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1.
J Invest Dermatol ; 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38848986

ABSTRACT

A better understanding of human melanocyte (MC) and MC stem cell biology is essential for treating MC-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical examinations, human cell assays, yeast 2-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in MC stem cell maintenance and discovered that TNKS2 is crucial for SASH1's role. In addition, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human MC stem cells. The findings offer insights into the roles of SASH1 and TNKS2 in MC stem cell maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.

2.
bioRxiv ; 2023 Sep 27.
Article in English | MEDLINE | ID: mdl-37808724

ABSTRACT

Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1 S519N variant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1 S519N was defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1's promotion of stem-like function. Further, the SASH1 S519N variant is in a bona fide Tankyrase-binding motif, and SASH1 S519N alters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.

4.
JAMA Dermatol ; 158(9): 1031-1039, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35857290

ABSTRACT

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.


Subject(s)
Lymphoma, T-Cell, Cutaneous , Mycosis Fungoides , Photochemotherapy , Skin Neoplasms , Adult , Anthracenes , Female , Humans , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/pathology , Male , Middle Aged , Mycosis Fungoides/pathology , Ointments/therapeutic use , Perylene/analogs & derivatives , Photochemotherapy/adverse effects , Photosensitizing Agents/adverse effects , Skin Neoplasms/pathology , Treatment Outcome
5.
Front Med (Lausanne) ; 8: 679294, 2021.
Article in English | MEDLINE | ID: mdl-34277658

ABSTRACT

Topical chlormethine yields high response rates in mycosis fungoides cutaneous T-cell lymphoma with early discontinuation often attributed to skin reactions. We evaluated over 4,000 patients and found an association of clinician case volume with treatment duration and early discontinuation of chlormethine gel. The minority of clinicians with high patient volume markedly outperformed clinicians with only few patients on both outcome parameters, yet case volume as low as five patients seemed to mark a threshold for avoiding early discontinuation of treatment regimen.

7.
Am J Dermatopathol ; 40(3): 185-190, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29470304

ABSTRACT

Central nervous system involvement by mycosis fungoides (MF) is rare and is usually seen in advanced stages of the disease. We describe a patient with early-stage follicular MF who presented with changes in mental status. Despite an initial diagnosis of vasculitis based on clinical and brain biopsy results, the postmortem examination revealed extensive infiltration of MF cells throughout the brain with leptomeningeal involvement. This case in addition to the accompanied review of literature illustrates the importance of the awareness of central nervous system involvement by MF and highlights the need for an urgent neurologic evaluation in patients with a history of MF now presenting with neurologic signs or symptoms.


Subject(s)
Brain Neoplasms/pathology , Mycosis Fungoides/pathology , Skin Neoplasms/pathology , Fatal Outcome , Humans , Male , Middle Aged
9.
Head Neck ; 34(7): 1045-50, 2012 Jul.
Article in English | MEDLINE | ID: mdl-21384456

ABSTRACT

BACKGROUND: Microcystic adnexal carcinoma is a rare, locally aggressive neoplasm most commonly occurring on the face. Minimal data are available regarding the role of radiation therapy (RT). METHODS: Cases treated with RT from 2 comprehensive cancer centers are reviewed along with a review of the literature. RESULTS: Three patients with microcystic adnexal carcinoma of the face were treated with curative intent. One patient received RT as monotherapy. Two patients received postoperative RT (PORT). The patient receiving RT as monotherapy experienced excellent clinical regression, had an in-field recurrence at 48-month follow-up, and is now without evidence of disease after reirradiation. Both patients receiving PORT are without evidence of disease. CONCLUSION: PORT may improve local control in patients with microcystic adnexal carcinoma, and its use should be considered in patients with high-risk features for local recurrence. RT as monotherapy should be considered when poor cosmetic outcome can be anticipated via standard surgical treatments.


