated that chemotherapy nonresponders showed greater expression of markers associated with M2 macrophage polarization and increased concentrations of circulating IL-6 and IL-10 cytokines. In contrast, chemotherapy responders showed an increase in CD15+ neutrophils in blood, as well as a decrease in arginase (a marker of protumor N2 neutrophils) in tumor biopsies obtained at the end of treatment. L-NMMA combined with taxane warrants further investigation in larger clinical studies of patients with breast cancer.
Subject(s)
Triple Negative Breast Neoplasms , Enzyme Inhibitors/pharmacology , Humans , Nitric Oxide/metabolism , Nitric Oxide Synthase/therapeutic use , Taxoids/pharmacology , Taxoids/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , omega-N-Methylarginine/pharmacology , omega-N-Methylarginine/therapeutic useABSTRACT
BACKGROUND: Although many treatments are available for acne keloidalis nuchae (AKN), no systematic classification scheme exists to evaluate the outcomes of these treatments. OBJECTIVE: This study aimed to propose an AKN classification scheme. METHODS: A retrospective data analysis of several parameters, including lesion distribution, lesion type, and scalp disease association, was conducted in 108 men diagnosed with AKN between July 2009 and November 2020 in an outpatient dermatology setting. A three-tier classification system was developed as follows: Tier 1, lesion distribution relative to an area demarcated by two horizontal lines on the occipital prominences and tips of the mastoid processes and lesion sagittal width defined using Classes I through IV; Tier 2, lesion types including papules/nodules (discrete/merged), plaques, and tumorous masses; and Tier 3, the presence or absence of folliculitis decalvans (FD) or dissecting cellulitis (DC). RESULTS: All patients were non-white men, with most being of African (58%) or Hispanic (37%) descent. The most prevalent Tier 1 AKN presentation was Class II (58%). The mean sagittal width for Classes I through III were 2.4cm (I), 4.5cm (II), and 8.0cm (III), with Class IV characterized by widespread scalp disease. Plaques were most common in Tier 2-type lesions. FD or DC was found in seven percent of the study participants. Patients of African descent had a greater tendency to develop tumorous masses (p<0.02). LIMITATIONS: The retrospective study design and possible selection bias. CONCLUSION: We proposed an AKN classification scheme as a tool for objectively describing AKN lesions and evaluating treatment outcomes.
Subject(s)
Health Knowledge, Attitudes, Practice , Hidradenitis Suppurativa/therapy , Information Dissemination/methods , Social Media/statistics & numerical data , Video Recording/statistics & numerical data , Cross-Sectional Studies , Hidradenitis Suppurativa/diagnosis , Hidradenitis Suppurativa/psychology , Humans , Quality of LifeABSTRACT
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.
Subject(s)
Cosmetic Techniques/trends , Patient Acceptance of Health Care/statistics & numerical data , Psoriasis/therapy , Adult , Biological Factors/therapeutic use , Cosmetic Techniques/statistics & numerical data , Dermatologic Agents/therapeutic use , Female , Humans , Male , Middle Aged , Patient Satisfaction , Psoriasis/diagnosis , Psoriasis/psychology , Quality of Life , Severity of Illness Index , Surveys and Questionnaires , Treatment OutcomeABSTRACT
N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells. NMT1 sustains proliferation and/or survival of cancer cells through mechanisms that are not completely understood. We used genetic and pharmacological inhibition of NMT1 to further dissect the role of this enzyme in cancer, and found an unexpected essential role for NMT1 at promoting lysosomal metabolic functions. Lysosomes mediate enzymatic degradation of vesicle cargo, and also serve as functional platforms for mTORC1 activation. We show that NMT1 is required for both lysosomal functions in cancer cells. Inhibition of NMT1 impaired lysosomal degradation leading to autophagy flux blockade, and simultaneously caused the dissociation of mTOR from the surface of lysosomes leading to decreased mTORC1 activation. The regulation of lysosomal metabolic functions by NMT1 was largely mediated through the lysosomal adaptor LAMTOR1. Accordingly, genetic targeting of LAMTOR1 recapitulated most of the lysosomal defects of targeting NMT1, including defective lysosomal degradation. Pharmacological inhibition of NMT1 reduced tumor growth, and tumors from treated animals had increased apoptosis and displayed markers of lysosomal dysfunction. Our findings suggest that compounds targeting NMT1 may have therapeutic benefit in cancer by preventing mTORC1 activation and simultaneously blocking lysosomal degradation, leading to cancer cell death.