Subject(s)
Adenoma/radiotherapy , Facial Neoplasms/radiotherapy , Skin Neoplasms/radiotherapy , Adenoma/surgery , Combined Modality Therapy , Facial Neoplasms/surgery , Female , Humans , Middle Aged , Mohs Surgery , Skin Neoplasms/surgery
11.
Clin Lymphoma Myeloma ; 9(6): 412-6, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19951879

ABSTRACT

INTRODUCTION: Vorinostat, an orally active histone deacetylase inhibitor, was approved in October 2006 by the US Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease during or after treatment with 2 systemic therapies. PATIENTS AND METHODS: A multicenter, open-label phase IIb trial evaluated the activity and safety of vorinostat 400 mg orally daily in patients with > or = stage IB, persistent, progressive, or treatment-refractory mycosis fungoides or Sézary syndrome CTCL subtypes. We report the safety and tolerability of long-term vorinostat therapy in patients who experienced clinical benefit in the previous phase IIb study. RESULTS: As of December 11, 2008, 6 of 74 patients enrolled in the original study had received vorinostat for > or = 2 years: median age, 65 years; median number of previous therapies, 2.5; median time from diagnosis to enrollment, 1.8 years. At enrollment into the continuation phase, 5 of the 6 patients had achieved an objective response, and 1 patient had prolonged stable disease. During the follow-up study, the most common drug-related grade 1-4 adverse events (AEs) were diarrhea, nausea, fatigue, and alopecia (6, 5, 4, and 3 patients, respectively). Incidence of grade 3/4 AEs was low: anorexia (n = 1), increased creatinine phosphokinase (n = 1), pulmonary embolism (n = 1), rash (n = 1), and thrombocytopenia (n = 1). Five patients have discontinued the study drug, and 1 patient is continuing therapy. CONCLUSION: This post hoc subset analysis provides evidence for the long-term safety and clinical benefit of vorinostat in heavily pretreated patients with CTCL, regardless of previous treatment failures.


Subject(s)
Antineoplastic Agents/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Hydroxamic Acids/therapeutic use , Lymphoma, T-Cell, Cutaneous/drug therapy , Skin Neoplasms/drug therapy , Aged , Female , Humans , Hydroxamic Acids/adverse effects , Male , Middle Aged , Vorinostat
12.
J Invest Dermatol ; 128(4): 949-56, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17989736

ABSTRACT

Hyperthermia has been revived as a promising approach for cancer treatment. To understand the underlying mechanisms of hyperthermic killing of cancer cells, we examined the cytotoxic effects of hyperthermia on various skin cancer cell lines using cell viability, morphological analyses, and caspase activation assays. Hyperthermia induced cytotoxicity in a time- and temperature-dependent manner. At middle dose/time combinations, heat-induced apoptosis, whereas at higher doses, necrosis was the mechanism of cell death. To investigate the mechanisms of hyperthermia-induced apoptosis, we examined the activation of extrinsic (Caspase 8) and intrinsic (Caspase 9) apoptotic pathways. Hyperthermia did not activate Caspases 8 or 9, but did activate Caspase 3/7, suggesting a non-conventional apoptotic pathway. Last, analysis of Grp78 expression and Caspase 12 or 4 activation indicated that hyperthermia induced endoplasmic reticulum-mediated apoptosis. Thus, hyperthermia induced apoptosis in two types of skin cancer cells through endoplasmic reticulum-mediated apoptosis and not through the classical intrinsic or extrinsic apoptosis pathways. Hyperthermia may be a promising treatment for basal cell carcinoma and melanoma, bypassing the antiapoptotic defenses concentrated in the intrinsic and extrinsic apoptosis pathways. These results also raise the possibility that heat may be combined with other approaches for induction of apoptosis to achieve synergistic killing of skin cancers.


Subject(s)
Apoptosis , Endoplasmic Reticulum/metabolism , Hyperthermia, Induced , Melanoma/therapy , Skin Neoplasms/therapy , Caspases/metabolism , Cell Line, Tumor , Endoplasmic Reticulum Chaperone BiP , Heat-Shock Proteins/metabolism , Humans , Melanoma/metabolism , Molecular Chaperones/metabolism , Skin Neoplasms/metabolism
13.
J Clin Oncol ; 25(21): 3109-15, 2007 Jul 20.
Article in English | MEDLINE | ID: mdl-17577020

ABSTRACT

PURPOSE: To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in persistent, progressive, or recurrent mycosis fungoides or Sézary syndrome (MF/SS) cutaneous t-cell lymphoma (CTCL) subtypes. PATIENTS AND METHODS: Patients with stage IB-IVA MF/SS were treated with 400 mg of oral vorinostat daily until disease progression or intolerable toxicity in this open-label phase IIb trial (NCT00091559). Patients must have received at least two prior systemic therapies at least one of which included bexarotene unless intolerable. The primary end point was the objective response rate (ORR) measured by the modified severity weighted assessment tool and secondary end points were time to response (TTR), time to progression (TTP), duration of response (DOR), and pruritus relief ( > or = 3-point improvement on a 10-point visual analog scale). Safety and tolerability were also evaluated. RESULTS: Seventy-four patients were enrolled, including 61 with at least stage IIB disease. The ORR was 29.7% overall; 29.5% in stage IIB or higher patients. Median TTR in stage IIB or higher patients was 56 days. Median DOR was not reached but estimated to be >or = 185 days (34+ to 441+). Median TTP was 4.9 months overall, and 9.8 months for stage IIB or higher responders. Overall, 32% of patients had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%); most were grade 2 or lower but those grade 3 or higher included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%). Eleven patients required dose modification and nine discontinued due to AE. CONCLUSION: Oral vorinostat was effective in treatment refractory MF/SS with an acceptable safety profile.


Subject(s)
Hydroxamic Acids/therapeutic use , Lymphoma, T-Cell, Cutaneous/drug therapy , Salvage Therapy , Skin Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Confidence Intervals , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Humans , Lymphoma, T-Cell, Cutaneous/mortality , Lymphoma, T-Cell, Cutaneous/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Probability , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Survival Analysis , Treatment Outcome , Vorinostat
14.
Pediatr Dermatol ; 24(3): E17-21, 2007.
Article in English | MEDLINE | ID: mdl-17509109

ABSTRACT

Several hereditary and nonhereditary gastrointestinal tract polyposis syndromes exhibit extra-intestinal manifestations, including cutaneous findings. However, a lack of information exists regarding cutaneous features of juvenile polyposis. Our objective was to document the prevalence of cutaneous hyperpigmented lesions in children with juvenile polyposis coli or juvenile polyposis coli and their first degree relatives.Children seen in the gastroenterology practice at The Children's Hospital in Denver, Colorado with polyps (juvenile polyposis coli, sporadic juvenile polyps, and familial adenomatous polyposis coli) and their first degree relatives were invited to participate in the study. A comprehensive skin examination was performed on those who consented to participate. We found that 8 of 14 patients (eight with juvenile polyposis coli, four with juvenile polyposis, and two with familial adenomatous polyposis coli) had at least one café-au-lait macule, compared with three of 27 relatives (p=0.003).The prevalence of at least one café-au-lait macule in our patients (8/14 or 57.1%, CI: 28.9­82.3%) was significantly higher than the general population prevalence of 28.5% (p=0.023). However, if the two patients with familial adenomatous polyposis coli were excluded, the comparison with the general population prevalence did not reach statistical significance (p=0.095). The prevalence of multiple cafe´-au-lait macules in our patients (4/14 or 28.6%; CI:8.4­58.1%) was significantly higher than the general population prevalence of 5.2% (p » 0.005). A notable finding was the presence of multiple café -au-lait macules in 4 of 12 juvenile polyposis coli/juvenile polyposis patients.Two patients with juvenile polyposis coli also had lentigines. In this selected case series, we observed single or multiple café-au-lait macules in a high proportion of children with the three types of polyps. Further studies are needed to assess a possible common pathway for hamartomatous polypsand café-au-lait macules.