Subject(s)
Acyltransferases/metabolism , Lysosomes/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Neoplasms/metabolism , Animals , Autophagy , Cell Line, Tumor , Endosomes/metabolism , Enzyme Activation , Fluorescent Antibody Technique , Humans , Mice , ProteolysisABSTRACT
Understanding the cellular interactions within the tumor microenvironment (TME) of melanoma paved the way for novel therapeutic modalities, such as T cell-targeted immune checkpoint inhibitors (ICI). However, only a limited fraction of patients benefits from such therapeutic modalities, highlighting the need for novel predictive and prognostic biomarkers. As myeloid cells orchestrate the tumor-specific immune response and influence the efficacy of ICI, assessing their activation state within the TME is of clinical relevance. Here, we characterized a myeloid activation (MA) signature, comprising the three genes Cxcl11, Gbp1, and Ido1, from gene expression data of human myeloid cells stimulated with poly(I:C) or cGAMP. This MA signature positively correlated to overall survival in melanoma. In addition, increased expression of the MA signature was observed in melanoma patients responding to ICI (anti-PD-1), as compared to non-responders. Furthermore, the MA signature was validated in the murine B16F10 melanoma model where it was induced and associated with decreased tumor growth upon intratumoral administration of poly(I:C) and cGAMP. Finally, we were able to visualize co-expression of the MA signature genes in myeloid cells of human melanoma tissues using RNAscope in situ hybridization. In conclusion, the MA signature indicates the activation state of myeloid cells and represents a prognostic biomarker for the overall survival in melanoma patients.
ABSTRACT
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.
Subject(s)
Breast Diseases/etiology , Breast Diseases/pathology , Epithelium/metabolism , Epithelium/pathology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Adult , Biomarkers , Breast Neoplasms/etiology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Count , Disease Susceptibility/immunology , Female , Follow-Up Studies , Humans , Immunologic Surveillance , Middle Aged , PhenotypeABSTRACT
BACKGROUND: Insulin resistance has been proposed as a mediator of the increased cancer incidence and mortality associated with obesity. However, prior studies included limited cancer deaths and had inconsistent findings. Therefore, we evaluated insulin resistance and cancer-specific and all-cause mortality in postmenopausal women participating in the Women's Health Initiative (WHI). METHODS: Eligible were a subsample of 22 837 WHI participants aged 50-79 years enrolled at 40 US clinical centers from 1993 to 1998 who had baseline fasting glucose and insulin levels. Baseline insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Cancers were verified by central medical record review and deaths verified by medical record and death certificate review enhanced by National Death Index queries. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality. All statistical tests were two-sided. RESULTS: During a median of 18.9 years of follow-up, 1820 cancer deaths and 7415 total deaths occurred. Higher HOMA-IR quartile was associated with higher cancer-specific mortality (Q4 vs Q1, HR = 1.26, 95% CI = 1.09 to 1.47; Ptrend = .003) and all-cause mortality (Q4 vs Q1, HR = 1.63, 95% CI = 1.51 to 1.76; Ptrend < .001). A sensitivity analysis for diabetes status did not change findings. Among women with body mass index less than 25 kg/m2, higher HOMA-IR quartile was associated with higher cancer mortality (Fine and Gray, P = .004). CONCLUSIONS: High insulin resistance, as measured by HOMA-IR, identifies postmenopausal women at higher risk for cancer-specific and all-cause mortality who could potentially benefit from early intervention.
Subject(s)
Cause of Death , Insulin Resistance , Neoplasms/epidemiology , Postmenopause , Women's Health , Aged , Aged, 80 and over , Body Mass Index , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasms/mortality , Proportional Hazards Models , Public Health Surveillance , Risk Factors , United States/epidemiologyABSTRACT
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.