Subject(s)
Cafe-au-Lait Spots/epidemiology , Intestinal Polyps/epidemiology , Adenomatous Polyposis Coli/epidemiology , Adolescent , Adult , Cafe-au-Lait Spots/complications , Cafe-au-Lait Spots/congenital , Child , Child, Preschool , Colorado/epidemiology , Female , Humans , Intestinal Polyps/complications , Intestinal Polyps/congenital , Male , Middle Aged
15.
J Am Acad Dermatol ; 55(2): 251-5, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16844507

ABSTRACT

BACKGROUND: Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that is typified by distinctive cutaneous findings and often by abnormalities of teeth, hair, nails, eyes, musculoskeletal system, and central nervous system. The gene that is mutated in patients with IP has been mapped to Xq28 and encodes the NF-kappaB essential modulator, NEMO. Female patients with IP show functional mosaicism and cutaneous manifestations follow Blaschko's lines of ectodermal embryologic development. The condition is generally considered to be lethal in utero in male fetuses, suggesting that having some normal gene expression is critical for survival. OBSERVATIONS: We observed 9 boys with IP. All had normal karotypes and no apparent family history of IP. In 8 of these 9 patients, lesions were localized to one extremity at presentation. The diagnosis was confirmed by histopathologic examination that showed eosinophils within intraepidermal, multiloculated vesicles. One of the boys later developed dental and neurologic abnormalities. LIMITATIONS: The case series was small and the workup for these patients from different sites was not uniform. CONCLUSIONS: Male individuals may show cutaneous and noncutaneous features of IP in a limited distribution that allows survival. Postzygotic mutation/somatic mosaicism is the likely mechanism. Given the potential sequelae associated with this condition, continuing follow-up of these patients is recommended.


Subject(s)
Incontinentia Pigmenti/genetics , Incontinentia Pigmenti/pathology , Diagnosis, Differential , Eosinophils , Humans , Incontinentia Pigmenti/diagnosis , Infant, Newborn , Karyotyping , Male , Mosaicism , Mutation , Nervous System Malformations , Skin/cytology , Tooth Abnormalities
16.
Biotechniques ; 36(6): 968-72, 974-6, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15211747

ABSTRACT

Hyperthermia, the procedure of exposing cells to a temperature between 42 degrees and 49 degrees C, has been shown to be a promising approach for cancer treatment. To understand the underlying mechanisms of hyperthermic killing of cancer cells, it is critical to have an accurate temperature measurement technique and a heating method with high reproducibility. To this end, we have developed a method using fine thermocouples with fast response time to measure the temperatures in multiple wells of a 96-well plate. The accuracy of temperature measurement was +/- 0.2 degree C. Such a capability allows a complete record of the time and temperature of the treatment procedure and helps define an accurate thermal dose. We have also compared several methods for heating 96-well plates and found that use of copper blocks in contact with the lower surface of the 96-well plate in an incubator provides a highly reproducible heating method. The common method of using water bath to heat cells in vitro resulted in a decrease of cell viability even at the control temperature of 37 degrees C and a decrease in the reproducibility of certain biological assays. In summary, using these improved techniques, proposed thermal dose can be defined more precisely, and highly reproducible heating in vitro can be achieved.


Subject(s)
Cell Culture Techniques/instrumentation , Cell Culture Techniques/methods , Equipment Failure Analysis , Hot Temperature , Hyperthermia, Induced/instrumentation , Melanoma/physiopathology , Specimen Handling/methods , Cell Line, Tumor , Cell Proliferation/radiation effects , Cell Survival/radiation effects , Equipment Design , Feedback , Humans , Hyperthermia, Induced/methods , Melanoma/therapy , Temperature , Treatment Outcome
18.
Arch Dermatol ; 140(5): 577-80, 2004 May.
Article in English | MEDLINE | ID: mdl-15148102

ABSTRACT

BACKGROUND: The number of melanocytic nevi is the best single marker of increased melanoma risk. In a previous study, adults with severe eczema were reported to have significantly fewer nevi than adults without eczema. OBSERVATIONS: In a nested case-control design within a randomized, controlled interventional trial of additional sun protection vs standard care in 269 children, a history of eczema was reported by the parents of 44 (16%) of the children. More nevi were found in children with a parental report of previous eczema diagnosis than in children without reported eczema (median, 7.5 nevi vs 5.0 nevi; P =.01). Eczema diagnosis was most significantly associated with more melanocytic nevi in children with lightly pigmented skin (8.5 nevi vs 6.0 nevi; P <.001). In multivariate logistical regression analysis, including assessment of hair color, sun protection practices, and study assignment (intervention vs standard care), eczema status remained significantly predictive of nevi number in children (P <.001). CONCLUSIONS: In contrast to a previous study that associated severe eczema with fewer nevi in adults, in the present study children with a reported history of eczema had more nevi than children without a reported history of eczema.


Subject(s)
Eczema/epidemiology , Nevus, Pigmented/epidemiology , Skin Neoplasms/epidemiology , Case-Control Studies , Child Welfare , Child, Preschool , Colorado/epidemiology , Eczema/complications , Female , Humans , Male , Medical Records , Nevus, Pigmented/complications , Retrospective Studies , Risk Factors , Skin Neoplasms/complications
19.
Dermatol Surg ; 30(4 Pt 2): 598-603, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15061842

ABSTRACT

BACKGROUND: Solid-organ transplant recipients constitute a complex patient population that experiences numerous and aggressive skin cancers. Proactive, comprehensive, ongoing, and effective dermatologic care of these patients is a necessity. OBJECTIVE: The objective of this study was to emphasize the need for organized dermatologic care for transplant recipients and to collect and present various proactive paradigms established in and designed for different practice settings to manage organ transplant recipients at high risk for skin cancer. METHODS: Information about practice setting, patient demographics, and the care model used was obtained through questionnaires sent to a selection of 12 physicians known to care for transplant recipients in various practice settings. RESULTS: All 12 physicians completed the questionnaire. The organized dermatologic care of transplant recipients occurs in three basic clinic settings: multidisciplinary transplant clinics, designated dermatology transplant subspecialty clinics, and integration of transplant recipient care within existing dermatology clinics. CONCLUSIONS: Various practice settings offer both advantages and disadvantages in providing preventive and therapeutic care of organ transplant recipients at risk for skin cancer. Regardless of the clinic design used, an organized and firmly established clinic model to allow proactive and ongoing care for these patients is important for education, prevention, and early intervention.


Subject(s)
Organ Transplantation/adverse effects , Outpatient Clinics, Hospital/organization & administration , Patient Care Management/organization & administration , Skin Neoplasms/diagnosis , Skin Neoplasms/therapy , Dermatology/methods , Humans , Patient Care/methods , Patient Care Team , Skin Neoplasms/etiology
20.
J Am Acad Dermatol ; 49(5 Suppl): S255-8, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14576645

ABSTRACT

Extramedullary plasmacytomas are an immunoproliferative, monoclonal disease of B-cell lineage and are classified as non-Hodgkin's lymphomas. Cutaneous extramedullary plasmacytomas are rare. We report 2 cases of transplantation-associated cutaneous extramedullary plasmacytomas in a setting of chronic immunosuppression.


Subject(s)
Heart Transplantation , Immunocompromised Host , Plasmacytoma/diagnosis , Skin Neoplasms/diagnosis , Diagnosis, Differential , Female , Forearm , Humans , Immunohistochemistry , Lower Extremity , Male , Middle Aged , Plasmacytoma/pathology , Skin Neoplasms/pathology
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